Role of assessment tests in the stability of intelligence scoring of pre-school children with uneven/delayed cognitive profile.

BACKGROUND: As part of an ongoing clinical service programme for pre-school children with developmental delay in an Asian developing country, we analysed the effect of three assessment tests, that is, Bayley Scale of Infant Development-II, Leiter International Performance Scale - Revised and Wechsler Preschool and Primary Scale of Intelligence - Revised - Chinese, on the stability of intelligence quotient (IQ) of children from pre-school through early childhood. METHODS: The participants were 313 Taiwanese pre-school children with uneven or delayed cognitive profile and they were followed through early childhood. IQ stability was explored by different tests and among children of different clinical diagnosis: 168 children with non-autistic intellectual disability, 73 children with autism spectrum disorder, 58 children with mixed receptive-expressive language disorder and 14 children of other heterogeneous diagnoses. Stability of scores was evaluated using the r-squared for Pearson's coefficients to see the correlation between initial IQ (IQ1) and follow-up IQ (IQ2). Multiple linear regressions were also applied to see whether IQ1 had predictive ability for IQ2 and test-test difference in the total 313 children and each diagnostic subgroup. RESULTS: Results revealed that mean IQ1 was 65.8 ± 15.4 while mean IQ2 was 73.2 ± 17.9 for the total 313 children. The IQs were stable across an average follow-up duration of 38.6 ± 22.1 month from pre-school into early childhood. Patterns of positive correlations between IQ1 and IQ2 were noted by all the tests (r-squared = 0.43-0.5, all P < 0.001) and in the majority of diagnostic subgroups. Multiple regressions analysis also revealed that IQ1 could predict IQ2 significantly in all the tests (all P < 0.001). DISCUSSION: After careful choice of appropriate initial test, stability of IQ in children with developmental delay was noted from pre-school through early childhood. In addition, the translated version of cognitive assessment was valid for the required context of an Asian developing country. With the current emphasis on early identification and intervention for pre-school children with developmental delay, this information bears merit in clinical practice.

Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy.

OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of hydroxyurea (HU) in spinal muscular atrophy (SMA) in a randomized, double-blind, placebo-controlled trial. METHODS: Twenty-eight patients with type 2 SMA and 29 patients with type 3 SMA were randomly assigned (2:1) to receive HU or matching placebo for 18 months. HU was initiated at 10 mg/kg/day with an 8-week titration to 20 mg/kg/day. Subjects were assessed at baseline (T0) and monthly for the first 2 months (T1-T2) and then every 2 months throughout treatment (T3-T10) and posttreatment periods (T11-T13). The primary outcome measures were the Gross Motor Function Measure (GMFM), Manual Muscle Test (MMT), and serum full-length survivor motor neuron (flSMN) mRNA. The secondary outcome measures were Modified Hammersmith Functional Motor Scale and forced vital capacity (FVC). RESULTS: Fifty-five patients completed this trial, which lasted from March 2007 to June 2009. Except for neutropenia, we found no differences in adverse events between the 2 groups. Compared with the placebo group, the HU group had -1.88 for GMFM (p = 0.11), -0.55 for MMT (p = 0.49), and 2.17 for flSMN mRNA (p = 0.13). Similarly, we found no difference in mean improvement of the secondary endpoints. Both groups had a trend toward a decline in FVC with little change in strength and motor function. CONCLUSION: Under the current regimen and schedule, HU brought about no improvement in patients with type 2 and 3 SMA, and its main side effect was neutropenia. CLASSIFICATION OF EVIDENCE: This trial provides Class I evidence that HU 20 mg/kg/day does not effectively treat SMA.

Regulation of cytokine expression in human plasmacytoid dendritic cells by prostaglandin I2 analogues.

Plasmacytoid dendritic cells (pDCs) are critical in controlling adaptive immunity, but the mechanisms governing cytokine expression remain incompletely defined. Analogues of prostaglandin (PG)I(2), such as iloprost, can modulate functions of myeloid dendritic cells, but their involvement in the regulation of human pDCs remains unknown. To this end, the regulatory role of PGI(2) analogues on cytokine expression in pDCs was investigated. Circulating pDCs were magnetically sorted with BDCA-4 cell isolation kits from human peripheral blood mononuclear cells and treated with varying concentrations of iloprost with or without the addition of Toll-like receptor agonists, or an I prostanoid (IP) receptor antagonist, CAY10449. The levels of tumour necrosis factor (TNF)-alpha, interferon (IFN)-alpha and interleukin (IL)-10 were measured by ELISA. Iloprost induced IL-10 expression, but suppressed CpG oligodeoxynucleotide- (or imiquimod-) induced TNF-alpha and IFN-alpha production in pDCs. This effect was reversed by the addition of CAY10449. Forskolin, a cyclic adenosine monophosphate activator, conferred a similar modulating effect to that noted in iloprost-treated pDCs, although a higher concentration of forskolin was required to exert the same effect. Iloprost enhanced interleukin-10 and suppressed Toll-like receptor-mediated tumour necrosis factor-alpha and interferon-alpha production of human plasmacytoid dendritic cells via the I prostanoid receptor and, in part, the cyclic adenosine monophosphate pathway.

Molecular profiling reveals diversity of stress signal transduction cascades in highly penetrant Alzheimer's disease human skin fibroblasts.

The serious and growing impact of the neurodegenerative disorder Alzheimer's disease (AD) as an individual and societal burden raises a number of key questions: Can a blanket test for Alzheimer's disease be devised forecasting long-term risk for acquiring this disorder? Can a unified therapy be devised to forestall the development of AD as well as improve the lot of present sufferers? Inflammatory and oxidative stresses are associated with enhanced risk for AD. Can an AD molecular signature be identified in signaling pathways for communication within and among cells during inflammatory and oxidative stress, suggesting possible biomarkers and therapeutic avenues? We postulated a unique molecular signature of dysfunctional activity profiles in AD-relevant signaling pathways in peripheral tissues, based on a gain of function in G-protein-coupled bradykinin B2 receptor (BKB2R) inflammatory stress signaling in skin fibroblasts from AD patients that results in tau protein Ser hyperphosphorylation. Such a signaling profile, routed through both phosphorylation and proteolytic cascades activated by inflammatory and oxidative stresses in highly penetrant familial monogenic forms of AD, could be informative for pathogenesis of the complex multigenic sporadic form of AD. Comparing stimulus-specific cascades of signal transduction revealed a striking diversity of molecular signaling profiles in AD human skin fibroblasts that express endogenous levels of mutant presenilins PS-1 or PS-2 or the Trisomy 21 proteome. AD fibroblasts bearing the PS-1 M146L mutation associated with highly aggressive AD displayed persistent BKB2R signaling plus decreased ERK activation by BK, correctible by gamma-secretase inhibitor Compound E. Lack of these effects in the homologous PS-2 mutant cells indicates specificity of presenilin gamma-secretase catalytic components in BK signaling biology directed toward MAPK activation. Oxidative stress revealed a JNK-dependent survival pathway in normal fibroblasts lost in PS-1 M146L fibroblasts. Complex molecular profiles of signaling dysfunction in the most putatively straightforward human cellular models of AD suggest that risk ascertainment and therapeutic interventions in AD as a whole will likely demand complex solutions.

Prenatal morphine alters the synaptic complex of postsynaptic density 95 with N-methyl-D-aspartate receptor subunit in hippocampal CA1 subregion of rat offspring leading to long-term cognitive deficits.

Infants who are passively exposed to morphine or heroin through their addicted mothers usually develop neurobiological changes. The postsynaptic density 95 (PSD-95) protein, a submembranous cytoskeletal specialization, is dynamically linked with N-methyl-d-aspartate receptors (NMDARs) to form a synaptic complex in postsynaptic neurons. This complex serves important neurobiological functions, including mammalian learning and memory. However, the effects of prenatal morphine exposure on this synaptic complex are not well understood. In this study, we determined whether prenatal morphine exposure altered the synaptic complex association between PSD-95 and three major NMDAR subunits (NR1, NR2A, and NR2B), at the mRNA and protein levels, within the hippocampal CA1 subregion (an important integration area for mammalian learning and memory) of rat offspring along with the performance of long-term cognitive functions. Sprague-Dawley rat offspring from morphine-addicted mothers were studied at a younger age (postnatal day 14; P14) and at an older age (P45). Subsequently, an eight-arm radial maze task was applied to analyze the working and cued reference memory in such offspring (P45). The real-time polymerase chain reaction results showed that prenatal morphine exposure caused significant decreases in mRNA levels of the PSD-95 and three NMDAR subunits (NR1, NR2A, and NR2B) in offspring (P14 and P45). Similarly, at the protein level, immunoblotting showed that decreased whole levels of PSD-95 and NMDAR subunits were seen in offspring subjected with prenatal morphine. Furthermore, the protein interaction of the synaptic complex between the PSD-95 and NMDAR subunit, as indicated by coimmunoprecipitation, was less in prenatal morphine samples than in vehicle controls (P14 and P45). The prenatal morphine group also showed poorer performance for an eight-arm radial maze task than the vehicle-control group. These results are particularly important for a better understanding of certain opioid-mediated neurobehavioral cognitive changes in offspring associated with altered protein interaction between PSD-95 and NMDAR subunits within the developing brain.

Effects of formoterol and salmeterol on the production of Th1- and Th2-related chemokines by monocytes and bronchial epithelial cells.

It is unknown whether formoterol and salmeterol, two long-acting beta(2)-adrenoreceptor agonists, have regulatory functions in the production of T-helper cell (Th) type 2- and Th1-related chemokines by monocytes and bronchial epithelial cells. In the present study, the effects of formoterol and salmeterol on lipopolysaccharide (LPS)-induced expression of the Th2-related chemokine macrophage-derived chemokine (MDC; CCL22) and the Th1-related chemokine interferon-gamma-inducible protein (IP)-10 (CXCL10) were investigated in a monocytic cell line, THP-1, and in human primary monocytes. In addition, their effects on the expression of the Th2-related chemokine thymus- and activation-regulated chemokine (TARC; CCL17) were evaluated in an epithelial cell line, BEAS-2B. Formoterol enhanced MDC but suppressed IP-10 production in monocytes induced by LPS. Higher doses of salmeterol were required to enhance LPS-induced MDC expression in THP-1 cells. Formoterol and salmeterol could significantly suppress TARC expression in BEAS-2B cells. These effects could be reversed by a selective beta(2)-adrenoreceptor antagonist, ICI-118551. Formoterol- and LPS-induced MDC expression was inhibited by budesonide. Both long-acting beta(2)-adrenoreceptor agonists suppressed thymus- and activation-regulated chemokine expression in bronchial epithelial cells mediated via beta(2)-adrenoreceptors. Formoterol at physiological concentrations could suppress lipopolysaccharide-induced T-helper cell type 1-related chemokine (interferon-gamma-inducible protein-10) but enhance T-helper cell type 2-related chemokine (macrophage-derived chemokine) expression in human monocytes. Long-acting beta(2)-adrenoreceptor agonists may increase T-helper cell type 2-related chemokine expression in monocytes and T-helper cell type 2 recruitment and, therefore, long-acting beta(2)-adrenoreceptor agonist monotherapy may not be an appropriate therapeutic option for asthma.

Outcomes of HIV-infected children with tuberculosis who are started on antiretroviral therapy in Malawi.

SETTING: Mzuzu Central Hospital, in the northern region of Malawi, which provides free antiretroviral therapy (ART) to human immunodeficiency virus (HIV) infected adults and children, including those with tuberculosis (TB). OBJECTIVES: To compare outcomes in HIV-infected children who have been started on ART because of 1) active TB, 2) a past history of TB in the last 2 years and 3) a non-TB diagnosis. DESIGN: Retrospective data collection using ART patient master cards and ART patient registers. RESULTS: Between July 2004 and September 2006, 439 (11%) children of a total 3908 patients were started on ART. There were 29 with active TB, 56 with a past history of TB in the last 2 years and 354 with a non-TB diagnosis. The three groups were similar in nutritional indices and CD4-lymphocyte percentages. The 6-month probability of survival was 0.86 in the active TB group, 0.94 in the past history of TB group and 0.89 in the non-TB group. 12-month survival probability for the same groups was 0.86, 0.86 and 0.88, respectively. CONCLUSION: HIV-infected children with active and previous TB who are started on ART have good outcomes that are similar to those of children started on ART due to a non-TB diagnosis.

Bradykinin receptor modulation in cellular models of aging and Alzheimer's disease.

Human fibroblast cell culture systems have been used to model both molecular events associated with the aging process and the biochemical anomalies found in the aging-associated neurodegenerative disorder Alzheimer's disease (AD). We demonstrate modulation of bradykinin (BK) B2 receptors that results in Intermediate (I, Kd 2.5-5 nM) and Low (L, Kd 44 nM) receptor affinity states in two cellular model systems that target aging and aging-associated disorders: the human lung fibroblast cell line WI-38 model for cellular aging and a skin fibroblast cell line from a patient with early onset familial Alzheimer's disease. In both cellular models the generation of I and L BK B2 receptors is extremely rapid, occurring within 1 min of activation of protein kinase C (PKC) by phorbol ester. Blocking phosphoprotein phosphatase activity further augments the cellular content of I and L receptors in the Alzheimer's skin fibroblast cell line. These two lines of evidence suggest that a phosphorylation cascade modifying the receptors is responsible for the I and L states. The I and L receptors remain biologically active and enhance cellular responsiveness to elevated levels of BK that are found in tissue injury, one of the major risk factors for development of Alzheimer's disease. The Alzheimer's disease skin fibroblast cell line presents a cellular environment highly enriched in the amyloid Abeta1-42 peptide that is the hallmark of Alzheimer's plaque lesions in the brain. This Abeta-rich environment may serve to foster the signal transduction mechanism that generates I and L BK B2 receptors.

Molecular analysis of SMN, NAIP and P44 genes of SMA patients and their families.

Mutations of the telomeric survival motor neuron gene (SMN1) are related to spinal muscular atrophy (SMA). However, no phenotype-genotype correlation has been observed since the SMN1 gene is lacking in the majority of patients affected with either the severe form (type I) or the milder forms (types II and III). Here, we analyze the SMN, NAIP and P44 genes in 132 Chinese SMA patients and their families. At least three types of normal allele, and four types of mutant allele were found in this study. The combination of one normal allele with one mutant allele resulted in carriers of different types, and the combination of different mutant alleles accounted for the different genotypes among different types of SMA. Deletions of mutant alleles can be further subgrouped into four types, which includes involving SMN1, SMN1 and NAIP(T) (telomeric portion of NAIP gene), SMN1 and NAIP(T) and P44(T) (telomeric portion of P44 gene), and SMN1 and SMN2 (centromeric portion of SMN gene). Some of the severe (type I) SMA cases correlated with the extent of deletions in the SMN, NAIP and P44 genes or the dosage of SMN gene when both SMN1 and SMN2 are deleted. We also found two novel point mutations, an A insertion at codon 8 (AGT-->AAGT) and an A substitution at codon 228 (TTA-->TAA).

Treatment of spinal muscular atrophy by sodium butyrate.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord, leading to muscular paralysis with muscular atrophy. No effective treatment of this disorder is presently available. Studies of the correlation between disease severity and the amount of survival motor neuron (SMN) protein have shown an inverse relationship. We report that sodium butyrate effectively increases the amount of exon 7-containing SMN protein in SMA lymphoid cell lines by changing the alternative splicing pattern of exon 7 in the SMN2 gene. In vivo, sodium butyrate treatment of SMA-like mice resulted in increased expression of SMN protein in motor neurons of the spinal cord and resulted in significant improvement of SMA clinical symptoms. Oral administration of sodium butyrate to intercrosses of heterozygous pregnant knockout-transgenic SMA-like mice decreased the birth rate of severe types of SMA-like mice, and SMA symptoms were ameliorated for all three types of SMA-like mice. These results suggest that sodium butyrate may be an effective drug for the treatment of human SMA patients.

Lack of association of dopamine D4 receptor gene polymorphisms with ADHD subtypes in a population sample of twins.

Attention-deficit hyperactivity disorder (ADHD) is a common, highly heritable syndrome of childhood characterized by problems with inattention, hyperactivity, and impulsivity. A variety of case control and family-based transmission distortion genetic studies of ADHD have focused on the possible involvement of polymorphisms of the DRD4 receptor gene. The majority of studies have examined the association of variously defined ADHD with an exon 3 polymorphism containing a variable number of imperfect 48 base pair repeats. Recently, McCracken et al. [2000: Mol Psych 5:531-536] reported an association of the DSM-IV primarily inattentive ADHD subtype with a 5' 120 base pair repeat polymorphism in the DRD4 gene. In this report, we test for the possible association of these two polymorphisms with population-derived samples of DSM-IV ADHD subtypes. Furthermore, we extend previous studies by testing for associations with ADHD subtypes derived from latent-class analysis of interview responses. In contrast to most, but not all, previous studies, we failed to demonstrate any significant association of the exon 3 7-repeat allele with ADHD. Nor did we replicate the association of the 5'120 base pair repeat polymorphism. We do find a significant association of the exon 3 3-repeat allele with a novel talkative/impulsive latent-class-defined subtype of ADHD.

An effective strategy of using molecular testing to screen mentally retarded individuals for fragile X syndrome.

Fragile X syndrome (FXS) is the most common form of familial mental retardation (MR). It is caused by the expansion of the CGG repeat in the FMR1 gene on the X chromosome. To date, FXS is not treatable, but can be prevented by prenatal genetic examination. Identifying women who carry a full mutation or premutation FMR1 gene is thus very important, and can be done by tracing family members of FXS subjects. However, most of the FXS subjects in Taiwan as well as those in many other countries have not been identified. In this study the authors attempt to develop reliable and inexpensive tests suitable for a large-scale screen of subjects with MR for FXS. Together with their previous study, a total of 311 male and 160 female subjects with MR were screened with nonradioactive Southern blot assay using mixed deoxyribonucleic acid from three subjects of the same sex. From these subjects, nine male subjects and one female FXS subject were diagnosed. All male subjects were also screened with nonradioactive polymerase chain reaction (PCR). These nine male FXS subjects were also detected on the basis of PCR amplification failure. No false-negative results were discerned. The PCR procedure was simplified further by combining it with an analysis of a blood spot on filter paper, which is a much simpler and cheaper method for sample collection and DNA preparation. This method was then used to screen 104 boys with MR. Two of them were suspected, and later confirmed with Southern blot assay, as subjects with FXS. This study suggests that simple PCR combined with blood spot analysis could be a reliable, inexpensive test that is feasible for a large-scale screening of male subjects with MR for FXS. However, Southern blot assay with mixed deoxyribonucleic acid is appropriate for screening female subjects. Based on this strategy, most FXS subjects could be identified easily for further management.

No association of the dopamine transporter gene 3' VNTR polymorphism with ADHD subtypes in a population sample of twins.

Dopamine pathway genes have been the subject of a variety of studies testing the association of candidate genes and liability for attention-deficit hyperactivity disorder (ADHD). Due to the known effects of stimulant medications such as methylphenidate on the dopamine transporter, a variety of case control and family-based transmission distortion genetic studies of ADHD have focused on DAT1 polymorphisms. The most widely reported positive finding has been with a variable number of tandem repeats (VNTR) polymorphism of unknown function in the 3' untranslated region of the DAT1 gene. In this report, we test for association of alleles of this polymorphism with ADHD using population-derived samples of twins. We use the transmission disequilibrium test and ADHD subtypes defined by both DSM-IV and latent class criteria. We fail to demonstrate any significant association or trend for association of any of the VNTR alleles with any of the variously defined ADHD subtypes.

Superior mesenteric artery syndrome associated with hereditary motor and sensory neuropathy type II--a case report.

A 14-year-old girl with superior mesenteric artery (SMA) syndrome associated with hereditary motor and sensory neuropathy (HMSN) type II is reported. The initial presentations of HMSN type II were developmental delay and gait disturbance at 2 years of age. All deep tendon reflexes were absent. Nerve conduction velocities and left sural nerve biopsy all revealed axonal changes. Recently, she suffered from intermittent bilious vomiting and epigastralgia for 6 months. That caused body weight loss from 40 kg to 28 kg. Abdominal echography showed narrowed superior mesenteric artery angle. Upper gastrointestinal series revealed obstruction of third portion of duodenum. Accordingly, SMA syndrome was diagnosed. To the best of our knowledge, this case is the first report of SMA with HMSN type II in the world. When a child with chronic neurological disease presents with intermittent vomiting, SMA should be considered as a disease entity of differential diagnosis.

Applicability of BSID-II in diagnosing developmental delay at Kaohsiung area.

The purpose of this study was to investigate the applicability of BSID-II in diagnosing children with developmental delay in Kaohsuing area. Five hundred and forty-four children, all who were patients of Developmental Delay Clinic of Kaohsuing Medical University, participated in this study. The instrument of this study was the Bayley Scales of Infant Development--second edition (BSID-II), the primary value of which was in diagnosing developmental delay and planning intervention strategies. The standardization and statistical properties of BSID-II made it one of the best measures of infant development available. The findings as follows: (1) the alpha coefficients were between .95 and .99, which were higher than data on manual of BSID-II; (2) the reproducibilities, which were different with each examiner, were between .9503 and .9633, that were good enough to be a developmental scale; (3) Standard Errors of Measurement were between 2.8589 and 3.8206. It was a restricted sample so that these also were lower than the data on manual of BSID-II. This evidence shows BSID-II is a highly reliable instrument of developmental assessment at Kaohsuing area. A special norm for developmentally delayed children and quality control of examiners are suggested.

Analysis of an SMN gene-like DNA fragment.

Part of a survival motor neuron (SMN) gene-like DNA fragment has been identified. This DNA fragment was accidentally isolated from cDNA by RT-PCR using primers specific for the region between exon 3 and 6 of the SMN gene. This fragment was used as a probe to hybridize the mRNA from several tissues, but we have been unable to detect any transcript of this SMN-like gene in these tissues. Thus, we have inferred this SMN gene-like fragment was a genomic product contaminant that was amplified in the reaction. Sequencing analysis of this fragment, which contains several stop codons, revealed a 74.6% nucleotide homology with the SMN gene. From these results, we believe that this DNA fragment is not a mutated form of SMN gene. Rather, it is an SMN-like pseudogene, which is variably present even in normal individuals.

Genetic heterogeneity in three Chinese children with Fukuyama congenital muscular dystrophy.

Three Chinese patients, two boys and one girl, were afflicted with the typical clinical, myopathological and neuroradiological findings of Fukuyama congenital muscular dystrophy (FCMD). Polymorphism analysis of our patients did not reveal the founder haplotype (138-192-147-183 in D9S2105-D9S2170-D9S2171-D9S2107) of Japanese FCMD, even though one patient was descended from Japanese ancestry. Full mutational analysis of the fukutin gene revealed that there is neither 3 kb insertion nor point mutation. These findings suggest genetic heterogeneity between Chinese and Japanese FCMD patients.