Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia

Down syndrome (DS) children with acute myeloid leukemia (AML) have significantly higher event-free survival (EFS) rates compared with non-DS children when treated with protocols containing 1-beta-D-arabinofuranosylcytosine (ara-C). Sensitivity and metabolism of ara-C was examined in myeloblasts from DS and non-DS patients with AML, DS infants with the transient myeloproliferative disorder, and Epstein-Barr Virus (EBV) transformed lymphoblastoid cell lines with and without trisomy 21. DS myeloblasts were approximately 10-fold more sensitive to ara-C (measured by the 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) colorimetric sensitivity assay), compared with non-DS myeloblasts, following exposure to ara-C for 72 hours. Mean levels of l-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) were significantly higher in DS myeloblasts compared with non-DS myeloblasts after incubation with 5 micromol/L ara-C (621.4 v 228.4 pmol/mg protein). DS cell lines also generated higher levels of ara-CTP compared with cell lines with diploid chromosome numbers (66.5 v 13.6 pmol/mg protein and 137.6 v 41.7 pmol/mg protein at 1 and 5 micromol/L ara-C, respectively). Elevated ara-CTP levels in the DS cells were accompanied by slightly lower levels of endogenous deoxycytidine triphosphate (dCTP) pools, slightly greater extent of ara-C incorporation into DNA, and increased relative numbers of double strand DNA strand breaks. There were no significant differences in the cell cycle distributions of DS and non-DS cells. These in vitro studies support our hypothesis that enhanced metabolism of ara-C in DS cells may be a contributing factor to the superior survival rate of DS children with AML and is possibly based on a gene dosage effect of genes localized to chromosome 21 including cystathionine-beta-synthase. Further study of the mechanisms (ie, alterations in dCTP pools and DNA methylation) involved may lead to improvements in the treatment of all AML patients.     

Genetic linkage of the tricho-dento-osseous syndrome to chromosome 17q21

Tricho-dento-osseous syndrome (TDO), MIM# 190320, is transmitted as a highly penetrant autosomal dominant trait that is characterized by variable clinical expression. The principal clinical features include kinky/curly hair in infancy, enamel hypoplasia, taurodontism, as well as increased thickness and density of cranial bones. Possible genetic linkage has been reported for TDO with the ABO blood group locus, but the gene defect remains unknown. We have identified four multiplex families (n = 63, 39 affected, 24 unaffected) from North Carolina segregating TDO. We previously have excluded a major locus for TDO in the ABO region for these families. Utilizing a genome-wide search strategy, we obtained conclusive evidence for linkage of the TDO syndrome locus to markers on chromosome 17q21 (D17S791, Z max = 10.54, Theta = 0.00) with no indication of genetic heterogeneity. Multipoint analysis suggests the TDO locus is located in a 7 cM chromosomal segment flanked by D17S932 and D17S941. This finding represents the first step towards isolation and cloning of the TDO gene. Identification of this gene has important implications for understanding normal and abnormal craniofacial development of hair, teeth and bone.     

Transient leukemia followed by megakaryoblastic leukemia in a child with mosaic Down syndrome

A case is presented of a child with mosaic Down syndrome, who presented at birth with a transient leukemia and later progressed to megakaryoblastic leukemia. Evidence is presented that both leukemias were of megakaryoblastic lineage and evolved from a trisomic hematopoietic precursor. This case is unique in the poor course of the initial transient neonatal leukemia with improvement following chemotherapy. It also highlights the form of leukemia and associated myelodysplasia that occurs in children with Down syndrome. This form of leukemia and transient leukemia are interrelated and are unique to children with Down syndrome.     

A novel gene isolated from human placenta located in Down syndrome critical region on chromosome 21

After the short summary of investigation methods of latent Squint the authors report about the method using the standard Trial Frame Okula and prism with a power of 16 pdpt, with Maddox lens from common trial case Okula. This method is used for an indication of magnitude of latent Squint for a short and a long distance. After the meaning of the authors is exoforia for a short distance one of the most frequent causes of muscular asthenopic disorders.     

Relative involvement of chromosome #21 in radiation induced exchange aberrations in lymphocytes of Down syndrome patients

The reaction of chemical carcinogens with DNA appears to be one of the earliest events in the initiation phase of cancer. These DNA reactions can be base- and position-specific, are affected by sequence context, and are repaired at different rates depending on whether or not they are on the transcribed or nontranscribed strand of DNA and which nucleotide sequence is modified. Thus, measurement of total genomic DNA reaction of carcinogens is only a crude first step in dissecting out which are the critical lesions for cancer initiation. On the other hand, we know that DNA adducts, which have been primarily characterised in experimental studies, appear to have similar structures in human DNA arising from occupational or environmental exposures. A number of different methods have been developed to detect and measure DNA adducts in man. These include physico-chemical methods such as mass spectrometry, 32P-postlabelling, fluorescence and accelerator mass spectrometry (AMS) and biological methods such as immunoassay. All these methods have their strengths and weaknesses. Human studies, using 32P-postlabelling, demonstrate that this method can be used to examine the effect of potential chemoprotective agents on DNA adduct level. AMS has been used to measure DNA adducts in human tissue after patients have ingested trace quantities of the food mutagens 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, a heterocyclic amine formed during the cooking of meat and the naturally occurring mycotoxin, aflatoxin B1. These studies can assist in assessing the risks associated with low-level exposure to food genotoxins.     

Primary care of infants and young children with Down syndrome

Down syndrome is caused by triplicate material of chromosome 21. The syndrome has a variable physical expression, but congenital cardiac defects, transient myelodysplasia of the newborn and duodenal atresia are highly specific for this chromosomal disorder. Routine health maintenance is important because infants and children with Down syndrome are more likely to have otitis media, thyroid disease, congenital cataracts, leukemoid reactions, dental problems and feeding difficulties. Since infants with this syndrome are prone to respiratory infections, immunization recommendations should be followed closely. Motor, language, social and adaptive skills should be assessed at each office visit. The psychosocial aspects of care should be discussed with the parents of an infant with Down syndrome. If necessary, the parents should be referred to family support and specialty resources. Institutionalization of infants with Down syndrome is now unlikely. With newer surgical techniques, early therapy to minimize developmental delay and proper health supervision, the functional prognosis for infants with Down syndrome is considerably improved.     

Nutrient intake and obesity in prepubescent children with Down syndrome

OBJECTIVE: The aim of this study was to measure nutrient intake and body composition in prepubescent children with Down syndrome to understand dietary barriers involved in the prevention and treatment of obesity. DESIGN: Dietary intake was determined from parent-reported 3-day diet records for children with Down syndrome and control subjects. Energy intake was compared with energy expenditure measured by the doubly labeled water method. Body composition was determined by deuterium dilution, bioelectrical impedance analysis, and skinfold thickness measurements. SUBJECTS/SETTING: Ten prepubescent children with Down syndrome and 10 control subjects were recruited from the hospital community. The study was conducted in the Clinical Research Center of the University of Chicago Medical Center. MAIN OUTCOME MEASURES: Nutrient intakes were compared with the Recommended Dietary Allowances (RDAs) to estimate risk for nutrient deficiency. Fat-free mass values determined by bioelectrical impedance analysis and measurement of skinfold thicknesses were compared with values determined using the deuterium dilution method. STATISTICAL ANALYSES PERFORMED: Unpaired t tests were used for comparisons between subjects groups and the Wilcoxon signed-rank test was used for comparison of nutrient intakes with RDAs. RESULTS: The subjects with Down syndrome were significantly shorter (P < .01) than control subjects; however, body composition did not differ between the groups. Reported energy intake was lower in subjects with Down syndrome. In addition, several micronutrients were consumed, especially among nonobese subjects with Down syndrome, at less than 80% of the RDA. APPLICATIONS: To avoid lowering already inadequate intakes of several vitamins and minerals, we suggest that treatment of obesity in children with Down syndrome combine a balanced diet without energy restriction, vitamin and mineral supplementation, and increased physical activity.     

IGF-I levels in prepubertal and pubertal children with Down syndrome

Medical behavior for intensive examination after colo-rectal cancer screening was examined in comparison with that after stomach cancer screening. Examinees who were positive in colo-rectal or stomach cancer screening, provided by an Occupational Health Organization from April 1993 to March 1994, were monitored for their medical behavior through notifications from physicians. The main results were as follows: 1. The proportion of those with the notification from a physician after colo-rectal cancer screening was half of that after stomach cancer screening. 2. Among those notified the rate of those who undertook intensive examination by the end of 12 weeks after the screening was 79.7% for a colo-rectal site and 87.0% for the stomach. The time interval from the screening to the intensive examination for the colo-rectal site was significantly longer than that for stomach. 3. For colo-rectal cancer screening, the proportion of those with the notification was lower in females than in males, and in those aged less than 50 than in those aged 50 or older. There were no differences in the proportion between those screened at the work site and those at the occupational health service center, and between those positive in the fecal occult blood test and those negative in the test but positive in the health interview. These results indicated, assuming that the probability of the physicians' notification was unrelated to the type of examination, a smaller proportion of the examinees positive in the colo-rectal cancer screening consulted a physician for the intensive examination later than those positive in the stomach cancer screening. It is therefore necessary to make colo-rectal cancer screening effective to establish a collaborating system which effectively facilitates the medical behavior of the screening positives.     

Gestures and words in early development of children with Down syndrome

Central neurokinin-1 (NK-1) receptors are thought to modulate aversion, whereas the periaqueductal gray matter (PAG) is a common pathway for the integration of fear behaviors. The authors determined whether injection of an NK-1 agonist (GR73632) into subregions of the PAG would alter fear-related behaviors. Behavioral inactivity was increased by GR73632 injected into the caudodorsal PAG or the dorsal raphe. Flight behavior induced by stimulation of the dorsal PAG or by a footshock was decreased after injection of GR73632 into the dorsal PAG. Rats that had 6 pairings of a tone with a footshock after injection of GR73632 into the dorsal PAG displayed more freezing behavior than controls at the beginning of the session. However, there was no change in the shock- or the tone-induced freezing because some GR73632-treated rats, but no controls, froze during the baseline period. It is concluded that NK-1 receptors in the dorsal PAG modulate the unconditional but not the mnemonic aspects of fear behaviors.     

The piloting of a group for the fathers of children with Down syndrome

Inflammatory lesions and cysts are by far the most common causes of swelling or enlargement of Bartholin's glands, and carcinomas, though rare, are the most frequent solid lesions that arise at this site. There have been very few reports of benign solid lesions of Bartholin's gland, and, among these lesions, the distinction between adenoma (AD) and hyperplasia has not been well defined. All cases diagnosed as either Bartholin's gland adenoma or hyperplasia in the Armed Forces Institute of Pathology files were reviewed. Using specific criteria, 17 qualified as nodular hyperplasia (NH), 1 as AD, and 1 as adenomyoma (AM). Five NHs, the AD, and the AM were studied with immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), MIB-1, and p53. The average age of the patients with NH was 35 years (range, 19 to 56). These lesions were solid or solid and cystic, had a mean maximal dimension of 2.3 cm, and were frequently thought to be Bartholin's cysts on clinical examination. Microscopically, the NHs had an irregular or lobulated contour and were composed of a proliferation of cytologically bland mucinous acini with maintenance of the normal duct-to-acinar relationship. Varying degrees of inflammation and squamous metaplasia of the ducts were common in NH. The patient with the AD was 45 years old and the patient with AM was 65. Both were well-circumscribed, solid lesions, 2.2 and 2.5 cm in maximal dimension, respectively, and composed of a haphazard proliferation of acini and tubules. A small adenoid cystic carcinoma (ACC) arose from the periphery of the AD. p53 positivity was evident in up to 40% of the ACC cells; the cells in the adjacent AD were negative for p53. Only occasional cells were MIB-1 positive (< 5%) in some cases, and ER and PR were absent in the epithelial elements in all 7 cases tested but were focally present in the stromal cells of 3 of the 5 NHs and the fibromuscular stroma of the AM. The patient with the AM and the one with the AD are alive without evidence of recurrent or metastatic disease after 4 months and 19.8 years, respectively. NH, AD, and AM of the Bartholin's gland, as defined in this study, are extremely rare lesions. NH occurs in younger patients and is often associated with inflammation or obstruction of Bartholin's duct.     

Language in Italian children with Down syndrome and with specific language impairment.

This article compares lexical and grammatical abilities of a mental-age-matched sample of Italian preschoolers with Down syndrome (DS), specific language impairment (SLI), or typical development. Results showed that the children with DS or with SLI performed significantly worse than did the typically developing children. Although no significant differences emerged in lexical abilities and morphosyntactic comprehension abilities between the children with DS or with SLI, significant differences did emerge in morphosyntactic production capacities. Qualitative analysis of the morphosyntactic errors revealed strong similarities between the two groups. The results are discussed in terms of the role of verbal memory abilities and the linguistic features of Italian. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mapping of the gene for the p60 subunit of the human chromatin assembly factor (CAF1A) to the Down syndrome region of chromosome 21

Exon trapping was used to clone portions of genes from the Down syndrome critical region (DSCR) of human chromosome 21. One trapped sequence showed complete homology with nucleotide sequence U20980 (GenBank), which corresponds to the gene for the p60 subunit of the human chromatin assembly factor-1 (CAF1A). We mapped this gene to human chromosome 21 by fluorescence in situ hybridization, by the use of somatic cell hybrids, and by hybridization to chromosome 21-specific YACs and cosmids. The CAF1A gene localizes to YACs 745H11 and 230E8 of the Chumakov et al. (1992, Nature 359: 380) YAC contig, within the DSCR on 21q22. This CAF1A, which belongs to the WD-motif family of genes and interacts with other polypeptide subunits to promote assembly of histones to replicating DNA, may contribute in a gene dosage-dependent manner to the phenotype of Down syndrome.     

Language skills of children and adolescents with Down syndrome: II. Production deficits

Hypotheses that children and adolescents with Down syndrome show (a) a specific expressive language impairment, (b) a "critical period" for language acquisition, (c) a "simple sentence syntactic ceiling" in production, and (d) deficit in grammatical morphology were investigated cross-sectionally. Conversational and narrative language samples from 47 children and adolescents with Down syndrome (Trisomy 21), aged 5 to 20 years, were compared to those from 47 control children aged 2 to 6 years matched statistically for nonverbal mental age. Children with Down syndrome appear to have a specific language impairment, compared to control children, in number of different words and total words (in the first 50 utterances) and in mean length of utterance (MLU). Total utterance attempts per minute were more frequent in the Down syndrome group. Narrative samples contained more word tokens, more word types, and longer MLU than conversation samples, for both groups. Intelligibility of narratives was significantly poorer for the Down syndrome group than controls. Analyses of narrative language sample by age sub-group showed no evidence of a critical period for language development ending at adolescence, nor of a "syntactic ceiling" at MLUs corresponding to simple sentences for the Down syndrome group. Omissions of word tokens and types were more frequent in the older Down syndrome than the younger control sample, matched on MLU.     

Quality of toddler-mother attachment in children with Down syndrome: limits to interpretation of strange situation behavior

Researchers studying social-emotional development have argued that primary attachment relationships, established by the end of the first year of life, are important organizing factors that influence the trajectory of development throughout childhood. Central to this argument is a dimension of "attachment security," along which attachments differ. For normally developing infants and toddlers, attachment security is assessed using the Ainsworth Strange Situation. However, it is not clear that this procedure is appropriate for evaluating attachment security in atypical populations. In this report, 3 samples of children with Down Syndrome (total N = 138) were assessed using the Strange Situation. The procedures were scored according to traditional protocols. Although the 3 samples differed with respect to chronological and developmental age, they showed basic similarity with respect to attachment variables. However, developmentally younger children were more difficult to classify using the standard scoring rules. Scores and classifications for the sample were compared to scores from a sample of normally developing children tested at about 12 months of age. Significant differences with respect to the distributions of cases to classification categories and with respect to the interactive scale scores suggest that the Strange Situation may be measuring different aspects of behavior for children with Down Syndrome, even when they are tested at similar developmental age levels.     

Caring for the child with Down syndrome

This article reviews the etiology, treatment, and prognosis of Down syndrome. Effects of Down syndrome on growth and development, specific physiologic manifestations, and implications for school-based practice are discussed.     

The structure of mother–child play: Young children with Down syndrome and typically developing children.

This study explored developmental changes and effects of Down syndrome on mothers' structuring of their children's play. Mothers and their young children with Down syndrome (n?=?28) were compared with socioeconomically matched samples of mothers and their mental age-matched (n?=?28) and chronological age-matched (n?=?28) typically developing children. Mothers of typically developing children exhibited more object demonstrations with their developmentally younger children, who exhibited less object play. Mothers of children with Down syndrome were more directive and supportive than were mothers of younger and older typically developing children, who did not differ in their frequencies of these behaviors. More maternal supportive object behavior was associated with more object play and vocalization by children with Down syndrome. Mothers and children in all 3 groups were contingently responsive to their partners' behavioral signals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Atypical background somatic mutant frequencies at the HPRT locus in children and adults with Down syndrome

Sixty-six human enterovirus serotypes have been described using antibody neutralization, with antigenic variants defined within several serotypes. Despite the availability of sequence data for numerous enteroviruses, the molecular basis of serotype is unknown. Previous studies by others have identified four major phylogenetic groups within the human enteroviruses, but there has been no complete database of homologous sequences for all human enterovirus serotypes. We have determined the homologous partial VP2 sequences for the 12 prototype strains for which VP2 sequence was unavailable and for eight well-characterized antigenic variants. Phylogenetic analysis of all prototype strains produced four major groups, consistent with published enterovirus phylogenies. Many antigenic variants, however, failed to cluster with their respective prototype strains, suggesting that this portion of VP2 may be inappropriate for consistent molecular inference of serotype and for detailed study of enterovirus evolution.     

Bacterial contig map of the 21q11 region associated with Alzheimer's disease and abnormal myelopoiesis in Down syndrome

We present a high-resolution bacterial contig map of 3.4 Mb of genomic DNA in human chromosome 21q11-q21, encompassing the region of elevated disomic homozygosity in Down Syndrome-associated abnormal myelopoiesis and leukemia, as well as the markers, which has shown a strong association with Alzheimer's Disease that has never been explained. The map contains 89 overlapping PACs, BACs, or cosmids in three contigs (850, 850, and 1500 kb) with two gaps (one of 140-210 kb and the second <5 kb). To date, eight transcribed sequences derived by cDNA selection, exon trapping, and/or global EST sequencing have been positioned onto the map, and the only two genes so far mapped to this cytogenetic region, STCH and RIP140 have been precisely localized. This work converts a further 10% of chromosome 21q into a high-resolution bacterial contig map, which will be the physical basis for the long-range sequencing of this region. The map will also enable positional derivation of new transcribed sequences, as well as new polymorphic probes, that will help in elucidation of the role the genes in this region may play in abnormal myelopoiesis and leukemia associated with trisomy 21 and Alzheimer's Disease.