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Pituitary-thyroid feedback hypersensitivity as a novel cause of hypothyroidism in children.

Recognition and treatment of childhood hypothyroidism is essential to prevent serious developmental abnormalities, and neonatal screening based on detection of raised thyrotropin concentrations is routine. We investigated an adolescent who had developmental retardation because of an undiagnosed and novel cause of childhood hypothyroidism associated with normal circulating thyrotropin concentrations. Dynamic testing showed a hypersensitive pituitary-thyroid feedback axis with no evidence of other pituitary or hypothalamic disease, and sequence analysis of four candidate causative genes was negative. A high index of suspicion is required to diagnose and treat this disorder to prevent the consequences of long-term hypothyroidism on development.

Adolescent↗

Epigenetics: interaction of DNA methylation and chromatin.

Epigenetic regulation is the mechanism by which gene function is selectively activated or inactivated in the cells. It provides higher-ordered and more specified genetic information, compared with the whole genome itself. Recently, a variety of regulatory proteins including DNA methyltransferases, methyl-CpG binding proteins, histone-modifying enzymes, chromatin remodeling factors, and their multimolecular complexes have been identified. These facilitate our understanding of the molecular basis for transcription, DNA replication, mutation and repair, DNA recombination, and chromosome dynamics, which are crucial for normal cell regulation. Abnormalities in the epigenetic states represent human disease phenotypes, especially developmental defects and tumorigenesis. Therefore, epigenetics will become the focus and a major target for emerging biological and medical discoveries.

Acetylation↗

Chiari I malformation.

Chiari I malformation (CM1), the most common structural hindbrain disorder in humans, is traditionally characterized by the downward displacement of the cerebellar tonsils through the foramen magnum. However, this definition does not reflect the variability in clinical presentation, natural history and treatment response of this disorder. Some individuals with minimal tonsillar descent have severe neurological symptoms and syringomyelia, whereas others with extensive descent remain asymptomatic. Emerging evidence from neuroimaging, developmental biology and human genetics indicates that CM1 is not a single anatomical entity but a spectrum of disorders resulting from disruptions in coordinated growth and homeostasis across the cerebellum, posterior fossa, craniocervical junction, cerebrospinal fluid and neurovascular systems. CM1 may be best understood as a disorder of disrupted developmental scaling, in which the tightly regulated relationships between cerebellar growth and cranial accommodation are altered within a dynamic neurovascular and cerebrospinal fluid environment. In this context, tonsillar herniation is a geometric consequence rather than the primary disease process. This Primer synthesizes current knowledge on the epidemiology, mechanisms, diagnosis and management of CM1 across the lifespan. We highlight advances in neuroimaging, genomics and phenomics that support a shift from anatomy-based definitions towards an integrated genomic-phenomic classification.

Humans↗

Genome-wide gene expression profiles of the developing mouse hippocampus.

We have analyzed the developmental molecular programs of the mouse hippocampus, a cortical structure critical for learning and memory, by means of large-scale DNA microarray techniques. Of 11,000 genes and expressed sequence tags examined, 1,926 showed dynamic changes during hippocampal development from embryonic day 16 to postnatal day 30. Gene-cluster analysis was used to group these genes into 16 distinct clusters with striking patterns that appear to correlate with major developmental hallmarks and cellular events. These include genes involved in neuronal proliferation, differentiation, and synapse formation. A complete list of the transcriptional changes has been compiled into a comprehensive gene profile database (http://BrainGenomics.Princeton.edu), which should prove valuable in advancing our understanding of the molecular and genetic programs underlying both the development and the functions of the mammalian brain.

Animals↗

Molecular genetics, reductionism, and disease concepts in psychiatry.

The study of mental illness by the methods of molecular genetics is still in its infancy, but the use of genetic markers in psychiatry may potentially lead to a Virchowian revolution in the conception of mental illness. Genetic markers may define novel clusters of patients having diverse clinical presentations but sharing a common genetic and mechanistic basis. Such clusters may differ radically from the conventional classification schemes of psychiatric illness. However, the reduction of even relatively simple Mendelian phenomena to molecular genetics has been shown to be a surprisingly complex and problematic enterprise. Mental illnesses exist at many levels of including social, environmental, and developmental interactions. Reductionistic shifts in the classification of such a disease entity will have to address the interlevel dynamics that take place within the structure of theories of mental illness. The question of how molecular analysis of psychiatric disease will impact on the structure of existing theories and classification systems is the central topic of this paper.

Bipolar Disorder↗

Klein's archaic Oedipus complex and its possible relationship to the myth of the labyrinth: notes on the origin of courage.

The ancient Greek myth linking the images of the labyrinth and the Minotaur provides an allegory for Melanie Klein's conception of the archaic Oedipus complex as well as a vivid illustration of Winnicott's notions of object usage and the 'subjective object'. The labyrinth is suggestive of mother's body as the first area for an infant's exploration and putative sadistic conquest. The Minotaur, in turn, suggests the infant's unconscious phantasies about the content of mother's body, namely such projective identifications onto that body as the paternal penis and the 'internal babies'. Further, the heroic dynamic personified by Theseus in the myth of the labyrinth metaphorically signifies what is here proposed as a developmental line that involves the courage to do a number of things, including to become, to create, to seek, to explore, to do, to challenge, to undertake risks, to accept, to rescue, to initiate, to think, to know and to realize. The Minotaur can thus be thought to serve as a universal subjective signifier for an 'Object of Challenge', which, if not successfully dealt with by the ego-development of the infant, transforms that default into the 'Object of Nemesis'. Ultimately, this myth of mastery speaks to the psychoanalytic process itself as well as casting light on the transformative aspects of sexual intercourse as a personal healing ritual.

Ego↗

Effects of demographic and health variables on Rasch scaled cognitive scores.

OBJECTIVES: To determine whether demographic and health variables interact to predict cognitive scores in Asset and Health Dynamics of the Oldest-Old (AHEAD), a representative survey of older Americans, as a test of the developmental discontinuity hypothesis. METHODS: Rasch modeling procedures were used to rescale cognitive measures into interval scores, equating scales across measures, making it possible to compare predictor effects directly. Rasch scaling also reduces the likelihood of obtaining spurious interactions. Tasks included combined immediate and delayed recall, the Telephone Interview for Cognitive Status (TICS), Series 7, and an overall cognitive score. RESULTS: Demographic variables most strongly predicted performance on all scores, with health variables having smaller effects. Age interacted with both demographic and health variables, but patterns of effects varied. DISCUSSION: Demographic variables have strong effects on cognition. The developmental discontinuity hypothesis that health variables have stronger effects than demographic ones on cognition in older adults was not supported.

Age Factors↗

[Genetic ecology of rice allelopathy on receiver plant].

In this study, 5 parental rice lines with different allelopathic potential were employed in partial diallel cross (4 x 5) to get 10 groups of F1 seeds. After testing the inhibitory effects of 5 parents and 10 F1s under different environment at different leaf stage on the shoot length of receiver plant lettuce(Lactuca sativa L.), dynamic genetics of rice allelopathy and its genotype x environment effects were analyzed by using additive-dominant developmental genetic models. The results showed that additive and dominant effect genes expressed alternatively during 3-leaf stage to 8-leaf stage in rice seedling. As additive effect genes were pronounced at 7-leaf stage, dominant effect genes appeared to play the most important role at 3-leaf stage and 6-leaf stage but the two effect genes were equally important at 5-leaf stage and 8-leaf stage. Heritabilities analysis indicated that the general heritability in the narrow sense(HN2) was significant at 5-, 7- and 8-leaf stage, and decreased with increasing leaf stage. Rice allelopathy was significantly affected by genotype x environment (GE) interaction, suggesting that the environment of allelopathic rice development must be controlled for practical use.

Ecology↗

The hallucinating patient and nursing intervention.

This paper has been concerned with a patient's problematic behavior pattern, namely hallucinations. The social and dynamic significance of the behavior for the individual have been explored and analyzed and a formulation of possible developmental processes influencing the patient to utilize hallucinations has been discussed. On the basis of these analyses, formulations for a psychiatric nursing treatment plan of intervention have been presented. In conclusion, it is well to bear in mind that the schizophrenic patient, who is hallucinating, is striving to communicate in as clear and straightforward a way as he knows, the nature of his anxieties and experiences, despite how radically different they are from the nurse's, with speech content that is diffucult to follow. Thus, with this understanding, it behooves us as nurses to intervene accordingly and "decode" the hallucinated messages and thereby assist in breaking into the third stage in the evolutionary cycle of a psychosis, as cited by R.D. Laing: Stage 1 = Good (me); Stage 2 = Bad (me); Stage 3 = Mad (not me).

Ego↗

[In vitro study of the fusion products and cell hybrids of mouse oocytes, zygotes and blastomeres].

Several variants of mouse embryos were received by polyethylene glycol-induced fusion of ovulated oocytes, blastomeres from various developmental stages, zygotes and their fragments. Cytological analysis and observation in culture have been carried out. The nuclear dynamics during the process of fusion, onset of mitosis in fusion products, their cleavage and initial morphogenetic processes in developing embryos have been followed. The possibility of directed constitution of embryos with varying quantitative and qualitative combination of nuclei and cytoplasm is, thus, shown. Some aspects of application of these models in studying the controlling mechanisms of early embryogenesis are considered.

Animals↗

Regulation of microtubule dynamics by microtubule-associated protein expression and phosphorylation during neuronal development.

Neuronal morphogenesis is driven by cytoskeletal changes in which microtubules play a leading role. A very heterogeneous group of microtubule-associated proteins (MAPs) seems to control the dynamics and contribute to the organization of the microtubule cytoskeleton. Of great importance in this regard is the developmental regulation of the expression of certain MAPs in specific neuronal compartments. Furthermore, MAP functionality is also modulated by phosphorylation and dephosphorylation events. A correlation between the expression and/or phosphorylation of distinct MAPs and definite stages of neuronal development may be established. A putative role in synaptic plasticity for MAP modifications similar to those occurring during development can be anticipated. Interestingly, gross alterations in microtubule-associated proteins are found in several neuropathologies including Alzheimer's disease. In this review we focus on recent advances in the understanding of the molecular properties of major neuronal MAPs which may be relevant to these issues.

Animals↗

The development of family medicine in Israel.

Israeli family medicine provides an example of the accelerated development of a new discipline. This development occurred in a highly dynamic and rapidly growing society against a background of conflicting cultural traditions within the health care field. The developmental stages included: 1) the preponderance of specialists over generalists, 2) the introduction of family medicine teaching into the undergraduate medical curriculum, 3) the achievement of family medicine's independence from the status of a branch of internal medicine or community medicine, 4) the development of the residency training programs, and 5) the establishment of a national academic infrastructure. This paper analyzes the unsolved problem of gaining significant numbers of university academic appointments. Also, two major challenges for the future are examined: 1) the integration of preventive care into family practice, and 2) the exposure of primary care to competition from hospital-based specialists in an atmosphere of increasing commercialism. The Israeli experience forms a basis for comparison for family medicine in other countries.

Cross-Cultural Comparison↗

A conserved Notch-Meis1-Pbx cascade specifies secretory progenitors into spatially diverse intestinal best4 + cells.

best4 + cells are a recently described vertebrate intestinal epithelial cell type. best4 + cells are altered in inflammatory bowel disease and colorectal cancer, suggesting that stimulation of their homeostatic replenishment may have therapeutic potential. However, the development and function of best4 + cells remain unclear. Since mice lack best4 + cells, we established zebrafish as a tractable in vivo model to observe, manipulate, and remove best4 + cells in an organismal context. We dissected best4 + cell developmental regulation in vivo from birth to differentiation and specialization, focusing on factors conserved in best4 + cells across vertebrates. Lineage tracing demonstrated that best4 + cells arise from secretory progenitors, where Notch/Dll4 signaling mediates a decision between best4 + and enterochromaffin cells by triggering meis1b expression. Following specification by meis1b, pbx3a spatially diversifies best4 + cells, which develop regional heterogeneity in gene expression, intracellular pH, and function. In vivo live imaging and removal of best4 + cells showed that best4+ cells sense luminal pH changes and extend dynamic luminal and stromal projections, but are not required to restore global luminal pH after challenge. Altogether, this study experimentally delineates best4 + cell developmental regulation and develops a genetic toolkit to examine their function in vivo, both of which will aid investigating how best4 + cells are altered or can be restored during disease.

Animals↗

[Developmental changes of cardiac mechanics during fetal and postnatal life. Diagnostic role of Doppler echocardiography].

The advent of fetal echocardiography combined with Doppler technology gave the clinicians the possibility to evaluate and clarify the main aspects of fetal and postnatal circulatory physiology. From the end of cardiogenesis to the end of gestation the developmental changes of the fetal myocardial structure, ventricular function and circulatory physiology have all been studied. Also the physiological features of the transitional circulation in the first postnatal period, as well as the developmental changes in the morphology and function of the neonatal ventricles can be assessed by Doppler echocardiography. This review is divided in two parts. In the first one we will briefly discuss the contractile properties of the fetal myocardium, the cardiac performance and dynamics of the fetal circulation; in the second one we will consider the physiological aspects of the transitional circulation, the structural features of the immature neonatal myocardium, as well as the developmental changes of the myocardial mechanics as shown by Doppler ultrasound.

Age Factors↗

Changing chromatin dynamics and nuclear organization during differentiation in Drosophila larval tissue.

Global changes in gene expression and exit from the cell cycle underlie differentiation. Therefore, understanding chromatin behavior in differentiating nuclei and late G1 is key to understanding this developmental event. A nuclear event that has been shown to specifically occur in late G1 is the association of two heterochromatic blocks in Drosophila. The brown(Dominant) (bw(D)) chromosome of Drosophila melanogaster contains a large block of heterochromatin near the end of 2R. This distal block associates with centric heterochromatin (2Rh), but not until at least 5 hours into G1. We used the bw(D) allele as a model for nuclear organization to determine whether its association with the heterochromatic compartment of the second chromosomes (2Rh) strictly requires differentiation or if this change is a stochastic event, its occurrence being proportional to time spent in G1/G0 phase of the cell cycle. Fluorescence in situ hybridization on eye imaginal discs showed increased association between the bw locus and 2Rh in differentiated cells. Interestingly, an increase in the number of nuclei showing bw(D)-2Rh association in the brains of developmentally delayed larvae that were compromised for differentiation was also observed. Live fluorescence imaging showed that the kinetics of chromatin movement remains unchanged in the developmentally arrested nuclei. These observations suggest that nuclear reorganization is not directly controlled by specific inductive signals during differentiation and that this nuclear reorganization can happen in a cell, regardless of differentiation state, that is arrested in the appropriate cell cycle stage. However, we did see changes that appear to be more directly correlated with differentiation. Dynamic imaging in eye imaginal discs showed that the movement of chromatin is more constrained in differentiated cells, implying that confinement of loci to a smaller nuclear space may help to maintain the changed organization and the transcription profile that accompanies differentiation.

Alleles↗

Rewiring Cellular Context as A Central Mechanism Governing Cancer Stem Cell Survival: Insights from ESC Comparisons.

Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance, yet their remarkable persistence remains poorly understood. While CSCs share stemness attributes with embryonic stem cells (ESCs), including self-renewal, transcriptional plasticity, and permissive chromatin, they exhibit a fundamentally divergent regulatory logic that prioritizes survival over developmental fidelity. ESCs maintain globally open chromatin that supports transcriptional hyperactivity but predisposes them to apoptosis under genotoxic stress, whereas CSCs maintain dynamically inducible, permissive chromatin at survival loci while repressing differentiation programs, enabling adaptive stress responses. We advance the hypothesis that CSC persistence emerges not from any single factor, but from the integrative rewiring of signaling cascades (Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT/mTOR), stress-responsive transcription factors (HIFs, NF-κB, STAT3), and core pluripotency networks (OCT4, SOX2, NANOG) within a survival-centric context, reinforced by dynamic chromatin remodeling, inducible super-enhancer landscapes, and microenvironmental cues (hypoxia, inflammation, matrix stiffness). Within this framework, the E2F family serves as a key contextual integrator: in ESCs, constitutive E2F activity triggers p53-mediated apoptosis upon DNA damage, preserving genomic integrity; in CSCs, deregulated E2F activity redirects transcription toward DNA repair, antioxidant defenses, and anti-apoptotic programs. This functional divergence underscores that phenotypic outcome is determined by the broader cellular and epigenetic landscape rather than any single factor. We conclude that CSC persistence is an emergent property of this integrated, survival-centric program, fundamentally distinct from the developmental imperative of ESCs. Effective therapeutic strategies must therefore move beyond targeting individual pathways to dismantle the interconnected regulatory networks that define the CSC survival context, offering a more robust approach to overcome therapy resistance and prevent tumor relapse.

Cancer Stem Cells (CSCs)↗

Osteon remodeling dynamics in Macaca mulatta: normal variation with regard to age, sex, and skeletal maturity.

As research into bone maintenance and turnover is accelerated and expanded due to public health concerns about osteoporosis and other age-related changes and pathologies of bone, nonhuman animal models are becoming increasingly important as they allow for enhanced experimental manipulation and environmental control relative to humans. Old World Monkeys, such as the rhesus macaque, share physiological and developmental characteristics that make these primates particularly well suited to such studies. The purpose of this study was to characterize normal age and sex variation in osteon remodeling dynamics in skeletally immature and mature rhesus macaques. Femoral cross-sections from 75 Macaca mulatta were examined to evaluate the effect of age, sex, and skeletal maturity on osteon remodeling dynamics in this popular research primate. Results indicate that sex has a significant effect on osteon area (On.Ar), but generally is not an important contributor to normal variation in intracortical remodeling dynamics. Age and skeletal maturity, however, contribute significantly to variation in osteon population density (OPD), activation frequency (Ac.f), and bone formation rate (BFR), as is the case in humans. This study is the first to characterize normal age and sex variation in osteon remodeling in growing and adult rhesus macaques and its results support the use of this animal as a model for age-related changes and pathologies in the human skeleton.

Age Factors↗

Developmental origins of motor coordination: leg movements in human infants.

The development of coordination of leg movements of human infants is discussed from the perspective of dynamic motor theory. Even in the newborn period, leg movements have topographical and temporal organization, but it is global and inflexible. During the first year, limb segments become both disassociated from these global synergies and reintegrated into more complex coalitions. Growth-related changes in the biodynamic properties of the body segments may be as important as neurological maturation in determining the movement outcomes and may help explain the spurts, regressions, and asymmetries seen in early infancy.

Biomechanical Phenomena↗