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PubMed1995

An outpatient treatment program for young children with pervasive developmental disorder.

Clinical experiences with some fourteen young children (under 3 1/2 years) suffering from pervasive developmental disorder led to the design of an outpatient treatment program. The conceptual basis for the program was facilitated by two important changes in theory. The first was a shift in our understanding of infancy, based on observations rather than reconstruction from adult and child analysis; the second was the gradual evolvement in our understanding of this disorder. The treatment program has three components: (1) a prolonged period of parent-child or adult-child interactions aimed at attracting the attention of the child and helping him or her develop imitations, interaction, and communication; (2) intense instruction, with the help of an occupational therapist, designed to teach the child basic life skills such as eating, dressing and undressing, and toilet training; and (3) exposure to normal social interactions with other children within a day-care or preschool facility to encourage joining in the usual childhood activities. The success of the program depends heavily on coordination among all the people involved: ideally they should include the parents, speech therapist, occupational therapist, teachers, child-care worker, and clinician.

Activities of Daily Living↗

PubMed2003

The novel ankyrin-repeat containing kinase ARCK-1 acts as a suppressor of the Spalten signaling pathway during Dictyostelium development.

Spalten (Spn), a member of the PP2C family of Ser/Thr protein phosphatases, is required for Dictyostelium cell-type differentiation and morphogenesis. We have identified a new protein kinase, ARCK-1, through a second site suppressor screen for mutants that allow spn null cells to proceed further through development. ARCK-1 has a C-terminal kinase domain most closely related to Ser/Thr protein kinases and an N-terminal putative regulatory domain with ankyrin repeats, a 14-3-3 binding domain, and a C1 domain, which is required for binding to RasBGTP in a two-hybrid assay. Disruption of the gene encoding ARCK-1 results in weak, late developmental defects. However, overexpression of ARCK-1 phenocopies the spn null phenotype, consistent with Spn and ARCK-1 being on the same developmental pathway. Our previous analyses of Spn and the present analysis of ARCK-1 suggest a model in which Spn and ARCK-1 differentially control the phosphorylation state of a protein that regulates cell-type differentiation. Dephosphorylation of the substrate by Spn is required for cell-type differentiation. Control of ARCK-1 and Spn activities by upstream signals is proposed to be part of the developmental regulatory program mediating cell-fate decisions in Dictyostelium.

14-3-3 Proteins↗

PubMed1993

The developmental stages of osteoblast growth and differentiation exhibit selective responses of genes to growth factors (TGF beta 1) and hormones (vitamin D and glucocorticoids).

Osteoblasts in vitro undergo a developmental sequence of growth and differentiation characterized by a stage-specific expression of cell growth and bone-related genes. Our studies show that contributions to development of the osteoblast phenotype include: (1) the down-regulation of proliferation, (2) biosynthesis and organization of type 1 collagen extracellular matrix, and (3) mineralization of this matrix. Hormones and growth factors added to isolated osteoblasts during the initial proliferation period can dramatically alter the subsequent program of developmental stages of differentiation. Studies are presented that demonstrate alterations in gene expression in response to: (1) transforming growth factor beta (TGF beta 1), that prevents differentiation of the cells and their ability to form bony tissue-like nodules; (2) glucocorticoids, which induce and accelerate development of the bone-cell phenotype; and (3) the active metabolite of vitamin D, 1,25(OH)2D3, which results in both inhibitory and stimulatory effects of the hormone on growth and differentiation--effects that are dependent upon the differentiated state of the osteoblast. Thus, in the presence of these physiological mediators of bone-cell phenotype development, many of the growth and differentiation relationships operative in osteoblasts are modified or abrogated, precluding expression of the structural and functional properties of mature bone cells and tissue. These findings have significant implications for use of hormones or growth factors in the treatment of disorders where bone is involved.

Animals↗

PubMed2002

T-lineage specification and commitment: a gene regulation perspective.

T lymphocytes originate from pluripotent precursors and undergo lasting commitment to the T cell developmental fate during their processing in the thymus. Commitment includes both the acquisition of essential T cell characteristics and the foreclosing of other developmental options. Gain of T cell characteristics is probably mediated by separate mechanisms, at least in detail, from loss of alternative developmental potentials. Programmed shifts in survival requirements make changes irreversible. Here we review the current evidence identifying the regulatory components of this commitment pathway, and the first hints of how they work together. Roles for PU.1, GATA-3, and their target genes are highlighted.

Animals↗

PubMed2004

Strategies for the early diagnosis of cerebral palsy.

Abstract Strategies for the early detection and diagnosis of cerebral palsy include multiple measures of the underlying brain abnormalities and their neurodevelopmental consequences. These measures can be grouped into the categories of pathogenesis, impairment, and functional limitation. Neuroimaging techniques are the most predictive measures of pathogenesis of cerebral palsy in both the preterm and term infant. Measures of neurological impairment focusing on muscle tone, reflexes, and other features of the neurological examination are poorly predictive in the first months of life. Detection of functional limitations manifested by motor developmental delay is sensitive and specific for later cerebral palsy, but not until well into the second 6 months of life. Abnormal spontaneous general movements in the infant 16 to 20 weeks postterm and earlier reflect functional limitations in the first months of life and have been shown to predict later cerebral palsy. Recognition of abnormal spontaneous general movements may improve early detection and diagnosis of cerebral palsy if these techniques can be successfully incorporated into organized follow-up programs and developmental surveillance.

Activities of Daily Living↗

PubMed1999

The POU domain gene, XlPOU 2 is an essential downstream determinant of neural induction.

The POU domain gene, XlPOU 2, acts as a transcriptional activator during mid-gastrulation in Xenopus. Overexpression or misexpression of VP16-POU-GR, a fusion protein consisting of the strong activator domain of VP16 and the POU domain of XlPOU 2, results in ectopic expression of the neural-specific genes, nrp-1, en-2, and beta-tubulin. In contrast, overexpressing a dominant-inhibitory form of XlPOU 2 inhibits the chordin-induced neuralization of uncommitted ectoderm, and results in a loss of nrp-1 and en-2 expression in embryos. Furthermore, in uncommitted ectoderm, XlPOU 2 regulates the developmental neural program that includes a number of pre-pattern genes and at least one proneural gene, X-ngnr-1, thus playing a key role during neural determination.

Animals↗

PubMed1977

Approaches to management of the handicapped infant.

A form of management which has proven helpful in a developmental intervention program for handicapped infants is described. The use of ordinal rather than normative assessments when monitoring the infant's development and when teaching families about their infants is advocated. Two cases demonstrate ways to enhance the functioning of the handicapped infant and his family.

Blindness↗

PubMed2002

Between the laboratory and life: child development research in Toronto, 1919-1965.

Between 1919 and 1956, psychologists at the University of Toronto built a research program in developmental psychology on a functionalist, holistic, and ecological basis. They conducted longitudinal studies on mental health in growing children in educational settings instead of in laboratories and formed strong alliances with the local educational system in order to do so. They initially defined mental health as adjustment and considered conditions within schools to be conducive to its attainment. After developing a psychological theory of personality development, they came to view educational conditions as discouraging the development of mental health. The alliance between the educational system and psychology consequently unraveled, and the program declined.

Canada↗

PubMed1977

Establishing a normal peer as a behavioral model for developmentally delayed toddlers.

The present investigation demonstrated a systematic teaching procedure for establishing a normal toddler as a peer-model for three children showing delayed development, each one under 27 mo. of age. For each delayed subject, training consisted of adult-directed prompting and social reinforcement contingent upon the delayed children's imitations of material use and motor responses emitted by a normal peer. Within-subjects multiple-baseline designs across responses were used to demonstrate intrasubject control over imitative responding. Indices of stimulus and response generalization were assessed through having the peer-model present the trained responses along with untrained responses in a situation free of adult prompting and social reinforcement for imitative responding. Results indicated that the training in peer-imitation was successful for establishing the peer-model's behavior in a stimulus control relationship with the imitative responding of the delayed children. Moreover, the findings generally demonstrated transfer of training across stimulus situations and responses. Implications for educational programming with developmentally delayed children are discussed.

Behavior Therapy↗

PubMed1981

Early intervention-fact or fiction?

A group of 50 cerebral-palsied children seen in one clinic between 1952 and 1965 were compared with a second group of 50 seen between 1952 and 1978. The latter group had all been included in a developmental enrichment program at the clinic. The results showed that the later-treated group had had more surgical operations than the earlier group, and at younger ages; that they were able to sit and stand earlier; and that eventually they had greater ambulatory ability. Early intervention also improved family relationships, and parents and siblings became more involved in the team approach to the children's therapy.

Adult↗

PubMed2006

The SUMO pathway is developmentally regulated and required for programmed DNA elimination in Paramecium tetraurelia.

Extensive genome-wide remodeling occurs during the formation of the somatic macronuclei from the germ line micronuclei in ciliated protozoa. This process is limited to sexual reproduction and includes DNA amplification, chromosome fragmentation, and the elimination of internal segments of DNA. Our efforts to define the pathways regulating these events revealed a gene encoding a homologue of ubiquitin activating enzyme 2 (UBA2) that is upregulated at the onset of macronuclear development in Paramecium tetraurelia. Uba2 enzymes are known to activate the protein called small ubiquitin-related modifier (SUMO) that is covalently attached to target proteins. Consistent with this relationship, Northern analysis showed increased abundance of SUMO transcripts during sexual reproduction in Paramecium. RNA interference (RNAi) against UBA2 or SUMO during vegetative growth had little effect on cell survival or fission rates. In contrast, RNAi of mating cells resulted in failure to form a functional macronucleus. Despite normal amplification of the genome, excision of internal eliminated sequences was completely blocked. Additional experiments showed that the homologous UBA2 and SUMO genes in Tetrahymena thermophila are also upregulated during conjugation. These results provide evidence for the developmental regulation of the SUMO pathway in ciliates and suggest a key role for the pathway in controlling genome remodeling.

Animals↗

PubMed2006

Implicit learning is intact in adult developmental dyslexic readers: evidence from the serial reaction time task and artificial grammar learning.

Previous research yielded equivocal results concerning implicit learning abilities of developmental dyslexic readers. These studies employed a sequence learning task that requires a motor response to each stimulus. However, implicit learning has been often studied using non-motor tasks. Thus, we investigated implicit learning capabilities of adult developmental dyslexic readers in two standard implicit learning paradigms differing in the involvement of the motor system, namely the serial response time task (SRTT) and artificial grammar learning (AGL).Twelve adult developmental dyslexic and twelve age- and sex- matched normal readers were tested. In the serial response time task (SRTT), participants are exposed to a structured display. Learning is measured by comparing response time (RT) to the structured sequence with RT to a random display. In the artificial grammar learning task (AGL), letter strings following a markovian finite state grammar are presented. In a subsequent test phase subjects have to judge new letter strings according to their grammaticality. Learning of the stimulus regularities was found in both tasks and for both groups of subjects. Furthermore, participants were unaware of the underlying stimulus construction principles. Dyslexic readers were unimpaired in SRTT as well as artificial grammar learning relative to normal readers. These findings show that implicit learning is intact in dyslexia. Intact implicit learning capabilities should be taken into account when designing training programs for developmental dyslexic readers.

Adult↗

PubMedDate not supplied

Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?

The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.

Androgens↗

PubMed1998

Distinct molecular phenotypes in murine cardiac muscle development, growth, and hypertrophy.

The onset of cardiac hypertrophy is associated with characteristic changes in myocardial gene expression that are thought to recapitulate a developmental gene program. We report here the first gene expression profile of the murine myocardium, using a rapid method of quantitative expression analysis based on real-time analytical RT-PCR. This assay was used to measure expression levels of 29 genes in (1) late stage development as represented by day 1 neonatal ventricles, (2) normal cardiac growth in 3 and 18 month old mice, and (3) cardiac hypertrophy following pressure overload by aortic constriction. For males and females normal growth is not associated with differential expression although there is elevated expression of skeletal and smooth muscle actin mRNA's in males compared to females. Using normal adult ventricles as a reference, there are many qualitative and quantitative differences between the day 1 neonatal myocardium and experimental cardiac hypertrophy. These data suggest that the response to POL involves a subset of re-expressed developmental genes together with altered expression of genes not necessarily associated with cardiac development.

Animals↗

PubMed1996

Acidic fibroblast growth factor inhibits osteoblast differentiation in vitro: altered expression of collagenase, cell growth-related, and mineralization-associated genes.

Fibroblast growth factors (FGF) are osteoblast mitogens, but their effects on bone formation are not clearly understood. Most in vitro studies examining the effects of FGFs on osteoblasts have been performed only during the initial proliferative stage of osteoblast culture. In these studies, we examined the consequential effect of acidic FGF in cultures of rat fetal diploid osteoblasts that undergo a developmental differentiation program producing a mineralized bone-like matrix. During the initial growth period (days 1-10), addition of acidic FGF (100 micrograms/ml) to actively proliferating cells increased (P < 0.05) 3H-thymidine uptake (2,515 +/- 137, mean +/- SEM vs. 5,884 +/- 818 cpm/10(4) cells). During the second stage of maturation (days 10-15), osteoblasts form multilayered nodules of cells and accumulate matrix, followed by mineralization (stage 3, days 16-29). Addition of acidic FGF to the osteoblast cultures from days 7 to 15 completely blocked nodule formation. Furthermore, addition of acidic FGF after nodule formation (days 14-29) inhibited matrix mineralization, which was associated with a marked increase in collagenase gene expression, and resulted in a progressive change in the morphology of the nodules, with only a few remnants of nonmineralized nodules present by day 29. Histochemical and biochemical analyses revealed a decrease in alkaline phosphatase and mineral content, confirming the acidic FGF-induced inhibition of nodule and matrix formation. To identify mechanisms contributing to these changes, we examined expression of cell growth and bone phenotypic markers. Addition of acidic FGF during the proliferative phase (days 7-8) enhanced histone H4, osteopontin, type I collagen, and TGF-beta mRNA levels, which are coupled to proliferating osteoblasts, and blocked the normal developmental increase in alkaline phosphatase and osteocalcin gene expression and calcium accumulation. Addition of acidic FGF to the cultures during matrix maturation (days 14-15) reactivated H4, osteopontin, type I collagen, and TGF-beta gene expression, and decreased alkaline phosphatase and osteocalcin gene expression. In an in vivo experiment, rats were treated with up to 60 micrograms/kg/day acidic FGF intravenously for 30 days. Proliferation of osteoblasts and deposition of bone occurred in the marrow space of the diaphysis of the femur in a dose-related fashion. The metaphyseal areas were unaffected by treatment. In conclusion, our data suggest that acidic FGF is a potent mitogen for early stage osteoblasts which leads to modifications in the formation of the extracellular matrix; increases in TGF-beta and collagenase are functionally implicated in abrogating competency for nodule formation. Persistence of proliferation prevented expression of alkaline phosphatase and osteocalcin, also contributing to the block in the progression of the osteoblast developmental sequence.

Alkaline Phosphatase↗

PubMed1997

Developmental care does not alter sleep and development of premature infants.

OBJECTIVE: The Neonatal Individualized Developmental Care Program (NIDCAP) for very low birth weight (VLBW) preterm infants has been suggested by Als et al to improve several medical outcome variables such as time on ventilator, time to nipple feed, the duration of hospital stay, better behavioral performance on Assessment of Preterm Infants' Behavior (APIB), and improved neurodevelopmental outcomes. We have tested the hypothesis of whether the infants who had received NIDCAP would show advanced sleep-wake pattern, behavioral, and neurodevelopmental outcome. METHODS: Thirty-five VLBW infants were randomly assigned to receive NIDCAP or routine infant care. The goals for NIDCAP intervention were to enhance comfort and stability and to reduce stress and agitation for the preterm infants by: a) altering the environment by decreasing excess light and noise in the neonatal intensive care unit (NICU) and by using covers over the incubators and cribs; b) use of positioning aids such as boundary supports, nests, and buntings to promote a balance of flexion and extension postures; c) modification of direct hands-on caregiving to maximize preparation of infants for, tolerance of, and facilitation of recovery from interventions; d) promotion of self-regulatory behaviors such as holding on, grasping, and sucking; e) attention to the readiness for and the ability to take oral feedings; and f) involving parents in the care of their infants as much as possible. The infants' sleep was recorded at 36 weeks postconceptional age (PCA) and at 3 months corrected age (CA) using the Motility Monitoring System (MMS), an automated, nonintrusive procedure for determining sleep state from movement and respiration patterns. Behavioral and developmental outcome was assessed by the Neurobehavioral Assessment of the Preterm Infant (NAPI) at 36 weeks PCA, the APIB at 42 weeks PCA, and by the Bayley Scales of Infant Development (BSID) at 4, 12, and 24 months CA. RESULTS: Sleep developmental measures at 3 months CA showed a clear developmental change compared with 36 weeks PCA. These include: increased amount of quiet sleep, reduced active sleep and indeterminate sleep, decreased arousal, and transitions during sleep. Longest sleep period at night showed a clear developmental effect (increased) when comparing nighttime sleep pattern of infants at 3 months with those at 36 weeks of age. Day-night rhythm of sleep-wake increased significantly from 36 weeks PCA to 3 months CA. However, neither of these sleep developmental changes showed any significant effects of NIDCAP intervention. Although all APIB measures showed better organized behavior in NIDCAP patients, neither NAPI nor Bayley showed any developmental advantages for the intervention group. The neurodevelopmental outcome measured by the Bayley at 4, 12, and 24 months CA showed 64% of the NIDCAP intervention group at the lowest possible score compared with 33% of the control group. These findings could not be explained by the occurrence of intraventricular hemorrhage or the socioeconomic status of the parents, which showed no significant group effect. CONCLUSION: The results of this study, including measures of sleep maturation and neurodevelopmental outcome up to 2 years of age did not demonstrate that the NIDCAP intervention results in increased maturity or development. Buehler et al (Pediatrics. 1995;96:923-932) have reported that premature infants (N = 12; mean gestational age 32 weeks, mean birth weight 1700 g) who received developmental care compared with a similar group of infants who received routine care showed better organized behavioral performance on an APIB assessment at 42 weeks PCA. None of the medical outcome measures were significantly different in this study. Although our APIB results are in agreement, the results of the NAPI, the Bayley and sleep measures do not show an increase in neurodevelopmental maturation. In the earlier report by Als et al (Journal of the American Medical Associatio

Adult↗

PubMed1999

Developmental regulation of Bcl-2 family protein expression in the involuting mammary gland.

Epithelial cells within the mammary gland undergo developmental programmes of proliferation and apoptosis during the pregnancy cycle. After weaning, secretory epithelial cells are removed by apoptosis. To determine whether members of the Bcl-2 gene family could be involved in regulating this process, we have examined whether changes in their expression occur during this developmental apoptotic program in vivo. Bax and Bcl-x were evenly expressed throughout development. However, expression of Bak and Bad was increased during late pregnancy and lactation, and the proteins were present during the time of maximal apoptotic involution. Thereafter, their levels declined. In contrast, Bcl-w was expressed in pregnancy and lactation but was downregulated at the onset of apoptosis. Bcl-2 was not detected in lactating or early involuting mammary gland. Thus, the pro-apoptotic proteins Bax, Bak and Bad, as well as the death-suppressors Bcl-x, Bcl-2 and Bcl-w, are synthesised in mouse mammary gland, and dynamic changes in the expression profiles of these proteins occurs during development. To determine if changes in Bak and Bcl-w expression could regulate mammary apoptosis, their effect on cultured mouse mammary epithelial cells was examined in transient transfection assays. Enforced expression of Bak induced rapid mammary apoptosis, which could be suppressed by coexpression of Bcl-w. In extracts of mammary tissue in vivo, Bak heterodimerized with Bcl-x whereas Bax associated with Bcl-w, but Bak/Bcl-w heterodimers were not detected. Thus, Bak and Bcl-w may regulate cell death through independent pathways. These results support a model in which mammary epithelial cells are primed for apoptosis during the transition from pregnancy to lactation by de novo expression of the death effectors Bak and Bad. It is suggested that these proteins are prevented from triggering apoptosis by anti-apoptotic Bcl-2 family proteins until involution, when the levels of Bcl-w decline. Our study provides evidence that regulated changes in the expression of cell death genes may contribute to the developmental control of mammary apoptosis.

Animals↗

PubMed1983

Extracellular matrix and the maintenance of the differentiated state: proteoglycans synthesized by replated chondrocytes and nonchondrocytes.

It has been previously shown that undifferentiated stage 23 to 24 chick limb bud mesenchymal cells can be maintained in culture under conditions which promote chondrogenesis. As the chondrocytes mature in vitro, their proteoglycan synthesis progresses through a specific and reproducible biosynthetic program. By the eighth day of culture, the chondrocytes are making proteoglycans that are similar to proteoglycans isolated from adult animal tissues. Relative to the Day 8 proteoglycans, the proteoglycans synthesized by chick limb bud chondrocytes earlier in culture have a smaller monomer size, longer chondroitin sulfate chains, shorter keratan sulfate chains, a higher ratio of chondroitin-6-sulfate to chondroitin-4-sulfate, and a decreased ability to interact with hyaluronic acid. We have reported a procedure to remove the cells from Day 8 cultures and strip away most, if not all, of the extracellular matrix. In addition, the chondrocytes can be separated from the 40-50% nonchondrocytic cells normally found in Day 8 cultures, and the two cell populations replated separately. This report describes the analysis of the proteoglycans synthesized by replated cells; this analysis demonstrates quantitative and qualitative differences between chondrocyte and nonchondrocyte proteoglycans. The overall rate of proteoglycan synthesis is fourfold higher and the rate of synthesis of high buoyant density proteoglycans 30-fold higher for replated chondrocytes relative to nonchondrocytes. Qualitatively, more newly synthesized nonchondrocyte proteoglycans partition at lower buoyant density on CsCl equilibrium density gradients than do chondrocyte proteoglycans. Nonchondrocyte proteoglycans are of two major classes: One has a monomer size slightly smaller than that of Day 8 chondrocyte proteoglycan, but has much longer glycosaminoglycan chains. The other is considerably smaller than Day 8 chondrocyte proteoglycans, but has glycosaminoglycans of slightly larger size. In contrast, replated chondrocytes synthesize, even as soon as 4.5 hr after replating, proteoglycans that are identical to Day 8 chondrocyte proteoglycan in monomer size, in glycosaminoglycan chain size, in aggregability, and in the ratio of 6-sulfated to 4-sulfated chondroitin. Since denuding mature Day 8 chondrocytes of their extracellular matrix does not cause them to recapitulate their developmentally regulated program for the biosynthesis of proteoglycans, it is concluded that the quality of mature chondrocyte proteoglycan is not altered by the absence of extracellular matrix.

Animals↗