Hyperglycemia is associated with simultaneous alterations in electrical brain activity in youths with type 1 diabetes mellitus.

OBJECTIVE: To assess the association between hyperglycemia and electrical brain activity in type 1 diabetes mellitus (T1DM). METHODS: Nine youths with T1DM were monitored simultaneously and continuously by EEG and continuous glucose monitor system, for 40 h. EEG powers of 0.5-80 Hz frequency bands in all the different brain regions were analyzed according to interstitial glucose concentration (IGC) ranges of 4-11 mmol/l, 11-15.5 mmol/l and >15.5 mmol/l. Analysis of variance was used to examine the differences in EEG power of each frequency band between the subgroups of IGC. Analysis was performed separately during wakefulness and sleep, controlling for age, gender and HbA1c. RESULTS: Mean IGC was 11.49 ± 5.26 mmol/l in 1253 combined measurements. IGC>15.5 mmol/l compared to 4-11 mmol/l was associated during wakefulness with increased EEG power of low frequencies and with decreased EEG power of high frequencies. During sleep, it was associated with increased EEG power of low frequencies in all brain areas and of high frequencies in frontal and central areas. CONCLUSIONS: Asymptomatic transient hyperglycemia in youth with T1DM is associated with simultaneous alterations in electrical brain activity during wakefulness and sleep. SIGNIFICANCE: The clinical implications of immediate electrical brain alterations under hyperglycemia need to be studied and may lead to adaptations of management.

Erythropoietin-driven signalling and cell migration mediated by polyADP-ribosylation.

BACKGROUND: Recombinant human erythropoietin (EPO) is the leading biotechnology engineered hormone for treatment of anaemia associated with chronic conditions including kidney failure and cancer. The finding of EPO receptors on cancer cells has raised the concern that in addition to its action in erythropoiesis, EPO may promote tumour cell growth. We questioned whether EPO-induced signalling and consequent malignant cell manifestation is mediated by polyADP-ribosylation. METHODS: Erythropoietin-mediated PARP (polyADP-ribose polymerase-1) activation, gene expression and core histone H4 acetylation were examined in UT7 cells, using western blot analysis, RT-PCR and immunofluorescence. Erythropoietin-driven migration of the human breast epithelial cell line MDA-MB-435 was determined by the scratch assay and in migration chambers. RESULTS: We have found that EPO treatment induced PARP activation. Moreover, EPO-driven c-fos and Egr-1 gene expression as well as histone H4 acetylation were mediated via polyADP-ribosylation. Erythropoietin-induced cell migration was blocked by the PARP inhibitor, ABT-888, indicating an essential role for polyADP-ribosylation in this process. CONCLUSIONS: We have identified a novel pathway by which EPO-induced gene expression and breast cancer cell migration are regulated by polyADP-ribosylation. This study introduces new possibilities regarding EPO treatment for cancer-associated anaemia where combining systemic EPO treatment with targeted administration of PARP inhibitors to the tumour may allow safe treatment with EPO, minimising its possible undesirable proliferative effects on the tumour.

Long-term outcome following selective serotonin reuptake inhibitor induced neonatal abstinence syndrome.

OBJECTIVE: To assess the long-term neurodevelopment of children exposed in utero to selective serotonin reuptake inhibitors (SSRIs) that developed a neonatal abstinence syndrome (NAS). STUDY DESIGN: Neurodevelopmental evaluation was performed at the age of 2 to 6 years. Children who developed NAS were compared with those who did not using univariate and logistic regression analyses. RESULT: Thirty children with NAS and 52 without NAS participated in the study. Both groups were similar in mean cognitive ability (106.9±14.0 vs 100.5±14.6, P=0.12) and developmental scores (98.9±11.4 vs 95.7±9.9, P=0.21). However, there was a trend towards small head circumference in the NAS group (20 vs 6%, P=0.068). NAS was associated with an increased risk of social-behavior abnormalities (odds ratio (OR) 3.03, 95% confidence interval (CI) 1.07 to 8.60, P=0.04) and advanced maternal age (OR 1.12, 95% CI 1.00 to 1.25, P=0.04). CONCLUSION: Infants who developed NAS had normal cognitive ability, but were at an increased risk for social-behavioral abnormalities. Follow-up evaluation of symptomatic neonates should be considered.

Neuropsychological aspects of benign childhood epilepsy with centrotemporal spikes.

PURPOSE: To establish whether the disability in benign epilepsy with centrotemporal spikes (BECTS) is the result of the number of seizures, the anti-epileptic therapy or is an inherent characteristic of the syndrome itself. METHODS: Thirty-six children with BECTS were tested for cognitive functions prior to commencing treatment with anti-epileptic drugs, and the findings were compared with those in 15 children with normal electroencephalograms, performed for unrelated reasons. The data in the study group were further correlated with the laterality of the epileptic focus and the number of seizures. RESULTS: Scores for verbal functioning on neuropsychological tests were significantly lower in the study group than the control group. There was no relationship between the neuropsychological scores in the patients and either lateralization of the epileptic focus or number of seizures. DISCUSSION: Children with BECTS have an impaired ability to process verbal information. The deficiency is apparently a result of the pathological electrical discharges that are part of the syndrome and are not dependent on the epileptic focus laterality, the number of seizures, or the anti-epileptic treatment.

Epilepsy in children with infantile thiamine deficiency.

OBJECTIVE: To report the follow-up findings of 7 children with severe epilepsy as a result of thiamine deficiency in infancy caused by a defective soy-based formula. METHODS: The medical records of 7 children aged 5-6 years with thiamine deficiency in infancy who developed epilepsy were reviewed and their clinical data, EEG tracings, and neuroimaging results were recorded. The clinical course and present outcome of these children, now 5 years after exposure to thiamine deficiency, are described. RESULTS: All infants displayed seizures upon presentation, either tonic, myoclonic, or focal. Six infants had an EEG recording at this stage and all showed slow background. Five of them had no epileptic activity and only 1 displayed focal activity. Following a seizure-free period of 1-9 months, the seizures recurred, and all 7 children displayed either myoclonic or complex partial seizures. Multifocal or generalized spike wave complexes were recorded on the EEGs of all 7 patients, and the tracings of 3 children evolved into hypsarrhythmia. The seizures were refractory to most antiepileptic drugs, and 4 children remain with uncontrolled seizures. All children have mental retardation and motor disabilities as well as symptoms of brainstem dysfunction. CONCLUSIONS: Our findings indicate that severe infantile thiamine deficiency may result in epilepsy.

Expanding the phenotypic spectrum of L1CAM-associated disease.

Mutations in the L1CAM gene cause neurological abnormalities of variable severity, including congenital hydrocephalus, agenesis of the corpus callosum, spastic paraplegia, bilaterally adducted thumbs, aphasia, and mental retardation. Inter- and intrafamilial variability is a well-known feature of the L1CAM spectrum, and several patients have a combination of L1CAM mutations and Hirschsprung's disease (HSCR). We report on two siblings with a missense mutation in exon 7 (p.P240L) of the L1CAM gene. In one of the siblings, congenital dislocation of the radial heads and HSCR were present. Neither patient had hydrocephalus, adducted thumbs, or absent speech, but both had a hypoplastic corpus callosum. We suggest that L1CAM mutation testing should be considered in male patients with a positive family history compatible with X-linked inheritance and either the combination of agenesis of the CC and HSCR or the combination of agenesis of the CC and limb abnormalities, including abnormalities other than adducted thumbs.

An autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy, and seizures.

The authors describe three siblings born to consanguineous parents with early onset ataxia, dysarthria, myoclonic, generalized tonic clonic seizures, upward gaze palsy, extensor plantar reflexes, sensory neuropathy, and normal cognition. Direct screening excluded mutations in FRDA, TDP1,and SACS genes and at 8344, 3243, and 8993 positions of mitochondrial DNA. Linkage analysis excluded AOA-1, EPM1, EPM2A, EPM2B, CAMOS, and recessive ataxias linked to chromosome 9q34-9qter. This clinical constellation may represent a distinct form of early onset cerebellar ataxia.

A prevalence estimate of pervasive developmental disorder among immigrants to Israel and Israeli natives- a file review study.

BACKGROUND: The prevalence rates of pervasive developmental disorder (PDD) have risen in the West over the last 10 years. There is argument over the etiology of this change in rates. Social and cultural processes including migration have been hypothesized. Israel, as a country of ongoing immigration with a national registry of children diagnosed with PDD, offers an opportunity to compare rates of PDD among immigrants from developing countries and native Israelis. METHOD: A Social Security national registry of 1004 children diagnosed with PDD was reviewed and rates were calculated using data extracted from the Israel National Bureau of Statistics. Of all Jewish children that were born in the years 1983-1997 and who are currently living in Israel, we defined four groups: (1). native Israelis of non-Ethiopian extraction (N = 1198, 300), (2). native Israelis of Ethiopian extraction (N = 15600), (3). immigrants of non-Ethiopian extraction (N = 110300) and (4). children born in Ethiopia (N = 11800). A further breakdown of groups 1 and 3 by well-characterized ethnic or geographical origins was not possible. RESULTS: The rate of PDD was significantly elevated in native Israelis as compared to all immigrant children. Among immigrants, the rate of PDD in Ethiopian-born children was lower than that of those born in other countries. The rate of PDD in immigrant Ethiopian children was much lower than in native Israeli children of Ethiopian extraction. CONCLUSIONS: Birth in Israel, an industrialized country, is a marker for an environmental risk factor for PDD. This may indicate that gestation, birth or infancy in industrialized countries exposes children to environmental insults that increase the risk for contracting PDD.

Mapping of a new locus for autosomal recessive non-syndromic mental retardation in the chromosomal region 19p13.12-p13.2: further genetic heterogeneity.

OBJECTIVE: To identify and clinically evaluate four consanguineous families of Israeli Arab origin with non-syndromic mental retardation (NSMR), comprising a total of 10 affected and 24 unaffected individuals. PARTICIPANTS AND METHODS: All the families originated from the same small village and had the same family name. Association of the condition in these families with the two known autosomal recessive NSMR loci on chromosomes 3p25-pter and 4q24 (neurotrypsin gene) was excluded. RESULTS: Linkage of the disease gene to chromosome 19p13.12-p13.2(Zmax = 7.06 at theta = 0.00) for the marker D19S840 was established. All the affected individuals were found to be homozygous for a common haplotype for the markers cen-RFX1-D19S840-D19S558-D19S221-tel. CONCLUSIONS: The results suggest that the disease is caused by a single mutation derived from a single ancestral founder in all the families. Recombination events and a common disease bearing haplotype defined a critical region of 2.4 Mb, between the loci D19S547 proximally and D19S1165 distally.

Ectodermal dysplasia, ectrodactyly and macular dystrophy (EEM syndrome) in siblings.

We report a brother and sister with ectodermal dysplasia, ectrodactyly, and macular dystrophy (the EEM syndrome). Both children had abnormalities of the hands and the hair, and bilateral macular degeneration. The clinical picture in both is similar to, but less severe than, that described in the previously reported cases of this rare syndrome. Even though the parents are not related, they are both of Jewish Yemenite origin, and the possibility of a common ancestor cannot be ruled out. This would suggest autosomal recessive inheritance. The clinical picture in these patients suggests either variable expression or genetic heterogeneity in the EEM syndrome and further delineates the clinical and genetic spectrum of this condition.

Lack of effect of methylphenidate on serum growth hormone (GH), GH-binding protein, and insulin-like growth factor I.

The aim of this study was to assess the growth hormone (GH) axis in methylphenidate (MPH)-treated and untreated boys with attention-deficit and hyperactivity disorder (ADHD), by evaluating serum GH, GH-binding protein (GHBP) activity, and insulin-like growth factor I (IGF-I) levels as compared to age-matched normal controls. Blood samples were taken from 42 boys (aged 6-16 years) diagnosed as having ADHD according to DSM-III-R criteria and confirmed by using the Schedule for Affective Disorder and Schizophrenia for school-age children (K[Kiddle]-SADS). A total of 21 patients were treated with MPH (5-20 mg/day; 0.15-0.77 mg/kg/day), on a drug holiday protocol, for 1-36 months, and 21 were drug naive. A total of 46 age-matched normal boys at height and weight within normal range served as controls. No significant differences were detected between the MPH-treated ADHD children, the untreated ADHD children, and the control children on fasting serum GH levels, GHBP activity, or IGF-I levels. Active treatment with MPH, in ADHD children on a drug holiday protocol, does not cause changes in GH axis as manifested by normal values of GH, GHBP, and IGF-I.

Thyroid function in attention deficit and hyperactivity disorder.

In view of the recent conflicting findings regarding the causative role of thyroid abnormalities in attention deficit hyperactivity disorder (ADHD), we performed a replication study to clarify the issue and establish clinical guidelines. Thyroid tests were performed in 43 ADHD children and 28 age- and gender-matched controls. Sixteen ADHD children showed total triiodothyronine (TT3) levels which were slightly above the upper limit of normal, but no significant difference in TT3 values was noted between the ADHD and the control groups. Moreover, none of the ADHD subjects had abnormal levels of total thyroxine, free thyroxine, thyroid stimulating hormone or total triiodothyronine reuptake. The present study supplies additional evidence for the lack of an association between thyroid function and ADHD, and counters the suggestion that thyroid function be routinely screened for in ADHD children.

Agenesis of the corpus callosum in a mother and son.

Most reported familial cases of agenesis of the corpus callosum have followed either an autosomal recessive or an X-linked recessive pattern of inheritance. To the best of our knowledge, there is only one previous report of a family showing clear-cut autosomal dominant inheritance. We present the second such family, among whom a mother and her son had moderately severe coordination problems and low-normal intelligence. We suggest that agenesis of the corpus callosum, when transmitted as an autosomal dominant trait, is clinically characterized by a relatively milder phenotype than that occurring when inheritance is either autosomal or X-linked recessive and may be more common than has been thought.

Platelet serotonin transporter in drug-naive migrainous children and adolescents.

Platelet [3H]imipramine binding was measured in 17 children and adolescents suffering from common (n = 10) and classical (n = 7) migraine and 10 healthy control subjects. All patients had more than a 1-year history of the disease and suffered at least one attack per month. All subjects had been drug-free for at least 4 weeks prior to the study and had never been treated with drugs active at the serotonergic system. An increased density in [3H]imipramine binding sites was detected in the migraine patients (+51%; p < 0.05). The increase in maximal binding was more prominent in the classical migraine group (+63%) than in the common migraine group (+43%). These results disagree with previous studies that reported decreased platelet imipramine binding in adult migraine patients. The discrepancy may be related to chronicity of drug treatment, long-term duration of disease and comorbidity of depression and anxiety disorders in adult migrainous patients.

Officers' attitudes toward combat stress reaction: responsibility, treatment, return to unit, and personal distance.

This study examines the attitudes of 176 Israel Defense Forces officers toward combat stress reaction (CSR) in four areas: (1) the degree of personal responsibility the officer accepts for the treatment of the CSR casualty; (2) the type of treatment the officer views as most effective for CSR; (3) the officer's willingness to accept the CSR casualty's return to the unit following treatment; and (4) the personal distance the officer experiences between himself and the phenomenon. The impact of the following variables on officers' attitudes was assessed: casualty's rank, casualty's level of combat skill, presence of an additional physical injury, type of symptomatology, and respondent's background variables. Each officer was presented with one of 24 vignettes describing a CSR incident and was requested to fill in an attitudes questionnaire. Findings revealed that officers were more severe and less tolerant in relation to the CSR casualty who was an officer than toward lower ranking casualties. Officers were expected to take more responsibility for their own recovery than simple soldiers, support of commanding officers was seen as less effective in their treatment, and respondents were less willing to accept them back into their units after treatment.

Multiple use of one-piece microtitration plates in ELISA (enzyme-linked immunosorbent assay) tests for the detection of cytomegalovirus and rubella virus antibodies.

Ninety-six-well, one-piece microtitration plates coated with rubella virus or cytomegalovirus (CMV) antigen can be used for multiple ELISA (enzyme-linked immunosorbent assay) testings. Only the number of test wells required per test need be used and the remaining unused test wells can be retained for subsequent assay. Consequently, as the one-piece microtitration plate is not a single-use, "all or none" element of the ELISA system, it is therefore as suitable for multiple ELISA testings as for one-time use. An alternate system of result interpretation for ELISA is introduced. Results are presented comparing the conventional optical density (OD) readings to values of the ratio: OD sample/OD low-positive sample.

Homogeneous substrate-labeled fluorescent immunoassay for human serum albumin.

A homogeneous substrate-labeled fluorescent immunoassay for human serum albumin (HSA) has been developed, similar to previously described immunoassays for Immunoglobulin G and Immunoglobulin M. HSA was covalently linked to 6-(7-beta-galactosylcoumarin-3-carboxamide) hexylamine. The resulting conjugate had minimal fluorescence at 450 nm (with excitation at 400 nm). However, when the acetal linkage of the galactosyl moiety was hydrolyzed by beta-galactosidase, a substantial increase in the fluorescence was obtained. This increase was specifically inhibited by antibody to HSA. A competitive binding immunoassay was established by letting the conjugate compete with HSA in the serum for the limited number of antibody-binding sites. The level of fluorescence resulting from the addition of enzyme was proportional to the amount of HSA in the serum. Precision, analytical recovery and serum dilution studies were carried out on the assay. The immunoassay was compared to an albumin assay using the dye-binding method.