Merlin G. Butler

Obese children show hyperactivation to food pictures in brain networks linked to motivation, reward and cognitive control.

Objective:To investigate the neural mechanisms of food motivation in children and adolescents, and examine brain activation differences between healthy weight (HW) and obese participants.Subjects:Ten HW children (ages 11–16; BMI < 85%ile) and 10 obese children (ages 10–17; BMI >95%ile) matched for age, gender and years of education.Measurements:Functional magnetic resonance imaging (fMRI) scans were conducted twice: when participants were hungry (pre-meal) and immediately after a standardized meal (post-meal). During the fMRI scans, the participants passively viewed blocked images of food, non-food (animals) and blurred baseline control.Results:Both groups of children showed brain activation to food images in the limbic and paralimbic regions (PFC/OFC). The obese group showed significantly greater activation to food pictures in the PFC (pre-meal) and OFC (post-meal) than the HW group. In addition, the obese group showed less post-meal reduction of activation (vs pre-meal) in the PFC, limbic and the reward-processing regions, including the nucleus accumbens.Conclusion:Limbic and paralimbic activation in high food motivation states was noted in both groups of participants. However, obese children were hyper-responsive to food stimuli as compared with HW children. In addition, unlike HW children, brain activations in response to food stimuli in obese children failed to diminish significantly after eating. This study provides initial evidence that obesity, even among children, is associated with abnormalities in neural networks involved in food motivation, and that the origins of neural circuitry dysfunction associated with obesity may begin early in life.

Neural mechanisms underlying hyperphagia in Prader-Willi syndrome.

Objective: Prader‐Willi syndrome (PWS) is a genetic disorder associated with developmental delay, obesity, and obsessive behavior related to food consumption. The most striking symptom of PWS is hyperphagia; as such, PWS may provide important insights into factors leading to overeating and obesity in the general population. We used functional magnetic resonance imaging to study the neural mechanisms underlying responses to visual food stimuli, before and after eating, in individuals with PWS and a healthy weight control (HWC) group.

Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism

To assess the feasibility and relevance of using lymphoblastoid cell lines to study the role of noncoding RNAs in the etiology of autism, we evaluated global expression profiling of 470 mature human microRNAs from six subjects with autism compared with six matched controls. Differential expression (either higher or lower) for 9 of the 470 microRNAs was observed in our autism samples compared with controls. Potential target genes for these microRNAs were identified using computer tools, which included several autism susceptibility genes. Our preliminary results indicate microRNAs should be considered and evaluated in the etiology of autism. In addition, analysis of this class of noncoding RNAs in lymphoblastoid cells has the potential to reveal at least a subset of brain‐related microRNAs implicated in autism. Subsequently, this model system should allow for detection of complex subtle changes in susceptibility genes/pathways contributing to autism.

Self-Injurious Behavior and Prader-Willi Syndrome: Behavioral Forms and Body Locations

With few exceptions (e.g., Lesch-Nyhan syndrome), the specific nature of self-injury in relation to identified genetic syndromes associated with mental retardation is poorly understood. In the present study we surveyed the families of 62 persons with Prader-Willi syndrome to determine the prevalence, topographies, and specific body locations of self-injurious behavior. Self-injury was reported for 81% of the participants. Skin-picking was the most prevalent form, with the front of the legs and head being disproportionately targeted as preferred self-injury body sites. Individuals with the 15q11-q13 deletion injured significantly more body sites than did individuals with maternal disomy 15. Results are discussed in relation to previous self-injury body site findings and implications for the relevance of syndrome-specific behavioral phenotypes.

Comparison of Chromosome Telomere Integrity in Multiple Tissues from Subjects at Different Ages

Telomere DNA, at the ends of each chromosome, is conserved in nature and required for chromosome replication and stability. Reduction in telomere length has been observed in several malignancies as well as in leukocytes from healthy persons with advancing age. There is a paucity of data regarding telomere length and the effects of in vivo aging in different tissues. These data could be helpful in interpreting telomere length and understanding the role of telomere integrity and telomerase activity in malignant cells. We report telomeric DNA integrity studies of blood and skin collected from eight Caucasians of both sexes representing each decade of life from the fetus to 72 years of age without exposure to chemotherapy or radiation. In addition, telomeric data from 15 other tissues from the fetus and 8 other tissues from the 72-year-old male were examined. No significant differences were found in the shortest telomere size, the average telomere size, or telomere size variation between blood and skin from subjects at different ages. The average telomere size was 11.7 +/- 2.2 kb for blood and 12.8 +/- 3.7 for skin in all subjects studied. The shortest telomere length was 5.4 +/- 1.9 kb for blood and 4.3 +/- 0.9 kb for skin. Significant differences (P < 0.001) were found in the overall length of the DNA hybridization signal representing the shortest telomere size and the length of the DNA peak migration hybridization signal representing variation in telomere size between the 20-week fetus and the 72-year-old male. The 72-year-old male showed the shortest telomeres and the most variation (heterogeneity) in telomere size for all tissues studied, but the greatest differences were observed in blood compared with other tissues (e.g., average telomere length was 12.2 kb in the fetus and 7.2 kb in the 72-year-old male). The size of the telomere was negatively correlated with age for all tissues studied.

Neuroimaging findings in macrocephaly–capillary malformation: A longitudinal study of 17 patients

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly–Capillary Malformation (M–CM). This syndrome has been traditionally known as Macrocephaly–Cutis Marmorata Telangiectatica Congenita (M–CMTC), but we explain why M–CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2‐weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow–Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M–CM.

Emergence of Compulsive Behavior and Tantrums in Children with Prader-Willi Syndrome

Many adults with Prader-Willi syndrome are affected by behaviors such as tantrums, skin-picking, and compulsions. The nature and extent of these problems suggest more attention be directed to their emergence in childhood. Our purpose was to investigate behavior problems in children with this syndrome and identify the age at which these behaviors emerge. Parents of children with Prader-Willi syndrome, Down syndrome, and those developing typically completed questionnaires. Children with Prader-Willi syndrome exhibited more compulsions, skin-picking, and tantrums than did the other groups. A discriminant analysis of behavior variables derived two statistically significant functions that were interpreted as developmental milestones and problematic behavior. These functions correctly predicted membership for 79% of grouped cases.

Telomerase activity and oncogenesis in giant cell tumor of bone

Background. Benign giant cell tumor of bone (GCT) is a primary skeletal neoplasm with an unpredictable pattern of biologic aggressiveness and cytogenetic findings characterized by telomeric associations and telomeric reduction. The role of maintaining telomeric integrity is performed by telomerase. To determine if telomerase activity is present, cell extracts from fibroblasts and tumor cells from five patients with GCT were analyzed and compared with HeLa (a positive control cell line).

Telomere reduction in giant cell tumor of bone and with aging

Giant cell tumor of bone is a benign, primary skeletal neoplasm that has an unpredictable pattern of biologic aggressiveness, and cytogenetically demonstrates genetic instability by exhibiting telomeric associations. Molecular analysis of telomeres from giant cell tumor of bone demonstrated reduction of telomere length (average loss of 500 base pairs) in eight individuals when compared with their leukocyte DNA. Those tumors which exhibited telomeric associations were found to have a greater reduction in telomere length than tumors not exhibiting them. For comparison, eleven cytogenetically healthy control individuals (7 females and 4 males, age range 2 weeks to 70 years) were included in this study. They demonstrated loss of telomere size (average 40 base pairs per year) with advancing age and the greatest rate of telomere reduction was identified in the young. Thus, the functional consequences of telomere shortening in a neoplastic cell may prove fundamental to sustaining the transformed phenotype in giant cell tumor of bone.

Metacarpophalangeal pattern profile analysis in Noonan syndrome

Metacarpophalangeal pattern (MCPP) analysis is an application of an anthropometric technique that provides a quantitative assessment of the amount and direction of abnormality in the hand skeleton. MCPP analysis was undertaken on 15 individuals (9 males, 6 females) with Noonan syndrome ranging in age from 0.1 to 36 years with a mean age at 11.6 years. The overall average Z score for the MCPP variables was -2.1 and the range was -2.5 (for metacarpal two) and -1.5 (for middle phalanx 5). The average hand pattern variability index, a measure of hand bone length relationships, was abnormal. A Pearsonian correlation analysis was used to assess similarity between the mean pattern and each of the 15 individual patterns. Nine (60%) of the fifteen individuals with Noonan syndrome had significant positive correlations (P < 0.05), indicating homogeneity or similarity in the hand patterns. A stepwise discriminant analysis was performed on Z score data from the individual hand bone measurements on the 15 subjects with Noonan syndrome and 41 healthy controls (24 females, 17 males; mean age = 13.1 years with age range of 9.6 to 18 years). This analysis produced a discriminant function with two MCPP variables (metacarpal 1 and middle phalanx 3) entering into the function and producing a correct classification rate of 93%. The two MCPP variables contributed to the overall difference between individuals with Noonan syndrome and the normative sample. The hand pattern variability index was outside of the normal range, indicating an abnormal MCPP with multivariate analysis. The MCPP analysis may be useful as a tool for diagnosis in screening subjects for Noonan syndrome.