Normal Siblings Research Articles

Transcranial doppler and brain MRI in children with sickle cell disease and high hemoglobin F levels

While overt stroke and silent brain infarcts (SBI) are uncommon among Kuwaiti patients with sickle cell disease (SCD), there have been no previous transcranial Doppler (TCD) studies in this population. The main objective of this study is to determine TCD velocities in a group of Kuwaiti children with SCD and correlate same with brain magnetic resonance imaging (MRI) and angiography (MRA) findings. Forty-three steady-state, pediatric patients with SCD aged 10.1 ± 3.9 years (21 SS, 19 Sβ(0)Thal, and 3 SD) were studied. Twenty-six age-matched, normal siblings of the patients served as controls. TCD was performed using a General Electric (GE), Vivid 3 equipment and MRI/MRA with a GE Signa Excite HD 1.5 Tesla magnet. Complete blood count was with an electronic counter and Hb quantitation with cation-exchange high performance liquid chromatography (HPLC). The mean time-averaged mean of the maximum velocity (TAMV) was significantly higher in the SCD group than the controls, but was normal (<170 cm/second) in all. The mean values were comparable among the SS and Sβ(0)thal groups. Five (11.1%) patients had SBI and all were between 12 and 16 years of age. There was no significant difference of TAMV in this group compared to those without infarcts. No patient showed evidence of stenosis or any other abnormalities in the circle of Willis vessels. The mild phenotype among Kuwaiti patients with SCD is reflected in normal TCD velocities and a low prevalence of SBI in children with the disease.

Cloning Changes the Response to Obesity of Innate Immune Factors in Blood, Liver, and Adipose Tissues in Domestic Pigs

The objective of this study was to evaluate the usefulness of cloned pigs as porcine obesity models reflecting obesity-associated changes in innate immune factor gene expression profiles. Liver and adipose tissue expression of 43 innate immune genes as well as serum concentrations of six immune factors were analyzed in lean and diet-induced obese cloned domestic pigs and compared to normal domestic pigs (obese and lean). The number of genes affected by obesity was lower in cloned animals than in control animals. All genes affected by obesity in adipose tissues of clones were downregulated; both upregulation and downregulation were observed in the controls. Cloning resulted in a less differentiated adipose tissue expression pattern. Finally, the serum concentrations of two acute-phase proteins (APPs), haptoglobin (HP) and orosomucoid (ORM), were increased in obese clones as compared to obese controls as well as lean clones and controls. Generally, the variation in phenotype between individual pigs was not reduced in cloned siblings as compared to normal siblings. Therefore, we conclude that cloning limits both the number of genes responding to obesity as well as the degree of tissue-differentiated gene expression, concomitantly with an increase in APP serum concentrations only seen in cloned, obese pigs. This may suggest that the APP response seen in obese, cloned pigs is a consequence of the characteristic skewed gene response to obesity in cloned pigs, as described in this work. This should be taken into consideration when using cloned animals as models for innate responses to obesity.

Cognitive subtypes in non-affected siblings of schizophrenia patients: characteristics and profile congruency with affected family members

Although cognitive subtypes have been suggested in schizophrenia patients, similar analyses have not been carried out in their non-affected siblings. Subtype classification may provide more insight into genetically driven variation in cognitive function. We investigated cognitive subtypes in siblings. Cluster analyses were performed in 654 non-affected siblings, on a cognitive battery that included tests of attention, intellectual function and episodic memory. Resulting subtypes in the siblings were analyzed for cognitive, demographic and clinical characteristics and compared with those of their probands. Three sibling subtypes of cognitive function were distinguished: 'normal', 'mixed' and 'impaired'. Normal profile siblings (n = 192) were unimpaired on cognitive tests, in contrast to their proband (n = 184). Mixed profile siblings (n = 228) and their probands (n = 222) had a more similar performance pattern. Impaired profile siblings had poorer functional outcomes (n = 234) and their profile was almost identical to that of their proband (n = 223). Probands with cognitively impaired siblings could be distinguished from other schizophrenia patients by their own cognitive performance. They also had poorer clinical characteristics, including achievement of symptomatic remission. Unaffected siblings of patients with schizophrenia are heterogeneous with respect to cognitive function. The poorer the cognitive profile of the sibling, the higher the level of correspondence with the proband. The sibling's cognitive subtype was predictive for disease course in the proband. Distinguishing cognitive subtypes of unaffected siblings may be of relevance for genetic studies.

Investigation ofNRXN1deletions: Clinical and molecular characterization

Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1.

Cutaneous dyspigmentation in patients with ganglioside GM3 synthase deficiency

Ganglioside GM3 synthase deficiency is a rare autosomal recessive metabolic disorder characterized by infantile onset of severe irritability and epilepsy, failure to thrive, developmental stagnation, and cortical blindness. Because of the lack of easily recognizable dysmorphism and specific neurologic manifestations, identification of patients with this condition is extremely challenging. Here we report on previously undescribed pigmentary abnormalities in 20 of 38 patients with GM3 synthase deficiency. All 20 of the patients showed freckle-like hyperpigmented macules, ranging in size from 2 to 5 mm in diameter and usually found bilaterally on the extremities, especially the dorsal aspects of the hands and feet. Seven of these patients also had depigmented macules and patches, especially on the face and extremities. These cutaneous changes were asymptomatic, and were not associated with the severity or particular phenotype of the neurologic disease. They became visible only after the first years of life with an increased incidence with advancing age. These distinct pigmentary features are not identified in 54 normal siblings, and may provide a useful clue in identifying patients with ganglioside metabolic disorders.

658 – Patients' perceptions of family structure and support in schizophrenia

Introduction The family is the first universal institutional system that is necessary for human survival and development. The relationship between family members determine predisposition to illness and health. Objective The purpose of this study is to examine differences in perception between patients with schizophrenia and their normal siblings with regard to family functioning and support. Methods In this cross sectional study fifty schizophrenic patients admitted in 2 psychiatric hospital in shiraz and their 50 normal siblings were participated. A demographic questionnaire, The Perceived Social Support-Family Scale and Family Assessment Device were completed by participants. Result Significant differences were noted in perception of family structure and family support between patients with schizophrenia and their normal siblings (p = 0.001). Score of general family function, problem solving and emotional responsiveness in patients with schizophrenia were significantly lower than their normal siblings (P Conclusions Patients with schizophrenia perceive their family structure and support more negatively than their sibling. This difference was more significant in problem solving and emotional responsiveness dimensions. Family psycho education and therapy in patients with schizophrenia must consider these aspects of family dysfunction.

Effect of Growth Hormone and Calorie Restriction on the Expression of Antioxidant Enzymes in the Liver and Kidney of Growth Hormone Receptor Knockout Mice.

Caloric restriction (CR) can delay aging and prolong life span and these actions may be related to reduced oxidative damage. Mice with disrupted growth hormone (GH) receptor/binding protein knockout (GHRKO) live significantly longer than their normal siblings. Therefore, it is of interest to examine the effects of chronic CR on hepatic and renal antioxidant enzymes as well as lipid peroxidation (LP) as an oxidative stress marker in GHRKO mice. Female GHRKO and normal mice were either fed ad libitum (AL) or subjected to 30% CR starting at 2 months of age and examined at the age of 9 months. In the liver, catalase (CAT) activity was significantly increased in GHRKO-AL as compared to normal control -AL animals. CR reduced CAT activity in both GHRKO and normal phenotypes. Cu/Zn superoxide dismutase (SOD1) activity was also higher in GHRKO-AL as compared to normal-AL mice. However, CR reduced SOD1 activity in GHRKO mutants. Glutathione peroxidase (GPx) activity was significantly decreased in GHRKO-AL mice and further reduced in GHRKO-CR group of animals. CR significantly increased LP in GHRKOs while its activity was not altered in GHRKO-AL group of mice. In the kidney, CAT activity was lower in GHRKO-AL as compared to normal-AL, however CR did not induce any significant effect in both phenotypes. Similarly, SOD1 levels were significantly lower in GHRKO than in normal mice. GPx expression was higher in GHRKO-AL as compared to control-AL. CR reduced GPx activity in GHRKO mice but increased it in controls as compared to their AL counterparts. There was no difference in LP expression between GHRKO-AL and normal-AL mice. However, CR significantly increased its levels in both phenotypes. Although these findings do not support the hypothesis that CR would increase the capacity of ROS defense mechanisms in GHRKO mice by increasing antioxidant enzymes levels, they do agree with some of the reported effects of CR on their expression. We suspect that GH resistance and CR may affect aging by different mechanisms and if CR delays aging in GHRKO animals it is not due to changes in the activity of antioxidant enzymes.

Do Ames dwarf and calorie-restricted mice share common effects on age-related pathology?

Since 1996, aging studies using several strains of long-lived mutant mice have been conducted. Among these studies, Ames dwarf mice have been extensively examined to seek clues regarding the role of the growth hormone/insulin-like growth factor-1 axis in the aging process. Interestingly, these projects demonstrate that Ames dwarf mice have physiological characteristics that are similar to those seen with calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, this introduces the question of whether Ames dwarf and calorie-restricted (CR) mice have an extended lifespan through common or independent pathways. To answer this question, we compared the disease profiles of Ames dwarf mice to their normal siblings fed either ad libitum (AL) or a CR diet. Our findings show that the changes in age-related diseases between AL-fed Ames dwarf mice and CR wild-type siblings were similar but not identical. Moreover, the effects of CR on age-related pathology showed similarities and differences between Ames dwarf mice and their normal siblings, indicating that calorie restriction and Ames dwarf mice exhibit their anti-aging effects through both independent and common mechanisms.

1979 – Cognitive subtypes in non-affected siblings of patients with schizophrenia: Characteristics and profile congruency with affected family member

Although cognitive subtypes have been suggested in schizophrenia patients, similar analyses have not been carried out in their unaffected siblings. Subtype classification may provide more insight into genetically driven variation in cognitive function. To investigate cognitive subtypes in siblings. Cluster analyses were performed in 654 unaffected siblings, on a cognitive battery that included tests of attention, intellectual function, and episodic memory. Resulting subtypes in the siblings were analyzed for cognitive, demographical, and clinical characteristics and compared with that of their proband. Three sibling subtypes of cognitive function were distinguished: ‘normal’, ‘mixed’, and ‘impaired’. Normal profile siblings (n= 192) were unimpaired on cognitive tests, in contrast to their proband (n= 184). Mixed profile siblings (n= 228) and their probands (n= 222) had a more similar performance pattern. Impaired profile siblings had poorer functional outcomes (n= 234), and their profile was almost identical to that of their proband (n= 223). Probands with cognitively impaired siblings could be distinguished from other schizophrenia patients by their own cognitive performance. They also had poorer clinical characteristics, including achievement of symptomatic remission. Unaffected siblings of patients with schizophrenia are heterogeneous with respect to cognitive function. The poorer the cognitive profile of the sibling, the higher the level of correspondence with the proband. The sibling's cognitive subtype was predictive for disease course in the proband. Distinguishing cognitive subtypes of unaffected siblings may be of relevance for genetic studies.

Dietary Practice and Physical Activity in Children with Down Syndrome and Their Siblings in Saudi Arabia

Background: Feeding difficulties and inappropriate nutrition are common problems among children with Down Syndrome (DS). Objective: The aim of this study is to investigate the dietary practice and physical activity among children with DS. Methodology: The study groups were pre-pubertal DS boys and girls, aged 5 to 12 years clinically and cytogenetically proven to be suffering from DS. Healthy siblings, closest in age to the DS children were used as a control group. Breast feeding, eating difficulties, fast food intake, and physical activity were measured for both groups. Results: During infancy period, 36.4% of the DS children were bottle fed, compared to only 5.5% of the normal siblings. Nearly half of the breast-fed DS children were fed for duration of less than 6 months. The percentage of the DS children experiencing dietary difficulties is significantly higher compared to the siblings. Concerning physical activity, 73.1% of DS children did not exercise as compared to 44.2% of the control siblings. Conclusion: Controlling feeding practices and encouraging Down syndrome children to participate in physical activity either through support from parents or through designing special programs and facilities and are two avenues that can be used for obesity prevention.

High Dose Sargramostim (GM-CSF) Combined with IV Plerixafor for the Mobilization of Peripheral Blood Stem Cells (PBSC) From Normal HLA-Matched Allogeneic Sibling Donors Results in Hypercoagulability

AbstractAbstract ▪4095▪This icon denotes a clinically relevant abstractWe report an interim safety analysis of a phase II trial evaluating GM-CSF and plerixafor for the mobilization of peripheral blood stem cells in normal HLA-matched allogeneic sibling donors, performed due to unexpected toxicity observed with this combination.We have previously reported a lower than expected incidence of acute GVHD in recipients of sibling donor allogeneic HSC transplants mobilized with GM-CSF alone (Devine et al. Blood), as well as similar results using a mouse model of GVHD, in which increased Tregs as well as putative myeloid derived suppressor cells (MDSCs) were observed. However, the use of GM-CSF as a single agent for stem cell mobilization has been limited by an unacceptably high (∼30%) incidence of failure to mobilize and collect adequate stem cell numbers in a single 20 L apheresis procedure. Based upon observed synergy between GM-CSF and plerixafor for HSC mobilization in mice, we hypothesized that this combination in humans might overcome the low stem cell yields observed with either agent alone and result in a PBSC product enriched in Tregs and MDSCs that could reduce GvHD after transplant.A phase II trial was designed, which is ongoing, to evaluate the efficacy of GM-CSF, initially at a dose of 10 mcg/kg SC daily × 5 – 6 days, and plerixafor 320 mcg/kg IV daily starting on day 5, with the primary objective of reduction in the day 1 mobilization failure rate from 33% to <10%, and a planned enrollment of 17 patients. To date 14 donors have been mobilized and 13 recipients transplanted. Initial mobilization with GM-CSF 10mcg/kg was complicated by a high incidence (4/4 donors) of unexpected catheter and IV tubing-associated thrombosis at the time of apheresis, requiring line revision, and in some cases placement of central venous access. The trial was halted for an interim safety analysis, resulting in reduction in the dose of GM-CSF to 5 mcg/kg SC daily × 5–6 days. Since this dose reduction, no significant problems with thrombosis precluding a full 20 L apheresis have been observed among 13 subsequent donors. No evidence of systemic thrombosis has been observed in any donors with this combination. The most common adverse effects have included first dose reaction of severe acute onset bone pain (only in 10mcg/kg dose of GM-CSF), diarrhea, nausea, fatigue, bone pain, injection site reaction, and cardiovascular disorders including bradycardia and transient hypotension. There have been no grade 3–4 adverse events related to mobilization.A preliminary analysis of mobilization in 10 donors with a 20 L minimum apheresis volume demonstrated a failure to collect ≥2×106 CD34/kg recipient weight in 1/10 donors. The mean CD34/Kg recipient weight collected from these donors was 5.25 × 106 CD34/Kg. Among donors who failed to undergo a minimum 20 L apheresis collection, only 2/4 required a second day of aphereis to achieve a collection goal of 2 × 106 CD34/kg, and no donor failed to reach this goal after two days of apheresis. CD34 cell mobilization peaked at 4–9 hours after plerixafor infusion with mean CD34/uL = 38 at 6 hours (SD = 10.35).No recipients had primary graft failure. The median time to neutrophil engraftment was 13 days (range 11 – 15), and median time to platelet engraftment was 24 days (range 19 – 28). All evaluable recipients had 100% peripheral blood donor chimerism at day 30 post transplant. One recipient developed secondary graft failure at day +51, and required reinfusion of G-CSF-mobilized stem cells from his initial donor.The incidence of grades II–IV and III-IV acute GvHD, respectively, among recipients of a GM+P mobilized product was 45% and 18%. The incidence of cGvHD was not evaluable due to the short duration of follow-up. CMV viremia incidence was 38%.Peripheral blood from donors was collected for correlative studies including phenotyping and functional studies, but has not yet been analysed. Further studies evaluating the hypercoagulability associated with higher doses of GM-CSF are ongoing.GM-CSF combined with IV plerixafor is a feasible combination. Higher doses of GM-CSF (10mcg/kg) are associated with first dose reactions, hypercoaguability and catheter thrombosis. Disclosures:Schroeder:Sanofi Oncology/Genzyme: Research Funding. DiPersio:genzyme: Honoraria.

IPS cell modeling of Best disease: insights into the pathophysiology of an inherited macular degeneration

Best disease (BD) is an inherited degenerative disease of the human macula that results in progressive and irreversible central vision loss. It is caused by mutations in the retinal pigment epithelium (RPE) gene BESTROPHIN1 (BEST1), which, through mechanism(s) that remain unclear, lead to the accumulation of subretinal fluid and autofluorescent waste products from shed photoreceptor outer segments (POSs). We employed human iPS cell (hiPSC) technology to generate RPE from BD patients and unaffected siblings in order to examine the cellular and molecular processes underlying this disease. Consistent with the clinical phenotype of BD, RPE from mutant hiPSCs displayed disrupted fluid flux and increased accrual of autofluorescent material after long-term POS feeding when compared with hiPSC-RPE from unaffected siblings. On a molecular level, RHODOPSIN degradation after POS feeding was delayed in BD hiPSC-RPE relative to unaffected sibling hiPSC-RPE, directly implicating impaired POS handling in the pathophysiology of the disease. In addition, stimulated calcium responses differed between BD and normal sibling hiPSC-RPE, as did oxidative stress levels after chronic POS feeding. Subcellular localization, fractionation and co-immunoprecipitation experiments in hiPSC-RPE and human prenatal RPE further linked BEST1 to the regulation and release of endoplasmic reticulum calcium stores. Since calcium signaling and oxidative stress are critical regulators of fluid flow and protein degradation, these findings likely contribute to the clinical picture of BD. In a larger context, this report demonstrates the potential to use patient-specific hiPSCs to model and study maculopathies, an important class of blinding disorders in humans.

English

In this study, we recorded and analyzed the growth data of 40 children with acute meningitis (age 5.8 &plusmn; 3.1 years) for a year or more after treatment, and compared them with their age and sex matched healthy siblings (n = 100). None of the patients had any meningitis complications that could affect linear growth. None of them were underweight and/or stunted for one year or more after treatment. The height standard deviation scores (HtSDS) of patients decreased significantly from -0.06 &plusmn; 0.95 at the onset of meningitis to -0.46 &plusmn; 1 after a year or more of follow-up and were significantly lower than those for their normal siblings (controls) (0.31 &plusmn; 0.5). Fifteen out of the 40 patients had decreased HtSDS &gt; -0.5, while 3 had decreased HtSDS &gt; -1 after &gt; 1 year of follow-up. The body mass index (BMI) of patients significantly increased after 1 year or more of the acute attack, but did not differ from the BMI for the controls. One patient and none of the controls had BMISDS &gt; 2 at presentation. Furthermore, 5/40 patients and 2/100 children from the control group had BMISDS &gt; 2 after 1 year or more of follow-up. The HtSDS decreased and BMI increased significantly in both groups with septic (n = 10) and aseptic meningitis (n = 30) with no significant difference among the 2 groups. It was concluded that long term growth delay and overweight and/or obesity appear to be risk factors following an acute attack of both septic and aseptic meningitis. &nbsp; Key words:&nbsp;Meningitis, pituitary dysfunction, body mass index, growth.

550 Growth Assessment in Children after Acute Septic Versus Aseptic Menengitis: a Controlled Study

We recorded and analyzed the growth data of 40 children with acute meningitis (age 5.8 +/– 3.1 years) for a year or more after treatment and compared them with their...

Multiple loci influencing hippocampal degeneration identified by genome scan

Large genome-wide association studies (GWASs) have identified many novel genes influencing Alzheimer disease (AD) risk, but most of the genetic variance remains unexplained. We conducted a 2-stage GWAS for AD-related quantitative measures of hippocampal volume (HV), total cerebral volume (TCV), and white matter hyperintensities (WMH). Brain magnetic resonance imaging measures of HV, TCV, and WMH were obtained from 981 Caucasian and 419 African American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer's Genetic Epidemiology) Study, and from 168 AD cases, 336 individuals with mild cognitive impairment, and 188 controls in the Alzheimer's Disease Neuroimaging Initiative Study. A GWAS for each trait was conducted in the 2 Caucasian data sets in stage 1. Results from the 2 data sets were combined by meta-analysis. In stage 2, 1 single nucleotide polymorphism (SNP) from each region that was nominally significant in each data set (p < 0.05) and strongly associated in both data sets (p < 1.0 × 10(-5)) was evaluated in the African American data set. Twenty-two markers (14 for HV, 3 for TCV, and 5 for WMH) from distinct regions met criteria for evaluation in stage 2. Novel genome-wide significant associations (p < 5.0 × 10(-8)) were attained for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set. Associations with different SNPs in the same gene (p < 1 × 10(-5) in Caucasians and p < 2.2 × 10(-4) in African Americans) were also observed for PICALM with HV, SYNPR with TCV, and TTC27 with WMH. Our study demonstrates the efficacy of endophenotypes for broadening our understanding of the genetic basis of AD.

Salivary antioxidants and oral health in children with autism

Individuals with autism vary widely in abilities, intelligence, and behaviours. Autistic children have preferences for soft and sweetened food making them susceptible to caries. A wide spectrum of medical and behavioural symptoms is exhibited by children with autism, which makes routine dental care very difficult in them. Mental retardation is evident in approximately 70% of individuals with autism and most psychiatric disorders including autism are associated with increased oxidative stress. ObjectivesTo evaluate the oral health status of children with autism and to determine the salivary pH and total salivary antioxidant concentration (TAC). Materials and methods101 subjects with autism between age group of 6 and 12 year were part of the study and 50 normal healthy siblings of same age group were taken as control group. Oral health status was analysed using oral hygiene index-simplified and dentition status index. The salivary total anti-oxidant level was estimated using phosphomolybdic acid using spectrophotometric method and the salivary pH using the pH indicating paper. The results were statistically analyzed using Mann–Whitney U test. ResultsA statistically very highly significant difference was seen in the mean oral hygiene index scores (autistic group – 1.2 and control group – 1, P<0.001) and the mean salivary total antioxidant concentration (autistic group – 5.7μg/ml and control group – 38μg/ml, P<0.001). No statistical significant difference was observed in the dental caries status and the salivary pH of autistic group and the control group. ConclusionsSimilar dental caries status was observed in children with autism and their healthy normal siblings. Oral hygiene was poor in children with autism whereas the Salivary TAC was significantly reduced in autistic children.

Salivary Sialic Acid Levels and Dental Health In Children with Congenital Heart Disease

Congenital cardiac disease is one of the most common developmental anomalies in children. Higher caries prevalence and gingivitis compared to healthy children have been shown in children with congenital heart disease which has a significant implication in the medical care of these patients associated with bacteraemia and endocarditis. Sialic acids being terminal sugar components and marker of chronic inflammatory response are found to be present at higher levels in children with poor oral health status. So the present study aimed to evaluate the oral health status and salivary sialic acid levels among the children with congenital heart disease and normal healthy siblings. A total of 71 children with heart diseases aged 6-10 years attending various heart institutes were examined for oral hygiene status, gingival status and dental caries status by using modified WHO oral assessment form. A case-matched control group of 50 children were also examined. Salivary flow rate, pH and sialic acid levels were measured after saliva collection. The results were subjected to Unpaired t test and Pearson's Correlation Coefficient Test. The salivary pH, salivary flow rate, dental caries status, oral hygiene and the gingival status were significantly compromised with a positive correlation with the sialic acid levels in saliva, leading to increased treatment needs in the study group. Therefore the amount of sialic acid in the saliva can be a useful index of the severity of oral disease.

Serum response factor regulates bone formation via IGF-1 and Runx2 signals

Serum response factor (SRF) plays vital roles in numerous cellular processes; however, the physiological function of SRF in skeletal tissue remains unknown. In several organ systems, SRF regulates the expression of insulin-like growth factor-1 (IGF-1), which is crucial for normal development of mineralized skeleton and bone remodeling throughout life. Here, we show that conditional deletion of SRF in osteoblasts by osteocalcin-Cre generated viable mice with normal body size and body weight. Compared with normal siblings, osteoblast-specific SRF-deficient adult mice exhibited a marked decrease in bone mineral density and bone formation rate. Deletion of SRF in primary mouse calvarial osteoblasts reduced cell differentiation and mineralization in vitro. This was accompanied by a decrease in IGF-1 expression and secretion. Addition of IGF-1 in the culture media enhanced osteoblast differentiation in control cells and partially restored the mineralization defect of SRF-deficient cells, supporting an important role of SRF in regulating IGF-1 and IGF-1-mediated osteoblast differentiation. IGF-1-induced Akt activation was inhibited in SRF-deficient calvarial cells and enhanced in the SRF overexpressed cells. In addition, SRF deficiency decreased the transcriptional activity of Runx2, the key transcription factor for osteogenesis. Overexpression of SRF induced Runx2 transactivity in control cells and restored Runx2 transactivity in the SRF-deficient cells. Taken together, we conclude that SRF is important for IGF-1-induced osteoblast differentiation and mineralization via regulating IGF-1 expression and Runx2 transactivity.

A missense mutation (p.G274R) in gene ASPA causes Canavan disease in a Pakistani family

Canavan disease (OMIM 271900) is an autosomal recessive lethal neurodegenerative disorder characterized by spongy degeneration of the brain. A highly consanguineous Pakistani family with Canavan disease was enrolled on the basis of diagnosis. All the affected individuals have mental retardation, megalocephaly and degradation of motor skills, poor head control, partial vision loss, weakness of the muscles and raised urinary concentration of N-acetyl aspartic acid in the urine. Blood samples were collected from affected as well as normal siblings and processed for DNA purification. Linkage analysis was performed by typing three short tandem repeat markers D17S1583 (7.19cM), D17S1828 (10.02cM) and D17S919 (14.69cM) for an already-reported gene/locus ASPA at chromosome 17p13.2 causing Canavan disease. During linkage analysis, all the affected individuals were homozygous for short tandem repeat markers while the normal siblings were heterozygous showing co-segregation of the disease. Gene ASPA (NM_000049) was undertaken to sequence for mutation analysis. As a result of sequence analysis, we found missense substitution 740A→G (p.G274R) in exon 6 of gene ASPA. To our knowledge, this is the first report about Canavan disease on a Pakistani family.

Linear growth in relation to the circulating concentration of insulin-like growth factor-I in young children with acyanotic congenital heart disease with left to right shunts before versus after surgical intervention.

Objectives:The aim was to determine the degree of linear growth retardation of patients with congenital acyanotic heart disease at presentation and the magnitude of catch-up growth, if any, in relation to their echocardiographic changes and insulin-like growth factor- I (IGF-I) concentration before versus after surgical intervention.Materials and Methods:This prospective study recorded the anthropometric data and measured the circulating IGF-I, free thyroxin (FT4), and thyrotropin (TSH) of 27 infants and children with congenital acyanotic heart disease with left to right shunt (10 with VSD, 8 with ASD, 9 PDA) without heart failure, or severe pulmonary hypertension, before and 12 months or more after surgical or catheter intervention. Eighty normal age and sex- matched normal siblings of these patients were included as controls for the auxologic data.Results:At presentation, patients’ mean age = 35.6 ± 26 months, height SDS (HtSDS) = -1.6 ± 1.1, and body mass index (BMI) = 15.1 ± 2.5. They were significantly shorter and with lower BMI compared to normal controls (HtSDS = 0.25 ± 0.3, BMI = 16.4 ± 1.5). One year or more after catheter or surgical treatment, the HtSDS and BMI increased significantly in patients to –0.55 ± 0.9 and 15.9 ± 1.5, respectively). IGF-I levels increased from 46.8 ± 29 mcg/L before to 77.3 ± 47.6 mcg/L after intervention. No significant change has been detected in circulating FT4 or TSH concentrations. The HtSDS after treatment was correlated with the IGF-I concentration (r = 0.804, P < 0.001). The change in the HtSDS after intervention was correlated significantly with BMI (r = 0.594, P 0.001) and negatively with age (r = -0.52, P< 0.01). The shunt size was correlated negatively with BMI and HtSDS before intervention (r = -0.35, P < 0.01 and 0.01 and r = -0.461, P < 0.05, respectively). GVSDS after intervention surgery was correlated with BMI after intervention (r = 0.495, P < 0.001) and negatively with the age at operation (r = -0.683, P < 0.001).Conclusions:In congenital acyanotic heart diseases, early surgical interference and weight gain have beneficial effect on postoperative growth spurt. This catch-up growth appears to be mediated through activation of the GH/IGF-I system and suggests an important role of increasing BMI (an indicator of nutrition) as an imperative factor.