RESUMEN
Congenital malformations are many times more common in individuals with Down syndrome (DS) than in the general population. The scope of these defects is as broad in DS as it is in the general population. A positive correlation exists between the prevalence of these defects in both groups, but the incidence of each is many times greater in DS. Two examples, Brushfield spots and anorectal abnormalities are noted in which racial/ethnic prevalence differences exist. The incidence of each condition in the subpopulation with DS is proportional to but many times greater than the incidence of that condition in the general population from which the subpopulation with DS was derived. Findings presented in this review support the notion that the autosomal trisomic state amplifies expression of exposure to teratogens.
Asunto(s)
Anomalías Congénitas/genética , Anomalías Congénitas/patología , Síndrome de Down/genética , Síndrome de Down/patología , Canal Anal/anomalías , Anomalías Congénitas/epidemiología , Anomalías Congénitas/etnología , Síndrome de Down/epidemiología , Síndrome de Down/etnología , Humanos , Grupos Raciales/genética , Recto/anomalíasRESUMEN
BACKGROUND: In the current study, the authors evaluated late neuropsychologic effects 7 years after diagnosis and the long-term survival in a cohort of patients treated for high-risk childhood acute lymphoblastic leukemia (ALL) with cranial radiation therapy. Efficacy and toxicity were evaluated in relation to patient age at diagnosis (age < or > or = 36 months). METHODS: Two hundred and one patients treated for high-risk ALL on the Dana-Farber Cancer Institute Consortium Protocol 87-01 were included, 147 of whom were in continuous complete disease remission and were eligible for cognitive testing. Sixty-one patients consented to undergo testing. All patients received 18 grays (Gy) of cranial radiation as a component of central nervous system treatment. RESULTS: For all 201 patients, the 5-year overall survival (% +/- the standard error) was 82% +/- 2 and the 5-year event-free survival (% +/- the standard error) was 75% +/- 3. Only two patients developed a central nervous system recurrence. Intelligence quotient (IQ) and memory were at the expected mean for age, but performance on a complex figure drawing task was found to be reduced. Children who were age < 36 months at the time of diagnosis were found to have an IQ in the average range, but showed verbal deficits. CONCLUSIONS: The results of the current study demonstrate excellent efficacy of therapy and relatively limited late neurotoxicity on a childhood ALL therapy protocol in which all evaluated patients had received 18 Gy of cranial radiation. Efficacious therapy that includes cranial radiation does not appear to necessarily incur a heightened risk for significant cognitive impairment.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Adolescente , Sistema Nervioso Central/efectos de la radiación , Niño , Preescolar , Cognición/efectos de la radiación , Irradiación Craneana , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Dosis de Radiación , Recurrencia , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
It has been recognized for many years that cerebellar abnormalities are frequently observed in association with Down syndrome (DS). An important question to be asked about these and other findings in DS is whether their occurrence (i) is attributable to specific loci on the triplicated chromosome or chromosomal segment or (ii) derives from exaggerated responses secondary to the genetic imbalance resulting from trisomy (Ts). Recently, similar cerebellar alterations were observed in subjects with DS and in Ts65Dn mice (Baxter et al., 2000), mice segmentally trisomic for a portion of chromosome 16, which is homologous for loci on the long arm of human chromosome 21. It was concluded by these authors that the occurrence of similar cerebellar changes in DS and in the DS mouse model resulted from triplication of these homologous loci in the two trisomic organisms, i.e. cerebellar development is affected similarly by homologous loci in each species. They wrote that their study of Ts65Dn mice "correctly predicts an analagous pathology in humans". . . and that. . . "The candidate region of genes on chromosome 21 affecting cerebellar development in DS is therefore delimited to the subset of genes whose orthologs are at dosage imbalance in Ts65Dn mice, providing the first localization of genes affecting a neuroanatomical phenotype in DS." Findings described in this review suggest otherwise--that cerebellar findings in DS and in the Ts65Dn mouse are a result of exaggerated vulnerability in general of the cerebellum to disturbing events and that liability to expression of response(s) is exacerbated by trisomy. This conclusion is based on the following: (i) the cerebellum has an extended postnatal development; (ii) numerous genetic, environmental, epigenetic and metabolic conditions express cerebellar changes similar to those observed in Down syndrome; (iii) most if not all chromosomal imbalance syndromes express similar cerebellar abnormalities; (iv) the cerebellum is particularly sensitive to diverse toxic agents which may act prenatally, postnatally and/or in the mature organism; and (v) cerebellar abnormalities similar to those found in Ts65Dn mice have been described in Ts19 mice which have no segments homologous to any segment of human chromosome 21. An unavoidable conclusion from the review is that triplication of specific loci on 21q is an unlikely explanation for the cerebellar findings in DS. A simple positive control, in which the effect of triplication of loci other than those in question on a specific phenotype, should be used in experiments comparing human and experimental trisomies. As pointed out many years ago by Lorke and his coworkers (Lorke et al., 1989; Lorke, 1994; Lorke and Albrecht, 1994) similar phenotypic findings in the presence of different trisomies in the same species would suggest that the trisomic state itself rather than the gene content of a particular trisomy is responsible for the genesis of traits at issue.
Asunto(s)
Cerebelo/anomalías , Síndrome de Down/patología , Animales , Síndrome de Down/genética , HumanosRESUMEN
Since the early 1970's numerous attempts have been made to learn whether specific segments of chromosome 21, when triplicated, are responsible for the clinical condition Down syndrome (DS). Studies were reported in which positive or negative clinical diagnoses of DS were made in the presence of partial trisomy of one or another segment of the chromosome. The distal half of the long arm of 21 (21q22) possesses most of the gene transcribing sites of the chromosome. It was this region that was thought to contain loci essential to production of the clinical syndrome. Subsequent studies identified subregions of this band as "minimal" or "critical" sites necessary and sufficient to produce the clinical condition. A major problem with these assignments was that different investigators defined different critical/minimal regions. In 1994 evidence was presented in which regions of most of the long arm of chromosome 21 were said to contribute to the DS phenotype. Soon after, a report described a child with DS and partial tetrasomy of the short arm and proximal long arm of 21, segments clearly distinct from the previously identified critical areas. Thus the clinical diagnosis of DS can be made in the presence of partial aneuploidy of nearly all segments of chromosome 21. It must be concluded that no evidence exists that individual loci on 21 are singularly responsible for specific phenotypic abnormalities in DS. Without exception, each of the clinical findings associated with DS is a multifactorial trait. The analysis of each trait in DS should thus be similar to analyses of the same traits in the general population with a focus on the way aneuploidy affects expression of multifactorial characteristics.
Asunto(s)
Cromosomas Humanos Par 21 , Síndrome de Down/genética , Niño , Mapeo Cromosómico , Marcadores Genéticos , Humanos , Transcripción GenéticaAsunto(s)
Síndrome de Down/fisiopatología , Medio Social , Niño , Desarrollo Infantil/fisiología , Síndrome de Down/complicaciones , Potenciales Evocados Somatosensoriales/fisiología , Habituación Psicofisiológica/fisiología , Humanos , Fenotipo , Ploidias , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Gemelos MonocigóticosRESUMEN
A cross-sectional study of prevalence of temporomandibular joint (TMJ) internal derangements, muscle disorders, and associated TM signs and symptoms was completed on 269 female nursing students. The prevalence of specific stages of internal derangements of the TMJ and muscle disorders was estimated, using established diagnostic criteria. The levels of dysfunction and symptomatology associated with each diagnosis were estimated with previously established indexes. When subjects with symptoms were asked if they had previous treatment for a TMJ problem, 6.7% responded positively. When subjects with symptoms who had not had treatment were asked why they had not sought treatment, most responded that it was not a problem or they could live with the symptoms. Thus, most subjects with clinically detectable dysfunction are functioning adequately without significant symptoms and do not need treatment.
Asunto(s)
Luxaciones Articulares/epidemiología , Músculos Masticadores/fisiopatología , Trastornos de la Articulación Temporomandibular/epidemiología , Adulto , Estudios Transversales , Dolor Facial/epidemiología , Femenino , Necesidades y Demandas de Servicios de Salud , Humanos , Luxaciones Articulares/fisiopatología , Anamnesis/métodos , Aceptación de la Atención de Salud , Prevalencia , Sonido , Trastornos de la Articulación Temporomandibular/fisiopatologíaRESUMEN
The spatiotemporal analysis of bioregulatory mechanisms at the level of intracellular multienzyme complexes and organelle interactions is made possible by the availability of endogenous and exogenous fluorescence probes, the development of microspectrofluorometers allowing one- and two-dimensional scans of intracellular fluorescence reactions, and the use of micromanipulatory techniques enabling the rapid alteration of metabolic states. Absorbed photons are not only a tool for quantitative evaluation of metabolic processes, they can also trigger alterations of cell membranes and functions as mediated by photosensitizer drugs. In the hierarchy of intracellular organization different levels of complexity are accessible to study, such as the regulation of multienzyme complexes and the interaction of organelle complexes. Typical applications of these methods are the investigation of drug effects (e.g., on melanoma cells), metabolic and structural alterations (e.g., in cystic fibrosis and Gaucher fibroblasts), organelle interactions in cells treated with toxic agents. The implications are relevant to biotechnology for better control of metabolite production and processing, design and testing of new drugs, understanding of drug resistance and better targeting of drugs or probes to selected intracellular sites. In addition, such in vitro methods can contribute to the provision of an alternative to "whole animal experiments" as already achieved in human and mouse fibroblasts, hepatocytes, hepatoma, Swiss 3T3 cells and other cells in culture, especially with regards to an analysis of the action of xenobiotics and drugs in cell physiology and pathology, fluorescence recovery after photobleaching, study of cytoskeleton dynamics and multiparameter probing of organelle activity during in vitro wound repair.
Asunto(s)
Orgánulos/metabolismo , Animales , Biotransformación , Fibrosis Quística/metabolismo , Fibroblastos/metabolismo , Colorantes Fluorescentes , Enfermedad de Gaucher/metabolismo , Humanos , Hígado/metabolismo , Orgánulos/ultraestructura , Espectrometría de Fluorescencia/métodos , Células Tumorales Cultivadas , Xenobióticos/farmacologíaRESUMEN
Cystic fibrosis (CF) remains a major problem in human genetics and cell pathophysiology. It is a single gene trait caused by a mutation on the long arm of chromosome 7. Among its expressions are abnormal regulation of chloride channels and/or microobstructions in exocrine tissues. Here, evidence is presented that mitochondria are dysfunctional in CF: the major site of increased intracellular Ca in CF is mitochondrial, cells from subjects with CF consume more oxygen than normal, respond differentially to inhibitors of mitochondrial function, express increased electron transport activity and altered kinetics of complex I (NADH dehydrogenase) of the mitochondrial electron transport system. Patients with CF express increased total and resting energy expenditure. Some of these differences from normal occur also in asymptomatic carriers of the CF gene.
Asunto(s)
Fibrosis Quística/metabolismo , Mitocondrias/metabolismo , Calcio/metabolismo , Fibrosis Quística/genética , Transporte de Electrón , Metabolismo Energético , Humanos , Consumo de OxígenoRESUMEN
Increased intracellular calcium (Ca) has been reported in several cell types in cystic fibrosis (CF). Because CF is an autosomal recessive trait examination of asymptomatic obligate carriers (HZ) of the gene is a powerful way to determine the relevance of this observation to the abnormal gene product. We report here that Ca as determined by atomic absorption spectrophotometry in cultured skin fibroblasts and circulating lymphocytes is greater in HZ than in control cells. Since an intracellular Ca increase is expressed in HZ the Ca differences in CF likely reflect action of the gene product responsible for CF and not some secondary or tertiary effect of the disease.
Asunto(s)
Calcio/metabolismo , Fibrosis Quística/metabolismo , Heterocigoto , Fibrosis Quística/genética , Fibroblastos/metabolismo , Humanos , Linfocitos/metabolismo , Espectrofotometría AtómicaRESUMEN
Cibacron Blue F3GA, the chromophore of blue dextran, was tested at 4-16 mumol/l for possible inhibition of NADH dehydrogenase activity when added to mitochondrial preparations from cultured human skin fibroblasts. The free dye was shown to be a competitive inhibitor for NADH in the oxidation of NADH catalyzed by the mitochondrial enzyme. The Ki (5.8 mumol/l) for Cibacron Blue F3GA was considerably lower than the Michaelis constant (Km) found for NADH substrate (13.2-16.1 mumol/l), indicating a strong binding of the dye to the substrate-binding site of the enzyme. This is the first report of the competitive inhibition by Cibacron Blue F3GA of mitochondrial NADH in any species.