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Biomedical subjects

Shaul Harel

Publications and source records attributed to Shaul Harel.

At least 19 recordsLinked to original sources
PubMed2006

Memory functions of children born with asymmetric intrauterine growth restriction.

OBJECTIVE: Learning difficulties are frequently diagnosed in children born with intrauterine growth restriction (IUGR). Models of various animal species with IUGR were studied and demonstrated specific susceptibility and alterations of the hippocampal formation and its related neural structures. The main purpose was to study memory functions of children born with asymmetric IUGR in a large-scale cohort using a long-term prospective paradigm. METHODS: One hundred and ten infants diagnosed with IUGR were followed-up from birth to 9 years of age. Their performance was compared with a group of 63 children with comparable gestational age and multiple socioeconomic factors. Memory functions (short-term, super- and long-term spans) for different stimuli types (verbal and visual) were evaluated using Visual Auditory Digit Span tasks (VADS), Rey Auditory Verbal Learning Test (Rey-AVLT), and Rey Osterrieth Complex Figure Test (ROCF). RESULTS: Children with IUGR had short-term memory difficulties that hindered both serial verbal processing system and simultaneous processing of high-load visuo-spatial stimuli. The difficulties were not related to prematurity, neonatal complications or growth catch-up, but were augmented by lower maternal education. Recognition skills and benefits from reiteration, typically affected by hippocampal dysfunction, were preserved in both groups. CONCLUSIONS: Memory profile of children born with IUGR is characterized primarily by a short-term memory deficit that does not necessarily comply with a typical hippocampal deficit, but rather may reflect an executive short-term memory deficit characteristic of anterior hippocampal-prefrontal network. Implications for cognitive intervention are discussed.

Child↗
PubMed2006

NAP enhances neurodevelopment of newborn apolipoprotein E-deficient mice subjected to hypoxia.

Perinatal hypoxic injury is associated with significant neonatal morbidity and long-term neurodevelopmental complications. NAP, a peptide derived from ADNP (activity-dependent neuroprotective protein), has previously shown neuroprotective abilities in various adult animal models. To evaluate its neuroprotective role in neonatal hypoxic-ischemic injury, we evaluated the neurodevelopmental outcome in apolipoprotein E (ApoE)-deficient (knockout) mice (a breed prone to brain damage during hypoxic insult) exposed to postnatal global hypoxic damage with and without treatment with NAP. ApoE-deficient (n = 80) and control (C57B6) mice pups (n = 81) were exposed to postnatal global hypoxia (35 min of 8% O(2) within 24 h of birth) or room air with or without subsequent subcutaneous NAP treatment during postnatal days 1 to 14. Pups were then evaluated for neonatal motor reflex attainment, spatial learning ability in the Morris water maze, and locomotor open-field activity. The C57B6 and ApoE-deficient anoxic groups showed significantly slower achievement of neonatal reflexes, diminished locomotor activity, and diminished spatial learning ability compared with their control groups. This was more pronounced in the anoxic ApoE-deficient pups. NAP treatment had a pronounced effect on neurodevelopmental outcome in both breeds, particularly in the ApoE-deficient mice. ApoE-deficient and control mouse pups exposed to postnatal hypoxia and treated with NAP showed improvement in neurodevelopmental outcome compared with nontreated mice pups. ApoE-deficient mice show a greater susceptibility to hypoxic damage and better response to NAP treatment.

Animals↗
PubMed2006

Neuropsychological outcome of children with intrauterine growth restriction: a 9-year prospective study.

OBJECTIVE: The aim was to evaluate the effect of late-onset intrauterine growth restriction on the neuropsychological profile and on academic achievements at 9 years of age using a large-scale prospective paradigm. STUDY DESIGN: We followed up 123 infants diagnosed with late-onset intrauterine growth restriction yearly for 9 years. They were matched with 63 children for gestation age and multiple socioeconomic factors and evaluated by an extensive neuropsychological battery to assess intelligence quotient, academic achievements, learning and memory, visuomotor skills, visuospatial integration, attention, language, executive functions, and creativity. RESULTS: Children with intrauterine growth restriction had lower intelligence quotient and more frequent neuropsychological difficulties. Difficulties in executive functioning, inflexibility-creativity, and language, indicative of frontal lobe dysfunction, were typically affected by intrauterine growth restriction and were rarely identified in the control group. Learning difficulties accompanied by lower academic achievements were more prevalent in the intrauterine growth restriction group, particularly when anthropometric catch-up was incomplete. CONCLUSIONS: The longitudinal findings reaffirm that functional coherence depends on preestablished structural growth and reorganization of the central nervous system. The neuropsychological profile at 9 years of age indicates that late-onset intrauterine growth restriction compromises frontal network functioning.

Attention↗
PubMed2005

The pregnant spontaneously hypertensive rat as a model of asymmetric intrauterine growth retardation and neurodevelopmental delay.

INTRODUCTION: Hypertension in pregnancy and vascular placental insufficiency are considered common pathogenic factors in human intrauterine growth retardation (IUGR). IUGR neonates experience higher mortality, and the surviving infants have a higher incidence of neurological and intellectual impairment. METHODS: To mimic this condition, we used pregnant spontaneously hypertensive rats (SHR) and performed biometric measurements on Embryonic Day 20, postnatal developmental reflexes, and locomotor activity evaluations. RESULTS: SHR fetuses had significant decreased body weight compared to the Wistar-Kyoto control fetuses (1.51+/-0.02 g vs. 2.05+/-0.01 g, respectively; p<0.0001), and were relatively microcephalic (2.86+/-0.04 cm vs. 3.3+/-0.03 cm, respectively; p<0.0001). Their cephalization index (head circumference/body weight) was increased (1.88+/-0.03 vs. 1.62+/-0.02, respectively; p<0.0001), indicating a "brain-sparing" process. The disproportional ratio indicated that the IUGR type in this model is asymmetric. The SHR pups exhibited a significant (p<0.04) neurodevelopmental delay in the acquisition of neonatal reflexes (righting, negative geotaxis, placing), but they spontaneously caught up with the control pups after approximately 10 days. On Day 30, the SHR pups exhibited significantly increased walking speed and distance and spent less time in quadrant than the controls (p<0.002). CONCLUSION: We speculate that the model of pregnant SHR closely simulate human IUGR caused by hypertension in pregnancy and should enable investigation of mechanisms of hypertension-mediated placenta-vascular injury as well as provide a system for preclinical evaluations of future preventive neuroprotective treatments.

Analysis of Variance↗
PubMed2005

Endocrine profile of children with intrauterine growth retardation.

BACKGROUND: Intrauterine growth retardation (IUGR) is a major cause of short stature in childhood. Most but not all children experience catch-up growth by 2 years of age. METHODS: We investigated the endocrine profile (thyroid function, prolactin, cortisol, C-peptide and insulin-like growth factor-I [IGF-IJ levels) of 57 children with IUGR, aged 2-10 years, and compared it with 30 controls whose birth weight was appropriate-for-gestational-age. RESULTS: The hormonal profile for both groups was similar for thyroid hormones, prolactin, C-peptide and IGF-I. Cortisol levels were significantly lower in the IUGR group compared to controls (p <0,05). When the IUGR group was divided into 'catch-up' growth and 'non-catch-up' subgroups, the latter had significantly lower IGF-I levels (p <0.001). CONCLUSIONS: Lower cortisol levels in children born with IUGR may reflect impaired function of the hypothalamic-pituitary-adrenal axis associated with this condition. The significantly lower IGF-I levels of the 'non-catch-up' subgroup may be involved in their failure to grow.

C-Peptide↗
PubMed2004

Role of thrombophilic risk factors in children with non-stroke cerebral palsy.

BACKGROUND: Thrombophilic risk factors play an important role in the pathogenesis of perinatal stroke and resultant cerebral palsy (CP). The association between thrombophilia and CP caused by etiologies other than stroke is undetermined. METHODS: We assessed three genetic thrombophilic markers (mutation of Factor V Leiden [FV G1691A], 677T polymorphism of thermolabile methylenetetrahydrofolate reductase [MTHFR] and G20210A mutation of the prothrombin gene) in 49 pediatric patients with non-stroke CP and compared the findings with 118 apparently healthy controls. CP in the study group was due to periventricular leukomalacia (n=27), intraventricular hemorrhage (n=9), hypoxic ischemic encephalopathy (n=4), prematurity with no apparent complication (n=8) and intrauterine growth retardation (n=1). Twenty-five children had spastic diplegia, 20 had spastic quadriplegia and 4 had spastic hemiplegia. CP was graded as being severe in 26 children (53%). RESULTS: No significant difference in the prevalence of thrombophilic risk factors was found between the study and control groups. Twelve study children (24.5%) had at least one of the three thrombophilic mutations compared with 27 controls (23%). There was no significant difference in the prevalence of each thrombophilic risk factor in the various etiologic groups and in the subgroups of mild/severe CP and the control group. CONCLUSION: These findings support the notion that thrombophilia neither contributes to the occurrence nor affects the clinical outcome and severity of non-stroke CP.

Case-Control Studies↗
PubMed2004

Neonatal general movements: an early predictor for neurodevelopmental outcome in infants with intrauterine growth retardation.

Intrauterine growth retardation plays a significant role in neurodevelopmental outcome. The assessment of general movements during the first 20 weeks is a new method for early detection of brain dysfunction. General movements in 31 infants with asymmetric intrauterine growth retardation and their appropriate for gestational age-matched controls were examined. General movements were scored as normal or abnormal by sequential videotape recordings in the writhing (term to 2 weeks), early fidgety (9-11 weeks), and late fidgety (14-16 weeks) periods. Scores were compared between the groups and correlated with neurodevelopmental outcome at 2 years. The incidence of normal general movements was lower in the intrauterine growth retarded infants than in the controls (P < .001). Significant correlations were found between general movement quality and neurodevelopmental scores in the intrauterine growth retarded group. The fidgety movements were the most sensitive and specific for prediction of neurologic outcome. The general movement assessment can, therefore, serve as an additional tool for examining the neurologic status of the preterm and term intrauterine growth retarded infant.

Birth Weight↗
PubMed2004

Antenatal diagnosis of central nervous system anomalies: can we predict prognosis?

Our technical ability to diagnose fetal anomalies of the central nervous system by ultrasonography and by fetal magnetic resonance imaging far exceeds our current knowledge of their possible neurodevelopmental implications later in life. This limitation often makes obstetric and clinical decisions very difficult. We retrospectively reviewed the ultrasonographic records of 6220 women who had been followed up at two large medical centers between 1994 and 1999. One hundred and sixty (2.6%) women had abnormal fetal central nervous system findings. The neurodevelopmental outcome of these children was assessed by a telephone interview with the parents. Small cerebellar size was the most frequent anomaly, followed by isolated mild ventriculomegaly and isolated choroid plexus pathology. Suboptimal neurodevelopmental outcome was found in 24% of children with isolated ventriculomegaly and in 9% with choroid plexus pathology. In the group of children with a "small cerebellum," suboptimal neurodevelopment was found in 19%. The measurement of transcerebellar diameter in respect to its developmental implication is, to our knowledge, described here for the first time. We believe that cerebellar measurements and their possible neurocognitive implications should be an integral part of future studies.

Abortion, Induced↗
PubMed2003

Neurodevelopmental and cognitive assessment of children born growth restricted to mothers with and without preeclampsia.

We examined neurological and intellectual outcome of growth-restricted newborns of pregnancies complicated with preeclampsia and without preeclampsia. Seventy-five consecutive growth restricted newborns (<5th percentile) were prospectively followed up at 6 months' intervals. Newborns with major congenital malformations and newborns with evident intrauterine viral infection were excluded. At 3 years of age all children had detailed neurological examination and intellectual examination using the Mean developmental index (Stanford Binnet-IQ). Eleven children were born to mother with preeclampsia (ACOG criteria), and 64 were born to mothers without a definite diagnosis of preeclampsia. Gestational age was 34.7 weeks in the preeclamptic group and 37 weeks in the non-preeclamptic group. After adjustment for gestational age, there was no significant difference in the neurological exam score between groups, but the IQ was 85.5 in the preeclamptic group and 96.9 in the non-preeclamptic group (p<0.03). We conclude that newborns born growth restricted after pregnancies complicated by preeclampsia have a lower IQ at the age of 3 years compared to growth-restricted babies without preeclampsia.

Adult↗
PubMed2003

Large in-frame deletions of the rod-shaped domain of the dystrophin gene resulting in severe phenotype.

BACKGROUND: The prediction that Duchenne muscular dystrophy patients have out-of-frame deletions and Becker muscular dystrophy patients have in-frame deletions of the dystrophin gene holds well in the vast majority of cases. Large in-frame deletions involving the rod domain only have usually been associated with mild (BMD) phenotype. OBJECTIVES: To describe unusual cases with large in-frame deletions of the rod-shaped domain of the dystrophin gene associated with severe (Duchenne) clinical phenotype METHODS: Screening for dystrophin gene deletion was performed on genomic DNA by using multiplex polymerase chain reaction. Needle muscle biopsies from the quadriceps were obtained using a Bergström needle. The biopsies were stained with histologic and histochemical techniques as well as monoclonal antibodies to dystrophin 1, 2 and 3. RESULTS: In three children with large in-frame deletions of the rod domain (exons 10-44, 13-40 and 3-41), early-onset weakness and a disease course suggested the DMD phenotype. CONCLUSIONS: This observation emphasizes the uncertainty in predicting the Becker phenotype in a young patient based on laboratory evaluation, and that the clinical picture should always be considered.

Dystrophin↗
PubMed2002

Winging of the scapula in a child with hereditary multiple exostoses.

A female, 10 years of age, with hereditary multiple exostoses presented with shoulder drop and asymmetry. The results of neurologic examination were normal and winging was not accentuated by active maneuvers of the shoulder. Scapular exostosis was demonstrated to be the structural cause of scapular winging. Only a few cases of children with scapular winging caused by scapular tumors have been reported. However, tumors of the scapula should be excluded in children with static winging of the scapula.

Child↗
PubMed2002

Macrocephaly in children with developmental disabilities.

In a community-based study of 4,309 children with neurodevelopmental disabilities who were referred to the Institute for Child Development, Tel Aviv, Israel, 62 (1.4%) had macrocephaly (head circumference above the ninety-eighth percentile for age), of whom 42 (1%) had macrocephaly not associated with hydrocephalus. With the exception of neonatal respiratory distress the incidence of perinatal complications was not different from that in other children referred to the Institute for Child Development. In children with developmental disabilities, macrocephaly was a significant risk factor for febrile seizures (odds ratio = 3.1, P < 0.001) and epilepsy (odds ratio = 7.7, P < 0.001), but not for mental retardation (odds ratio = 1.1, P = 0.78) or cerebral palsy (odds ratio = 1.3, P = 0.67). Children with macrocephaly had a high rate of comorbid diagnosis. We conclude that in children with developmental disabilities the presence of macrocephaly even when not associated with hydrocephalus is associated with an increased risk of seizures.

Cephalometry↗
PubMed2002

Significance of microcephaly among children with developmental disabilities.

To assess the clinical impact of microcephaly among children with developmental disabilities, we reviewed the charts of 1393 consecutive patients from birth to 5 years of age referred to our child development center. Comparisons were made between normal and low IQ microcephalic patients and between children with cerebral palsy with and without small head circumference. Microcephaly was detected in 15.4% of patients. Although mental retardation was more common among microcephalic children (P < .001), almost half had normal intelligence. Prematurity (P < .001), perinatal asphyxia (P < .001), small for gestational age (P < .001), respiratory distress syndrome (P < .001), and brain hemorrhage (P < .001) were associated with microcephaly. Hypotonia (P < .001) and spasticity (P < .001) were the most common neurologic findings. Cerebral palsy (P < .001), growth retardation (P < .001), epilepsy (P < .001), and strabismus (P < .001) were the main associated diagnoses found. Mental retardation was significantly more common among microcephalic patients with cerebral palsy than among normocephalic ones (P < .0004). Microcephaly is common among children evaluated for developmental disabilities. Many of these patients have normal or borderline IQ. Of several perinatal conditions associated with later microcephaly, respiratory distress syndrome and intraventricular hemorrhage show the strongest correlation. Mental retardation is not a risk factor for other neurologic complications in microcephalic children. However, in children with cerebral palsy, microcephaly is a risk factor for mental retardation.

Asphyxia Neonatorum↗
PubMed2002

Parameters for predicting favorable responses to botulinum toxin in children with cerebral palsy.

We sought markers for predicting a favorable outcome of botulinum toxin A injected to the lower-extremity muscles of 26 children with hemiplegic or diplegic cerebral palsy. Clinical assessment preceding and 1 month following injection included gross motor function measure, a modified Ashworth scale, and evaluation of range of motion of knee extension and ankle dorsiflexion. Response to treatment was classified based on a parent questionnaire. The 19 children (73%) considered by their parents as being good responders were compared to the 7 (27%) considered as being poor responders. In the good responders, the preinjection Ashworth scale (spasticity) was significantly higher (P < .05) and gross motor function measure scores (function) were lower (P < .05). Sixty-eight percent of the good responders were nonindependent walkers compared to 14% of the poor responders (P < .05). There were no differences in age, type of cerebral palsy, and dose of injection. An Ashworth scale indicating increased muscle tone, lower gross motor function measure scores, and nonindependent ambulatory status were predictive for a favorable response to botulinum toxin A injections and can guide patient selection and expectations of treatment outcome.

Botulinum Toxins, Type A↗
PubMed2002

Congenital muscular dystrophy in Israeli families.

Twelve patients from 11 Israeli families with congenital muscular dystrophy were evaluated between 1991 and 2001. There were six males and six females, of whom six were merosin negative and six were merosin positive. Serum creatine kinase levels were highly elevated in the merosin-negative group. Four of the children were cognitively normal but nonambulant. Two had unusual clinical findings of severe cognitive and motor developmental dysfunction. Four infants in the merosin-positive group who had normal serum creatine kinase levels had early-onset severe motor weakness and died within the first year of life owing to ventilatory insufficiency. The other two were ambulant and had normal cognitive development and elevated serum creatine kinase levels. Noteworthy, two of the six children with merosin-negative congenital muscular dystrophy had cognitive impairment, and four of the six children with merosin-positive congenital muscular dystrophy had a severe form of the disease with ventilatory insufficiency and death during infancy.

Antibodies, Monoclonal↗
PubMed2002

Myoclonic seizures as a main manifestation of Epstein-Barr virus infection.

A 15-year-old girl with clinical and serologic evidence of active Epstein-Barr virus infection presented with a new onset of myoclonic jerks, confirmed on electroencephalogram (EEG) by generalized polyspike-and-wave epileptiform activity. Family history for juvenile myoclonic epilepsy was negative, and brain magnetic resonance imaging was normal. The myoclonic jerks resolved spontaneously after 5 days, with gradual normalization of the EEG during the ensuing month and since then no resumption over the last 2 years. Previous reports have already linked Epstein-Barr virus infection to opsoclonus-myoclonus syndrome and hypsarrhythmia, but to the best of our knowledge, this is the first presentation of epileptic myoclonic jerks associated with acute Epstein-Barr virus infection. We suggest that acute myoclonic seizures with a transiently abnormal EEG and benign course can be associated with acute Epstein-Barr virus infection.

Adolescent↗
PubMed2002

Clinical characteristics and muscle pathology in myopathic mitochondrial DNA depletion.

Four nonrelated children with myopathic mitochondrial DNA depletion are described. Two of them initially had normal motor development and two had mild motor delay. Motor arrest and regression started at age 6 to 21 months. All four had mitochondrial DNA:nuclear DNA ratios reduced to 16 to 22% of the control mean and mutations in their mitochondrial thymidine kinase 2. Muscle pathology was genotype related: homozygosity for a missense mutation at position 181 was associated with severe myopathic changes, including marked variation in muscle fiber size, myofiber necrosis, regeneration, and interstitial fibrosis, whereas homozygosity for a missense mutation at position 90 was associated with essentially normal muscle histology. No ragged red fibers were detected in any study child. Mitochondrial DNA depletion should be considered in children with myopathy, worsening hypotonia, motor regression, and death during infancy or early childhood. The severity of pathologic findings on muscle biopsy is variable and may correlate with specific mutations and thymidine kinase 2 protein residual activity.

Child, Preschool↗