Normal Siblings Research Articles

Mealtime feeding behaviors and gastrointestinal dysfunction in children with classic autism compared with normal sibling controls

Introduction: We compared the frequency and duration of specific mealtime behaviors and GI dysfunction in children with classic autism to typically-developing siblings. Survey Method: A 41-item on-line parent survey. Statistics: Chi square and binomial logistical regression. Results: 79 children with classic autism matched with a normally-developing sibling. Logistic Regression Analysis Revealed: Dislike of new foods and bizarre mealtime mannerisms, were more frequent in those with classic autism (p < 0.01). They also had higher odds ratio of constipation and fecal incontinence (p < 0.01). 40% of children with classic autism had been on GFCF diets (p < 0.01). Only 1% of those children on a gluten-free diet had a biopsy-proven diagnosis of celiac disease. Conclusion: Children with classic autism had more frequent dislike of new foods, bizarre mealtime behaviors, constipation, and fecal incontinence.

Co-Inheritance of Delta Thalassemia Might Contribute to the High Fetal Hemoglobin in Sickle Cell Anemia Patients with the Saudi-Indian Haplotype

Abstract 1056Most sickle cell anemia patients (HBB glu6val homozygotes) indigenous to the Eastern Province of Saudi Arabia have a fetal hemoglobin (HbF) level of about 20% that is associated with a mild clinical phenotype. Their HbS gene is on the Saudi-Indian (SI) haplotype characterized by an Xmn1 restriction site at position −158 5’ to HBG2 (rs7482144), a Hinc2 site 5’ to HBE (rs3834466) and other polymorphisms in the HBB gene-like cluster. However, the functional elements within the HBB gene-like cluster and elsewhere in the genome causing high HbF are yet to be determined. In a previous study we found that Saudi HbS homozygotes with the SI haplotype had a common region of autozygosity that spanned about 126 kb and included the complete HBB cluster. We have sequenced 13.6 kb in the HBD-HBG1 intergenic region (chr11:5255683-5269326, HG19), the region of the Corfu deletion. We found a SNP at position −68 bp 5’ to HBD (c.-118 C>T) only in individuals with a SI haplotype. This SNP was not present in dbSNP build 132 or the 1000 Genomes databases. No other mutation in HBD was identified. This same SNP was recently associated with δ thalassemia (Phylipsen et al. Int. J. Lab. Hematol. 2011, 33: 85–91). Homozygotes for the −68 HBD SNP, who were not on hydroxyurea, had a mean HbF of 23%, range 12.1%-33.4% and mean HbA2 of 2.1%, range 1.2%-3%. We did not find the −68 HBD SNP in 15 African Americans with sickle cell anemia selected because of their unusually high HbF (mean HbF 17.2%, range 11%-28.9%). Parents and sickle cell trait carriers from the families of Saudi Eastern Province patients were heterozygous for the −68 HBD mutation (mean HbF 1.6%, range 0–4.2% and mean HbA2 2.7%, range 2.4%-3.2%) and one normal sibling did not carry this mutation (HbF 0 and HbA2 2.9%). Thirty patients with sickle cell disease indigenous to the Southwestern Province of Saudi Arabia, with the HbS gene on an African origin haplotype, (mean HbF 15.5%, range 4.5%-23% and mean HbA2 2.9%, range 2.1%-3.4% in HbS homozygotes) and 13 normal Saudi controls were examined and none carried the −68 HBD mutation. We also sequenced HBD and its promoter in 8 Southwestern Province HbS homozygotes with a Benin haplotype, 4 with HbF <5% and 4 with HbF >15%, and none had the −68 HBD SNP or any other mutation in HBD. Inverse relationships between percent HbF level and percent HbA2 was seen in 3 groups of HbS homozygotes:1) SI haplotype homozygotes; 2) Benin haplotype homozygotes from the Southwestern Province; 3) African Americans with diverse HbS haplotypes. The increased HbF in sickle cell anemia with δ thalassemia might involve both post-translational and transcriptional mechanisms. Increased HbF levels might in part be due to the preferential post-translational assembly of αγ dimers compared with αδ and αβS dimers. When δ thalassemia reduces available δ-globin chains, this might further favor preferential binding of less positively charged γ-globin subunits to positively charged α-globin compared with more positively charged δ-globin subunits. Perhaps more importantly, at the transcriptional level, the −68 HBD δ+-thalassemia promoter mutation might favor the interactions of transcription complexes with HBG promoters. The stimulus of hemolytic anemia and expanded erythropoiesis might be required before the favorable genetic milieu for increased HbF production can be fully utilized with the achievement of clinically significant increases in HbF that modulates the course of disease. For example, increased HbF levels of only 3.3%-4.7% have been reported in some hematologically normal individuals with homozygous δ0 thalassemia (Ohta et al. Hemoglobin 1980, 4: 417–425). High HbF levels in SI haplotype HbS homozygotes might involve the interactions of one or more HBG regulatory regions linked to the HBB gene-like cluster, like the −68 HBD SNP, perhaps with trans acting elements. Although the −68 HBD δ+-thalassemia mutation is associated with the SI haplotype and high HbF, functional studies are needed to establish causation. Disclosures:No relevant conflicts of interest to declare.

Growth hormone modulation of EGF-induced PI3K-Akt pathway in mice liver

The epidermal growth factor (EGF) activates the phosphatidylinositol 3-kinase (PI3K)-Akt cascade among other signaling pathways. This route is involved in cell proliferation and survival, therefore, its dysregulation can promote cancer. Considering the relevance of the PI3K-Akt signaling in cell survival and in the pathogenesis of cancer, and that GH was reported to modulate EGFR expression and signaling, the objective of this study was to analyze the effects of increased GH levels on EGF-induced PI3K-Akt signaling.EGF-induced signaling was evaluated in the liver of GH-overexpressing transgenic mice and in their normal siblings. While Akt expression was increased in GH-overexpressing mice, EGF-induced phosphorylation of Akt, relative to its protein content, was diminished at Ser473 and inhibited at Thr308; consequently, mTOR, which is a substrate of Akt, was not activated by EGF. However, the activation of PDK1, a kinase involved in Akt phosphorylation at Thr308, was not reduced in transgenic mice. Kinetics studies of EGF-induced Akt phosphorylation showed that it is rapidly and transiently induced in GH-overexpressing mice compared with normal siblings. Thus, the expression and activity of phosphatases involved in the termination of the PI3K-Akt signaling were studied. In transgenic mice, neither PTEN nor PP2A were hyperactivated; however, EGF induced the rapid and transient association of SHP-2 to Gab1, which mediates association to EGFR and activation of PI3K. Rapid recruitment of SHP2, which would accelerate the termination of the proliferative signal induced, could be therefore contributing to the diminished EGF-induced activity of Akt in GH-overexpressing mice.

Ritscher–Schinzel (cranio‐cerebello‐cardiac, 3C) syndrome: Report of four new cases with renal involvement

Ritscher-Schinzel (cranio-cerebello-cardiac, 3C) syndrome is a multiple congenital anomaly syndrome that is considered to be autosomal recessive although no genetic defect has yet been identified. In a consanguineous Saudi family, we have identified four patients who meet the diagnostic criteria of 3C syndrome and who also have alopecia, camptodactaly and significant renal involvement. Interestingly, two otherwise normal female siblings have unilateral renal agenesis only. This report expands the phenotypic spectrum of 3C syndrome.

Evaluation of Oral Hygiene Status, Salivary Characteristics and Dental Caries Experience in Acute Lymphoblastic Leukemic (ALL) Children

Leukemia constitutes approximately 30% of all childhood cancers and Acute Lymphoblastic Leukemia (ALL) is the most common type of malignancy. Oral dryness, ulceration, increased dental decay seen is due to altered salivary flow rate and buffering capacity in these children. Oxidative stress may play an important role in the malignancies resulting in onset of inflammatory oral pathologies. Saliva constitutes first line of defense against free radical-mediated oxidative stress. The present study attempted to relate the oral health status, salivary flow rate, salivary pH, gingival health status, dental caries experience and total salivary antioxidant levels in ALL children. A total of 120 children aged 4-10 years (90 leukemic children, study group and 30 normal healthy siblings, control group) were divided into 4 groups of 30 each. Oral health status, gingival status and dental caries experience was recorded followed by un-stimulated saliva collection. Total antioxidant capacity of un-stimulated saliva was evaluated. The results depicted deterioration in oral health status, gingival status and increased dental caries experience in leukemic children. Salivary flow rate, salivary pH and total salivary antioxidant levels were lowered in leukemic children when compared with control group.

Evaluation of Growth, Carcass, Immune Response and Stress Parameters in Naked Neck Chicken and Their Normal Siblings under Tropical Winter and Summer Temperatures

The performance of naked neck and normal chicken was evaluated with respect to growth, carcass, immune, biochemical and stress parameters under winter and summer seasons to assess the suitability of naked neck birds under high temperatures in the global scenario of climate change. The growth performance was significantly () higher in naked neck chicken in the summer season. The dressing percentage was significantly () higher in naked neck birds in both winter and summer season because of reduced plumage. The thigh, giblet and feather proportion significantly () varied between naked neck and normal chickens in summer season. The humeral immune response to sheep red blood cells (SRBC), Newcastle disease vaccine (NDV) and cutaneous basophil hypersensitivity (CBH) did not show any significant differences among the chicken groups. The protein and cholesterol concentration observed was within the normal ranges. The total cholesterol levels in plasma were significantly () lower in naked neck birds in both the seasons. H:L ratio was significantly () lower in summer season indicating less stress in naked neck chicken. Basophil and eosinophil concentration was significantly () higher in normal chicken in summer. The lipid peroxidation was higher in full feathered birds under summer stress. The enzyme glutathione reductase (GR) levels were significantly higher during the summer and varied significantly () between the normal and naked neck chicken in both seasons. The results indicated that the naked neck birds performed significantly better at high ambient temperatures with respect to growth, carcass and biochemical parameters. It was concluded that the ability of the naked neck chicken to adapt to high temperatures foresees a viable option for the biological mitigation of climate change.

Feeding problems and GI dysfunction in children with asperger syndrome or pervasive developmental disorder not otherwise specified; comparison with their siblings

Objective: There are few previously published studies of feeding problems and/or gastrointestinal dysfunction among children with Asperger syndrome (AS) or Pervasive Developmental Disorder (PDD-NOS), compared to sibling controls. Study Design: On-line parent autism groups 90% from North America. Statistical analysis: Chi square and binomial logistic regression statistical analysis Results: Completed surveys were received for 64 children with AS, 44 with PDD-NOS, total = 108), and 82 normal sibling matches. Children with high-functioning autism had higher likelihood of frequent (>50% of the time) problematic feeding behaviors and gastrointestinal dysfunction, such as unusual food preferences (OR 23.9, 95% CI 7.3 - 78.7), insistence on unusual food presentation (OR 5.8, 95% CI 1.8 - 18.4), and poor mealtime social behavior (OR 16.1, 95% CI 4.1 - 64.1). These children also had higher odds of frequent constipation (OR 8.3, 95% CI 2.2 - 31.9) and fecal incontinence (OR 5.4, 95% CI 1.1 - 27.3). Nine children in AS/PDD-NOS group (4%) were believed by parent to have celiac disease (3 or 1% had intestinal biopsy), compared to 2 in control group. Conclusion: 57% of the AS/PDD-NOS group had frequent unusual food preferences vs. 5% of controls. Forty-eight percent of children with AS/PDD-NOS had frequent dislikes of new foods, compared to 6% of controls. For symptoms of specific gastrointestinal dysfunction, children with AS/PDD-NOS had higher prevalence of frequent constipation (30% vs. 4%) and fecal incontinence (22% vs. 2%).

Quantitative computed tomography is unreliable for measurement of bone mineral density in inadequately chelated adolescent patients with β-thalassemia major: A case-control study

Utility of quantitative computed tomography (QCT) for assessment of bone mineral density (BMD) in patients with thalassemia is not fully established. Majority of patients with thalassemia in India receive suboptimal iron chelation. There is paucity of data on BMD in this population. Aim was to assess BMD by lumbar QCT in adolescent patients with transfusion dependent β-thalassemia major and compare with controls. Study was conducted prospectively, over 15 months. Single energy QCT was performed through first three lumbar vertebrae. Forty-five patients were enrolled (age: 10-19 years). Thirty-eight normal siblings of patients with thalassemia patients served as controls. Forty percent patients weighed <3rd percentile, 64% were stunted, and 40% had suboptimal sexual maturity scores. Eighteen (40%) patients were on iron chelation with deferiprone. Mean serum ferritin was 2,800 ± 1,473 ng/ml. Mean BMD (mg/cu mm) of cases and controls was 194.5 ± 27.1 and 170.4 ± 28.84, respectively (P = 0.0002). The mean BMD of patients with ferritin <2,000 ng/ml and those with a higher ferritin was 181.2 ± 14.9 and 196.7 ± 25, respectively (P = 0.07). The finding of increased BMD in patients with thalassemia is in stark contrast to published reports. Patients had several risk factors for low BMD, including growth retardation, delayed puberty, and iron overload. Single energy QCT of lumbar vertebrae is not reliable for measurement of BMD in inadequately chelated patients with β-thalassemia major. The deposition of iron in bone tissue may result in increased X-ray attenuation values of trabecular bone.

P04.12: Current status of prenatal diagnosis of beta‐thalassemia in Egyptian patients: a preliminary report

Objectives: Beta-thalassemia is the commonest genetic disorder in Egypt with an estimated carrier rate of 9–10%. The aim of the study was to look at the common mutations found in our population and the impact of prenatal diagnosis on parents attitudes. Methods: Prospective analysis of cases referred for prenatal diagnosis of thalassemia at Fetal Medicine Unit, Cairo University from 2007 till 2010. Families with previous affected child had molecular assessment of their mutations as well as in the affected siblings. In future pregnancies they would be referred for invasive testing at 11–12 weeks where chorionic villous samples (CVS) were obtained or amniocentesis samples were taken for those who show at later gestations. All cases would first undergo a detailed first trimester scan including assessment of risk for chromosome abnormalities using Medison Accuvix XQ machine (Korea). Samples were analyzed for point mutations using PCR reversed hybridization techniques, in cases with absence of mutant primers direct automated DNA sequencing is performed to located the uncharacterized DNA mutation. Patients with anomalies or high risk for chromosome abnormalities are counselled for fetal karyotype accordingly. Results: Forty one cases were sampled of which 28 cases were CVS and 13 were amniocentesis. Commonest mutations seen were IVS 110, IVS 1-6, IVS 1-1. Other mutations found were IVS 2-1, IVS 2848, IVS 2-745, Codon 5, 30, 39, 27, 87, some were uncharacterized. 13 cases were affected, 5 were normal and 23 cases were carriers. Nearly half of the affected cases were homozygous and other half were compound heterozygous. No miscarriages due to procedures occurred and 1 CVS case was repeated due to inadequate sample. Conclusions: Premarital counselling and couple screening is available but under-utilized. The availability of prenatal diagnosis service changed the current attitude of couples. The hope for bone marrow transplantation seems promising from normal siblings in carrier families.

The Effects of Group Arts Therapy for the Normal Siblings of Disabled Children on Reduction of Depression

The Effects of Group Arts Therapy for the Normal Siblings of Disabled Children on Reduction of Depression

Effect of Naked Neck Gene on Immune Competence, Serum Biochemical and Carcass Traits in Chickens under a Tropical Climate

A comprehensive study was undertaken to evaluate the effect of naked neck (Na) gene on immune competence, serum biochemical parameters and carcass quality traits in three genotypes (NaNa, Nana and nana) of the naked neck chicken under a tropical climate (Southern India). Sixty day-old chicks (20 from each genotype) were selected randomly and reared under similar environmental conditions up to eight weeks of age. The cell mediated immune (CMI) response to phytohaemoagglutinin-P (PHA-P) was significantly higher (p≤0.01) in NaNa and Nana genotypes compared to nana birds. The humoral response as measured by antibody titre to sheep red blood cells (SRBC) was also significantly higher in NaNa. The total cholesterol, LDL and VLDL cholesterol levels were significantly (p≤0.01) lower whereas HDL cholesterol level was significantly higher in NaNa and Nana compared to nana genotype. The presence of Na allele significantly increased the live weight and dressing yield, and decreased the feather cover and abdominal fat. The naked neck genotypes (NaNa/Nana) performed better than the normal (nana) siblings for almost all the traits studied.

Left hemisphere regions are critical for language in the face of early left focal brain injury

A predominant theory regarding early stroke and its effect on language development, is that early left hemisphere lesions trigger compensatory processes that allow the right hemisphere to assume dominant language functions, and this is thought to underlie the near normal language development observed after early stroke. To test this theory, we used functional magnetic resonance imaging to examine brain activity during category fluency in participants who had sustained pre- or perinatal left hemisphere stroke (n = 25) and in neurologically normal siblings (n = 27). In typically developing children, performance of a category fluency task elicits strong involvement of left frontal and lateral temporal regions and a lesser involvement of right hemisphere structures. In our cohort of atypically developing participants with early stroke, expressive and receptive language skills correlated with activity in the same left inferior frontal regions that support language processing in neurologically normal children. This was true independent of either the amount of brain injury or the extent that the injury was located in classical cortical language processing areas. Participants with bilateral activation in left and right superior temporal-inferior parietal regions had better language function than those with either predominantly left- or right-sided unilateral activation. The advantage conferred by left inferior frontal and bilateral temporal involvement demonstrated in our study supports a strong predisposition for typical neural language organization, despite an intervening injury, and argues against models suggesting that the right hemisphere fully accommodates language function following early injury.

Effects of Growth Hormone and Thyroxine Replacement Therapy on Insulin Signaling in Ames Dwarf Mice

Ames dwarf (Prop1(df), df/df) mice lack growth hormone (GH), prolactin, and thyrotropin and live remarkably longer than their normal siblings. Significance of reduced activity of the somatotropic and thyroid axes during development and adulthood on longevity are unknown. Because enhanced insulin sensitivity and reduced insulin levels are among likely mechanisms responsible for increased longevity in these mutants, we compared the effects of GH and thyroxine (T4) replacement on various parameters related to insulin signaling in young and old male df/df mice. The results suggest that altered plasma adiponectin and insulin-like growth factor-1 (IGF-1) and hepatic IGF-1, insulin receptor (IR), IR substrate-1, peroxisome proliferator-activated receptor (PPAR) gamma, and PPARgamma coactivator-1 alpha may contribute to increased insulin sensitivity in Ames dwarfs. The stimulatory effect of GH and T4 treatment on plasma insulin and inhibitory effect on expression of hepatic glucose transporter-2 were greater in old than in young dwarfs. These results indicate that GH and T4 treatment has differential impact on insulin signaling during development and adulthood.

MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging

The Ames dwarf mouse is well known for its remarkable propensity to delay the onset of aging. Although significant advances have been made demonstrating that this aging phenotype results primarily from an endocrine imbalance, the post-transcriptional regulation of gene expression and its impact on longevity remains to be explored. Towards this end, we present the first comprehensive study by microRNA (miRNA) microarray screening to identify dwarf-specific lead miRNAs, and investigate their roles as pivotal molecular regulators directing the long-lived phenotype. Mapping the signature miRNAs to the inversely expressed putative target genes, followed by in situ immunohistochemical staining and in vitro correlation assays, reveals that dwarf mice post-transcriptionally regulate key proteins of intermediate metabolism, most importantly the biosynthetic pathway involving ornithine decarboxylase and spermidine synthase. Functional assays using 3'-untranslated region reporter constructs in co-transfection experiments confirm that miRNA-27a indeed suppresses the expression of both of these proteins, marking them as probable targets of this miRNA in vivo. Moreover, the putative repressed action of this miRNA on ornithine decarboxylase is identified in dwarf mouse liver as early as 2 months of age. Taken together, our results show that among the altered aspects of intermediate metabolism detected in the dwarf mouse liver--glutathione metabolism, the urea cycle and polyamine biosynthesis--miRNA-27a is a key post-transcriptional control. Furthermore, compared to its normal siblings, the dwarf mouse exhibits a head start in regulating these pathways to control their normality, which may ultimately contribute to its extended health-span and longevity.

Mesenchymal Stem Cells Convert Human Macrophages to a Novel Type of Alternatively Activated Macrophages.

Abstract 3632Poster Board III-568Mesenchymal stem cells (MSCs) are capable of modulating the immune system through interaction with a wide range of immune cells. This study investigates the hypothesis that interaction of MSCs with macrophages could play a significant role in their anti-inflammatory/immune modulatory effects. All studies were approved by IRB of University of Wisconsin School of Medicine and Public Health. MSCs were culture expanded from discarded bone marrow filters after bone marrow harvest from normal healthy sibling HLA-matched donors. We used passages -35 for our experiments. Ex vivo culture expanded MSCs were characterized by their cell surface phenotype (positive for MSC markers: CD29, CD44, CD73, CD90, and CD105; and negative for hematopoietic markers: CD31, CD34, and CD45), and their differentiation potential into bone, fat and cartilage. Monocytes were isolated from peripheral blood mononuclear cell fraction of healthy donors using CD14+ Miltenyi magnetic bead cell separation method. We cultured human CD14+ monocytes for seven days without any added cytokines to generate macrophages, and then co-cultured them for three more days with culture-expanded MSCs. We used cell surface antigen expression and intracellular cytokine expression patterns to study the immunophenotype of macrophages at the end of this co-culture period, and phagocytic assays to investigate their functional activity in vitro. Macrophages co-cultured with MSCs consistently showed high level expression of CD206, a marker of alternatively activated macrophages, in addition to being positive fro CD14 marker. Using CD1a and CD209 staining we did not detect presence of any dendritic cells either at the end of seven days culture of monocyte-derived macrophages or at the end of co-culture period. Furthermore, macrophages that were co-cultured with MSCs expressed high levels of IL-10 and low levels of IL-12, as determined by intracellular staining, typical of alternatively activated macrophages. However, macrophages co-cultured with MSCs also expressed high levels of IL-6 and low levels of TNF-α, compared to controls. Functionally, macrophages co-cultured with MSCs showed a higher level of phagocytic activity using Alexa 488-conjugated E. coli phagocytic assay. In summary we describe a novel type of human macrophage generated in vitro after co-culture with MSCs that assume an immunophenotype defined as IL-10 high, IL-12 low, IL-6 high and TNF-α low secreting cells. These MSC-educated macrophages may be a unique and novel type of alternatively activated macrophages with potentially significant role in tissue repair. Disclosures:No relevant conflicts of interest to declare.

The Effects of Growth Hormone (GH) Treatment on GH and Insulin/IGF-1 Signaling in Long-Lived Ames Dwarf Mice

The disruption of the growth hormone (GH) axis in mice promotes insulin sensitivity and is strongly correlated with extended longevity. Ames dwarf (Prop1(df), df/df) mice are GH, prolactin (PRL), and thyrotropin (TSH) deficient and live approximately 50% longer than their normal siblings. To investigate the effects of GH on insulin and GH signaling pathways, we subjected these dwarf mice to twice-daily GH injections (6 microg/g/d) starting at the age of 2 weeks and continuing for 6 weeks. This produced the expected activation of the GH signaling pathway and stimulated somatic growth of the Ames dwarf mice. However, concomitantly with increased growth and increased production of insulinlike growth factor-1, the GH treatment strongly inhibited the insulin signaling pathway by decreasing insulin sensitivity of the dwarf mice. This suggests that improving growth of these animals may negatively affect both their healthspan and longevity by causing insulin resistance.

Thinning of the Motor–Cingulate–Insular Cortices in Siblings Concordant for Tourette Syndrome

Fraternal twin studies on normal subjects have demonstrated low heritability (intra-class correlation coefficient) estimates for frontal brain regions (r = 0.43). Here we aimed to investigate the relatedness/similarity estimates of the frontal brain regions in fraternal subjects concordant for Tourette syndrome (TS). We sought to identify regional brain similarities between siblings concordant for TS as an exploratory step towards the identification of potential brain structures involved in the TS phenotype. The identified brain structures may then serve in subsequent molecular genetic and linkage studies. In addition, we regressed cortical thickness and TS clinical severity scores to assess the relation between TS clinical symptoms and cortical structures. Sixteen sibling pairs concordant for TS were scanned using a 1.5 T magnetic resonance imaging scanner (age range 10-25, mean 17.19 +/- 4.1). Brain morphology was assessed using the fully automated Civet pipeline at the Montreal Neurological Institute. TS was assessed using the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Yale Global Tic Severity Scale (YGTSS) and the Goetz Tic Scale. We report high relatedness/similarity estimates for fraternal siblings concordant for TS (r = 0.86-0.60) in the middle frontal-motor/cingulate/insular cortices. Regression analysis revealed significant negative correlations in the right insula with the YGTSS (r = -0.41, F = 6.09, P < 0.02) and the left cingulated cortex with the (CY-BOCS) (r = -0.35, F = 4.30, P < 0.05). Since previous findings have concluded that normal fraternal siblings are less alike in frontal cortices, the present findings may be attributed to TS. We speculate that the high ICC between siblings and the negative correlation between TS symptoms severity and cortical thickness measurements are related to the disturbances in the maturation of the motor-cingulate-insular cortical neural system that mediate self-regulatory processes. Such delayed maturation may consequently contribute to the development of TS by releasing motor and vocal tics from regulatory control. These findings may have important genetic implications.

High‐Throughput Near‐Infrared Reflectance Spectroscopy for Predicting Quantitative and Qualitative Composition Phenotypes of Individual Maize Kernels

ABSTRACTNear‐infrared reflectance (NIR) spectroscopy can be used for fast and reliable prediction of organic compounds in complex biological samples. We used a recently developed NIR spectroscopy instrument to predict starch, protein, oil, and weight of individual maize (Zea mays) seeds. The starch, protein, and oil calibrations have reliability equal or better to bulk grain NIR analyzers. We also show that the instrument can differentiate quantitative and qualitative seed composition mutants from normal siblings without a specific calibration for the constituent affected. The analyzer does not require a specific kernel orientation to predict composition or to differentiate mutants. The instrument collects a seed weight and a spectrum in 4–6 sec and can collect NIR data alone at a 20‐fold faster rate. The spectra are acquired while the kernel falls through a glass tube illuminated with broad spectrum light. These results show significant improvements over prior single‐kernel NIR systems, making this instrument a practical tool to collect quantitative seed phenotypes at high throughput. This technology has multiple applications for studying the genetic and physiological influences on seed traits.

Treatment reduces or stabilizes brain imaging abnormalities in patients with MPS I and II

Background The mucopolysaccharidoses (MPSs) are a family of lysosomal storage disorders caused by impaired glycosaminoglycan degradation. Characteristic brain imaging abnormalities are seen in MPS patients. This study aims to determine the effects of hematopoietic stem cell transplantation (HSCT) and/or intravenous enzyme replacement therapy (ERT) on these abnormalities. Methods A retrospective chart and brain imaging study review was conducted of MPS types I and II patients with brain magnetic resonance imaging (MRI) performed at, and following, initiation of treatment. White matter abnormalities, dilated perivascular spaces, corpus callosal abnormalities, and ventriculomegaly were scored by three independent neuroradiologists blinded to cognitive status, date of treatment initiation, and type(s) of treatment. Results Five patients were identified: three patients with MPS I and two with MPS II. Duration of follow-up ranged from 13 to 51 months. One patient had severe MPS I (genotype W402X/35del12) and received ERT followed by HSCT. The remaining patients had ERT only. The other two MPS I patients were cognitively normal siblings (genotype P533R/P533R) with an intermediate phenotype. One MPS II patient had moderate cognitive impairment without regression (genotype 979insAGCA); the other (genotype R8X) had normal cognition. There was very little inter-observer variation in MRI scoring. The greatest abnormalities for each patient were found at initial MRI. All patients, including the ERT-only patients, demonstrated improved or unchanged MRI scores following treatment. Severity of white matter abnormalities or dilated perivascular spaces did not correlate with cognitive impairment; as such, extensive pre-treatment MRI abnormalities were noted in the older, cognitively normal MPS I sibling. In comparison, his younger sibling had only mild MRI abnormalities at the same age, after receiving 4 years of ERT. Conclusions This study represents one of the first to document the CNS effects of ERT in MPS patients utilizing serial brain MR imaging studies, and raises several important observations. Brain MRI abnormalities typically become more pronounced with age; initiation of ERT or HSCT reversed or stabilized this trend in the MPS patients studied. In addition, earlier initiation of treatment resulted in decreased severity of imaging abnormalities. Possible mechanisms for these observations include improved cerebrospinal fluid dynamics, reduced central nervous system glycosaminoglycan storage via efflux through the blood–brain barrier (BBB), repair of damaged BBB, reduction in CNS inflammation, or ERT permeability through the BBB.

Relationship between the IQ of people with Prader–Willi syndrome and that of their siblings: evidence for imprinted gene effects

Genetic disorders occasionally provide the means to uncover potential mechanisms linking gene expression and physical or cognitive characteristics or behaviour. Prader-Willi syndrome (PWS) is one such genetic disorder in which differences between the two main genetic subtypes have been documented (e.g. higher verbal IQ in one vs. higher performance IQ in the other; slower than normal reaction time in one vs. normal in the other). In a population study of PWS, the IQ distribution of people with PWS was approximately normal. This raises the question of whether this distribution arose from a systematic effect of PWS on IQ (hypothesis 1) or whether it was the fortuitous result of random effects (hypothesis 2). The correlation between PWS and sibling IQ was determined in order to discriminate between the two hypotheses. In the first case we would expect the correlation to be similar to that found in the general population (0.5); in the second case it would be zero. It was found that the overall PWS-sibling IQ correlation was 0.3 but that the two main genetic subtypes of PWS differed in their familial IQ relationships. As expected, the IQs of normal siblings correlated 0.5, and this was also the case with one genetic subtype of PWS (uniparental disomy) and their siblings, while the other subtype IQ correlated -0.07 with sibling IQ. This is a potentially powerful result that gives another clue to the role of genes on chromosome 15 in the determination of IQ. It is another systematic difference between the genetic subtypes of PWS, which needs an explanation in terms of the very small genetic differences between them.