Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy.

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a recently delineated, autosomal recessive condition caused by rare mutations in the N-acylsphingosine amidohydrolase 1 (acid ceramidase) ASAH1 gene. It is characterized by motor neuron disease followed by progressive myoclonic seizures and eventual death due to respiratory insufficiency. Here we report an adolescent female who presented with atonic and absence seizures and myoclonic jerks and was later diagnosed as having myoclonic-absence seizures. An extensive genetic and metabolic work-up was unable to arrive at a molecular diagnosis. Whole exome sequencing (WES) identified two rare, deleterious mutations in the ASAH1 gene: c.850G>T;p.Gly284X and c.456A>C;p.Lys152Asn. These mutations were confirmed by Sanger sequencing in the patient and her parents. Functional studies in cultured fibroblasts showed that acid ceramidase was reduced in both overall amount and enzymatic activity. Ceramide level was doubled in the patient's fibroblasts as compared to control cells. The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness. These findings expand the phenotypic spectrum of SMA-PME caused by novel mutations in ASAH1 and highlight the clinical utility of WES for rare, intractable forms of epilepsy.

Autosomal recessive hereditary spastic paraplegia-clinical and genetic characteristics of a well-defined cohort.

We describe the clinical and genetic features of a well-characterized cohort of patients with autosomal recessive hereditary spastic paraplegia (ARHSP) in the province of Ontario. Patients with documented corticospinal tract abnormalities were screened by whole gene sequencing and multiplex ligation probe amplification for mutations in nine genes known to cause ARHSP. Of a cohort of 39 patients, a genetic diagnosis was established in 17 (44 %) and heterozygous mutations were detected in 8 (21 %). Mutations were most frequent in SPG7 (12 patients), followed by SPG11 (10 patients), PNPLA6 (SPG39, 2 patients), and ZFYVE26 (SPG15, 2 patients). Although there are associations between some clinical manifestations of ARHSP and specific genes, many patients are tested at an early stage of the disease when phenotype/genotype correlations are not obvious. Accurate molecular characterization of well-phenotyped cohorts of patients will be essential to establishing the natural history of these rare degenerative disorders to enable future clinical trials.

18-Methoxycoronaridine blocks context-induced reinstatement following cocaine self-administration in rats.

Numerous studies utilizing drug self-administration have shown the importance of conditioned cues in maintaining and reinstating addictive behaviors. However, most used simple cues that fail to replicate the complexity of cues present in human craving and addiction. We have recently shown that music can induce behavioral and neurochemical changes in rats following classical conditioning with psychostimulants. However, such effects have yet to be characterized utilizing operant self-administration procedures, particularly with regard to craving and relapse. The goal of the present study was to validate the effectiveness of music as a contextual conditioned stimulus using cocaine in an operant reinstatement model of relapse. Rats were trained to lever press for cocaine with a musical cue, and were subsequently tested during reinstatement sessions to determine how musical conditioning affected drug seeking behavior. Additionally, in vivo microdialysis was used to determine basolateral amygdala involvement during reinstatement. Lastly, tests were conducted to determine whether the putative anti-addictive agent 18-methoxycoronaridine (18-MC) could attenuate cue-induced drug seeking behavior. Our results show that music-conditioned animals exhibited increased drug seeking behaviors when compared to controls during reinstatement test sessions. Furthermore, music-conditioned subjects exhibited increased extracellular dopamine in the basolateral amygdala during reinstatement sessions. Perhaps most importantly, 18-MC blocked musical cue-induced reinstatement. Thus,music can be a powerful contextual conditioned cue in rats, capable of inducing changes in both brain neurochemistry and drug seeking behavior during abstinence. The fact that 18-MC blocked cue-induced reinstatement suggests that α3ß4 nicotinic receptors may be involved in the mechanism of craving, and that 18-MC may help prevent relapse to drug addiction in humans.

Music and methamphetamine: conditioned cue-induced increases in locomotor activity and dopamine release in rats.

Associations between drugs of abuse and cues facilitate the acquisition and maintenance of addictive behaviors. Although significant research has been done to elucidate the role that simple discriminative or discrete conditioned stimuli (e.g., a tone or a light) play in addiction, less is known about complex environmental cues. The purpose of the present study was to examine the role of a musical conditioned stimulus by assessing locomotor activity and in vivo microdialysis. Two groups of rats were given non-contingent injections of methamphetamine (1.0 mg/kg) or vehicle and placed in standard conditioning chambers. During these conditioning sessions both groups were exposed to a continuous conditioned stimulus, in the form of a musical selection ("Four" by Miles Davis) played repeatedly for 90 min. After seven consecutive conditioning days subjects were given one day of rest, and subsequently tested for locomotor activity or dopamine release in the absence of drugs while the musical conditioned stimulus was continually present. The brain regions examined included the basolateral amygdala, nucleus accumbens, and prefrontal cortex. The results show that music is an effective contextual conditioned stimulus, significantly increasing locomotor activity after repeated association with methamphetamine. Furthermore, this musical conditioned stimulus significantly increased extracellular dopamine levels in the basolateral amygdala and nucleus accumbens. These findings support other evidence showing the importance of these brain regions in conditioned learning paradigms, and demonstrate that music is an effective conditioned stimulus warranting further investigation.

MEG source estimation from mesio-basal temporal areas in a child with a porencephalic cyst.

BACKGROUND: A child whose left temporal lobe contained mesial, anterior and basal structures but lacked superio-lateral cortex had intractable epilepsy secondary to a porencephalic cyst. Magnetoencephalography (MEG) shows equivalent current dipoles (ECDs) as dipole modeling for temporal lobe epilepsy rather than in an exact location. AIM: We hypothesized that the magnetic fields generated by the epileptic discharges in mesio-basal temporal areas could be detected by MEG without interference from the superio-lateral temporal cortices. METHODS: We analyzed MEG spikes using single dipole analysis and synthetic aperture magnetometry (SAM), and compared with EEG spike topography. RESULTS: Two MEG ECDs corresponding to T3 spikes localized to the anterior mesio-basal temporal region with vertical orientation. Sixteen MEG ECDs corresponding to T5 spikes localized to the middle to posterior mesio-basal temporal region with vertical orientation. SAM revealed maximum current density at hippocampus and anterior fusiform gyrus for T3 spikes, and at posterior hippocampus and fusiform gyrus for T5 spikes. CONCLUSION: Vertically oriented ECDs were obtained without superio-lateral temporal cortices because of temporo-parieto-occipital porencephalic cyst. The absence of superio-lateral temporal cortices, prominent temporal EEG spikes, less prominent MEG spikes, and mesio-basal SAM spikes indicated that the vertically oriented ECDs were projected directly from the mesio-basal temporal region.

[The effect of physical training on physical, mental and social conditions in drug and/or alcohol addicts]. / Fysisk traenings effekt på fysiske, psykiske og sociale forhold hos stof- og/eller alkoholmisbrugere.

The physical, mental and social conditions of eight drug and alcohol addicts were examined prior to and after a period of three months with systemical physical training. The condition improved significantly during training. The circulatory reaction to stress remained unchanged before and after training but the resting levels for pulse and blood pressure were lower after training. Prior to training, a significant correlation was observed between the excretion of adrenalin in the urine and the anxiety level and this was not observed after training. The anxiety level measured by a STAI test decreased during the period of training whereas the excretion of adrenalin in the urine was not altered significantly and remained within the normal range. The patients were followed-up for approximately 18 months after discharge from hospital. During this period, the result of the physical stress and a hiking holiday which was included in the treatment were discussed before discharge. None of the patients continued the physical training after discharge from hospital despite encouragement to do so. The group gradually disintegrated and two years after the conclusion of the training, five patients had resumed the addiction. This investigation suggests that physical training may be of significance in the treatment of addicts but continued contact with the therapist is of decisive significance.

[Rhinozygomycosis. Apropos of a case]. / Rinozigomicosis. A propósito de un caso.

The report of a case of rhinozigomycosis (Rhinoentomophtoromycosis) in a forty years old male patient is presented. Full recovery was observed after one year treatment with potassium iodide (saturated solution).

Outcome of very very low birth weight infants.

This review of the literature and selected unpublished data documents normal early outcome in 50 to 81 per cent of tiny infants. Educational outcome described by a few studies is less encouraging, with only 32 to 36 per cent considered normal. Each study investigated the contribution of different perinatal, environmental, or social variables, therefore it is difficult to determine which has most impact on neurodevelopmental outcome.

Prediction of growth and development in intensive care nursery graduates at 12 months of age.

Although many perinatal events have been linked with the outcome status of neonatal intensive care unit (NICU) graduates, few studies have evaluated the cumulative longitudinal prediction of outcome. This study followed up 65 term and 139 premature NICU graduates to 12 months' chronologic age. Variables that were utilized in predicting 12-month growth and the neurologic and developmental outcome were maternal and neonatal medical factors, prior growth measurements, and neonatal behavior, which was measured with the Brazelton Scale for term infants and with a modified version for premature infants. The neurologic status was normal in 141 (71.9%) of 204 infants. The average Bayley Scale Mental Developmental Index was 112.7, and the average Psychomotor Developmental Index was 97.5, which was corrected for early gestation. Predictions of 12-month neurologic and developmental status were weak and had been derived only by variables from the neonatal behavioral examination; endurance predicted neurologic status and the motor cluster predicted cognitive and motor development. The prediction of growth at 12 months was high and was derived from prior growth parameters. Thus, although predictions of neurodevelopmental status at 12 months' chronologic age were low, the variables that aided in predicting were from the neonatal behavioral evaluation. This finding provides support for recommending that the functional status of the NICU graduate as well as the more traditional list of perinatal problems be considered when contemplating the infants' short-term outcome.

Early identification of learning problems in neonatal intensive care graduates.

Most investigators have documented a notable frequency of educational problems in children who received treatment in the neonatal intensive care unit (NICU). Seventy-four children born between 1972 and 1976 and in NICUs were followed up prospectively. At ages 3 to 6 years, preschool development was within the normal range on the McCarthy scales. A school problem, defined as grade repetition and/or special help in school, occurred in 32 (48.8%). Those with school problems had significantly lower scores on the McCarthy scales at 4 to 6 years and on the Woodcock Johnson test than the group without school problems. Children with school problems were classified correctly 60.3% of the time by duration of neonatal hospitalization, and 72% to 80.9% of the time by preschool development. If replicable, the data indicate that potential school problems can be identified sufficiently early in NICU nursery graduates that intervention could be started before they enter school.

Persistent fetal circulation. Neurodevelopmental outcome.

Forty children who had persistent fetal circulation (PFC) were followed up for one to four years. At the most recent examination, 16 (40%) were normal, eight (20%) had neurosensory hearing loss, three (7.5%) were profoundly impaired, six (15.0%) had suspect or abnormal results of neurologic examinations exclusive of hearing loss, three (7.5%) had speech impairment and normal hearing, and one had a delay in motor development. The remaining three had clinically suspect speech. Neurosensory hearing loss correlated only with having a mother with insulin-dependent diabetes, hand-to-mouth facility on the Brazelton scale, and eight-month neurologic status. Earlier diagnosis of hearing loss may be facilitated by testing of neonatal auditory behavioral responses, neurologic status at eight months, and by attention to parental concern about abnormal speech development. Neonatal and infancy auditory screening are recommended in children who have PFC in the neonatal period.

Outcome of very low birth weight (VLBW) infants. I. Neonatal behavior of 188 infants.

Behavioral characteristics of very low birth weight infants (less than 1,501 gm) were determined with the term Brazelton Neonatal Behavioral Assessment Scale and selected items from a preliminary form of the scale for premature and at-risk infants. The behavior of 188 infants was assessed at a time as optimal as possible for social interaction. Our very low birth weight infants were upset less easily, had several reflexes with below average scores, and were less responsive to visual stimuli than term infants of other studies. Improved description of interactive abilities and tolerance of the testing procedure was made possible with some items from the preliminary premature scale. Orienting responses in 6 infants tested after 44 weeks because of prolonged illness were less than optimal with a single exception. This suggests that behavioral capacity, not age, should define where the Brazelton scale is not applicable. Perinatal factors including birth weight, gestational age, and age that weight gain began, predicted some motoric and state control responses. Whether this predictive capacity will persist or change with time awaits results of follow-up of these infants.

Hageman factor and disseminated intravascular coagulation (DIC) in newborns and rabbits.

There was no significant difference in the levels of factor XII between sick newborns and normal age-matched controls, although the levels of both groups were lower than normal older children. Detailed coagulation studies on 44 sick infants revealed 11 to have disseminated intravascular coagulation (DIC). In those with DIC, the mean Hageman factor was 20% and in those without DIC, 25% (P greater than 0.05). Rabbits given a constant infusion of lysozyme (which inhibits factor XII) showed laboratory evidence of endotoxin-induced DIC. The data suggest that neither reduced factor XII levels nor Hageman factor inhibition provided protection from DIC. The data further suggest that other coagulation pathways might be involved in order to elicit the DIC.

Association of premature rupture of membranes with idiopathic respiratory distress syndrome.

A retrospective study involving all admissions to two neonatal intensive care centers over a 4-year period was carried out to assess the protective effect, or lack of it, of prolonged rupture of membranes (ROM) on the prevalence of idiopathic respiratory distress syndrome (IRDS) in premature infants. Significantly fewer cases of IRDS were found in patients in all gestational age groups when ROM was greater than 24 hours as compared with those with ROM of less than 12 hours' duration. However, prolonged ROM was not consistently associated with a difference in prevalence of respiratory failure accompanying IRDS, or in the prevalence of sepsis or neonatal mortality in this patient population. It is concluded that benefit to a premature infant in the form of reduced risk of developing IRDS is possible if the mother is allowed 24 hours after ROM before the delivery is initiated.

Potentiometric determination of theopaverin components in nonaqueous media.

Potentiometric method for determination of papaverine hydrochloride (PAP) and theobromine (Tb) in a mixture, without separation of the components was designed. Determinations were carried out in nonaqueous media, using solvents differentiating the strength of estimated bases.