RESUMO
Hirschsprung disease (HSCR) is a complex genetic disorder characterized by the absence of enteric nervous system (ENS) in the distal region of the intestine. Down Syndrome (DS) patients have a >50-fold higher risk of developing HSCR than the general population, suggesting that overexpression of human chromosome 21 (Hsa21) genes contribute to HSCR etiology. However, identification of responsible genes remains challenging. Here, we describe a genetic screening of potential candidate genes located on Hsa21, using the zebrafish. Candidate genes were located in the DS-HSCR susceptibility region, expressed in the human intestine, were known potential biomarkers for DS prenatal diagnosis, and were present in the zebrafish genome. With this approach, four genes were selected: RCAN1, ITSN1, ATP5PO and SUMO3. However, only overexpression of ATP5PO, coding for a component of the mitochondrial ATPase, led to significant reduction of ENS cells. Paradoxically, in vitro studies showed that overexpression of ATP5PO led to a reduction of ATP5PO protein levels. Impaired neuronal differentiation and reduced mitochondrial ATP production, were also detected in vitro, after overexpression of ATP5PO in a neuroblastoma cell line. Finally, epistasis was observed between ATP5PO and ret, the most important HSCR gene. Taken together, our results identify ATP5PO as the gene responsible for the increased risk of HSCR in DS patients in particular if RET variants are also present, and show that a balanced expression of ATP5PO is required for normal ENS development.
Assuntos
Síndrome de Down , Sistema Nervoso Entérico , Doença de Hirschsprung , Animais , Humanos , Doença de Hirschsprung/genética , Doença de Hirschsprung/metabolismo , Síndrome de Down/genética , Síndrome de Down/metabolismo , Peixe-Zebra/genética , Sistema Nervoso Entérico/metabolismo , Biomarcadores/metabolismoRESUMO
BACKGROUND: Premature ovarian failure (POF) is characterized by elevated gonadotrophins and amenorrhea before the age of 40 years and occurs approximately in 1% of women. POF etiology is highly heterogeneous with a wide spectrum of etiological pathogenic mechanisms including genetic causes. These mostly involve numerical, structural or monogenic defects on the X-chromosome. Mutations in a small number of autosomal genes (such as FOXL2 and NOBOX) have been identified as a cause of POF. However, in most cases, the disease underlying mechanisms are largely unknown. METHODS: We performed a genome-wide linkage analysis in a relatively large Dutch family with seven patients suffering from POF, showing a dominant pattern of inheritance. A genome-wide analysis, using 50K single nucleotide polymorphism arrays, was combined with conventional parametric linkage analysis. RESULTS: We identified three genomic regions on chromosomes 5, 14 and 18 yielding suggestive linkage (multipoint LOD score of 2.4 for each region). After inclusion of one elder unaffected family member, only the region on chromosome 5 remains as a putative POF locus. In addition, we investigated a second family (three living patients over three generations) for the regions on chromosome 5, 14 and 18. Haplotype analysis supported only the locus on chromosome 5q14.1-q15. CONCLUSION: We performed the first genome-wide linkage search in familial POF and identified a region on chromosome 5q14.1-q15, which may harbor a novel POF susceptibility gene.
Assuntos
Predisposição Genética para Doença/genética , Insuficiência Ovariana Primária/genética , Adulto , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 5 , Feminino , Ligação Genética , Humanos , Masculino , Países Baixos , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We report on a multigenerational family with isolated Hirschsprung's disease (HSCR). Five patients were affected by either short segment or long segment HSCR. The family consists of two main branches: one with four patients (three siblings and one maternal uncle) and one with one patient. Analysis of the RET gene, the major gene involved in HSCR susceptibility, revealed neither linkage nor mutations. A genome wide linkage analysis was performed, revealing suggestive linkage to a region on 4q31-q32 with a maximum parametric multipoint LOD score of 2.7. Furthermore, non-parametric linkage (NPL) analysis of the genome wide scan data revealed a NPL score of 2.54 (p = 0.003) for the same region on chromosome 4q (D4S413-D4S3351). The minimum linkage interval spans a region of 11.7 cM (12.2 Mb). No genes within this chromosomal interval have previously been implicated in HSCR. Considering the low penetrance of disease in this family, the 4q locus may be necessary but not sufficient to cause HSCR in the absence of modifying loci elsewhere in the genome. Our results suggest the existence of a new susceptibility locus for HSCR at 4q31.3-q32.3.
Assuntos
Cromossomos Humanos Par 4 , Predisposição Genética para Doença , Doença de Hirschsprung/genética , Mapeamento Cromossômico , Feminino , Genes Dominantes , Humanos , Masculino , Países Baixos , Linhagem , Proteínas Proto-Oncogênicas c-ret/genéticaRESUMO
OBJECTIVE: Daily use of inhaled corticosteroids (ICS) reduces exercise induced bronchoconstriction (EIB) in asthmatic children. A high single dose of ICS also provided acute protection against EIB. Objective of this study is to investigate whether a low single dose of ICS offers protection against EIB in asthmatic children. METHODS: 31 Mild asthmatic children not currently treated with inhaled corticosteroids, 5-16 years, with EIB (fall in FEV0.5/1 ≥ 13%) were included in a prospective intervention study. They performed two ECT's within 2 weeks. Four hours before the second test children inhaled 200 µg beclomethasone-dipropionate (BDP) with a breath-actuated inhaler (BAI). RESULTS: The median fall in FEV0.5/1 after 200 µg BDP was significantly reduced from 30.9% at baseline to 16.0% (P < 0.001). Twenty children (64.5%) showed a good response to 200 µg BDP (≥ 50% decrease in fall of FEV0.5/1), while 8 children showed a moderate response (25-50%), and three children showed no response at all (< 25%). CONCLUSION: A low single dose ICS offers acute protection against EIB in the majority of asthmatic children not currently treated with inhaled corticosteroids.
Assuntos
Asma Induzida por Exercício/prevenção & controle , Beclometasona/administração & dosagem , Glucocorticoides/administração & dosagem , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Nebulizadores e Vaporizadores , Estudos ProspectivosRESUMO
When someone is tilted laterally, the shear force on the maculae of the utriculus and the sacculus is described by the sine and the cosine of the angle of tilt, respectively. So both the sacculus and the utriculus are stimulated, but in the literature, ocular torsion is normally attributed to utricular function alone (and, thus, seen as a response to y-axis linear acceleration). However, on the base of a series of experiments on a tilt chair, a linear track, human centrifuges, and during parabolic flights, we conclude that the sacculus contributes to ocular torsion as well (there is a response to z-axis linear acceleration). The data suggest that the ratio of the utricular and saccular impact on ocular torsion is 3:1. The utriculus generates conjugate and the sacculus disjunctive torsional eye movements.
Assuntos
Movimentos Sacádicos/fisiologia , Adulto , Humanos , Cinética , Masculino , Fenômenos Fisiológicos Oculares , Rotação , Anormalidade TorcionalRESUMO
In an experiment with 17 subjects, interactions of visual roll motion stimuli and vestibular body tilt stimuli were examined in determining the subjective vertical. Interindividual differences in weighting the visual information were observed, but in general, visual and vestibular responses added in setting the vertical. Despite the conflicting sensory information, motion sickness was not reported apart from one subject on one single occasion. This is in conflict with the sensory mismatch theory on motion sickness, but in agreement with the subjective vertical conflict theory.
Assuntos
Conflito Psicológico , Percepção de Movimento/fisiologia , Enjoo devido ao Movimento/fisiopatologia , Postura/fisiologia , Feminino , Gravitação , Humanos , Masculino , Estimulação Luminosa , RotaçãoRESUMO
To assess a possible otolith contribution to effects observed following prolonged exposure to hypergravity, we used video oculography to measure ocular torsion during static and dynamic conditions of lateral body tilt (roll) before and after 1 h of centrifugation with a Gx-load of 3 G. Static tilt (from 0 to 57 degrees to either side) showed a 10% decrease in otolith-induced ocular torsion after centrifugation. This implies a reduced gain of the otolith function. The dynamic condition consisted of sinusoidal body roll (frequency 0.25 Hz, amplitude 45 degrees) about an earth horizontal and about an earth vertical axis (respectively, "with" and "without" otolith stimulation). Before centrifugation the gain of the slow component velocity (SCV) was significantly lower "with" otolith stimulation than "without" otolith stimulation. Apparently, the contribution of the otoliths counteracts the ocular torsion response generated by the semicircular canals. Therefore, the observed increase in SCV gain in the condition "with" otolith stimulation after centrifugation, seems in correspondence with the decreased otolith gain in the static condition.
Assuntos
Movimentos Oculares/fisiologia , Membrana dos Otólitos/fisiologia , Adulto , Centrifugação , Feminino , Humanos , Masculino , Anormalidade TorcionalRESUMO
In reviewing the various forms of motion sickness, the classic sensory rearrangement theory has been redefined by demonstrating that only one type of conflict is necessary and sufficient to explain all different kinds of motion sickness. A mathematical description is provided from the summarizing statement that "All situations which provoke motion sickness are characterised by a condition in which the sensed vertical as determined on the basis of integrated information from the eyes, the vestibular system and the nonvestibular proprioceptors is at variance with the subjective vertical as expected from previous experience."
Assuntos
Conflito Psicológico , Enjoo devido ao Movimento/fisiopatologia , Simulação por Computador , Humanos , Propriocepção/fisiologia , Rotação , Vertigem/fisiopatologiaRESUMO
During smooth pursuit eye movement performance often an illusory motion of background objects is perceived. This so called Filehne illusion has been quantified and explored by Mack and Herman [Q. J.exp. Psychol. 25, 71-84 (1973); Vision Res. 18, 55-62 (1978)]. According to them two independent factors contribute to the Filehne illusion: (1) a subject relative factor, viz. the underregistration of pursuit eye movements by the perceptual system, and (2) an object relative factor, viz. adjacency of the pursued fixation point and the background stimulus. The evidence of the present experiment supports the former but rejects the latter as a contributing factor. Instead of the concept of adjacency, an alternative theoretical extension of the subject relative factor is offered.
Assuntos
Movimentos Oculares , Ilusões/fisiologia , Percepção de Movimento/fisiologia , Ilusões Ópticas/fisiologia , Acompanhamento Ocular Uniforme , Adulto , Feminino , Fixação Ocular , Humanos , Masculino , Limiar Sensorial/fisiologia , Fatores de TempoRESUMO
An experiment was set up to investigate the possible influence of oculomotor activity on experienced speed of circular vection. With the standard lined inner wall of an optokinetic drum as stimulus, we found that subjects, sequentially exposed to periods with or without fixation point, experienced an increment in speed of circular vection when the eyes were kept stationary as compared to when optokinetic nystagmus occurred. In a control condition, however, where the influence of optokinetic nystagmus vs fixed gaze on the speed of circular vection was measured separately, the effect was not significant. These findings might explain a discrepancy found in the literature.
Assuntos
Fixação Ocular/fisiologia , Percepção de Movimento/fisiologia , Nistagmo Fisiológico/fisiologia , Adulto , Feminino , Humanos , Masculino , Sensação/fisiologia , Fatores de TempoRESUMO
This paper shows that the experienced speed of circular vection depends on stimulus speed, not on stimulus temporal frequency. But why would anyone think the contrary? The point is that many modelers in the field of motion perception believe that perceived speed is determined by temporal frequency. Moreover, the optokinetic behaviour of the fly is said to be dependent on the temporal frequency, not the speed, of the stimulus pattern (Reichardt, 1987). It was the aim of the present experiment to test the notion that the experienced speed of circular vection is proportional to stimulus velocity information, which is carried by the temporal and the spatial characteristics of light.
Assuntos
Ilusões/fisiologia , Percepção de Movimento/fisiologia , Ilusões Ópticas/fisiologia , Adulto , Feminino , Humanos , Luz , Masculino , Movimento/fisiologia , Nistagmo Fisiológico/fisiologia , Fotometria , Sensação/fisiologia , Fatores de TempoRESUMO
The effect of irradiation on cardiac function was assessed using an isolated working rat heart preparation. The animals were given single doses of X-rays in the range 15-30 Gy to their hearts. Cardiac output (CO = aortic flow + coronary flow), heart weight and body weight were followed for a period of 10 months after treatment. Irradiation led to a decrease in cardiac function. This reduction was dose-dependent and progressive with time after treatment. The shape of the Frank-Starling curves constructed for irradiated hearts suggests a loss of contractile function of the myocardium. Coronary flow rates measured in 'working' hearts and in 'Langendorff' hearts were not significantly changed by the irradiation treatment. The isolated working rat heart preparation proved to be a simple and suitable animal model for the investigation of irradiation-induced cardiotoxicity.
Assuntos
Coração/efeitos da radiação , Animais , Peso Corporal/efeitos da radiação , Débito Cardíaco/efeitos da radiação , Circulação Coronária/efeitos da radiação , Relação Dose-Resposta à Radiação , Feminino , Coração/fisiologia , Técnicas In Vitro , Tamanho do Órgão/efeitos da radiação , Perfusão/instrumentação , Perfusão/métodos , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
The present paper describes a technique to quantify eye rotations about the visual axis (ocular torsion). Two digitized polar transformed images of the iris are displayed on a video monitor in order to facilitate a visual comparison and manual interaction. Emphasis is placed on error analysis and the method's simplicity when applied to static ocular torsion measurement. The implementation, applying averaging over ocular torsion determined in partitioned iris images, yields a theoretical resolution of 5' of arc. In a control experiment with an artificial eye, the accuracy showed to be better than 14' of arc. In practice, the measuring device was validated with the data from the literature by means of an experiment about ocular torsion in humans during tilt and hypergravity conditions (up to 3 g).
Assuntos
Processamento de Imagem Assistida por Computador , Transtornos da Motilidade Ocular/diagnóstico , Gravação em Vídeo , Viés , Estudos de Avaliação como Assunto , Olho Artificial , Humanos , Postura , Reprodutibilidade dos TestesRESUMO
A new, automatic method for determination of human ocular torsion (OT) was developed based on the tracking of iris patterns in digitized video images. Instead of quantifying OT by means of cross-correlation of circular iris samples, a procedure commonly applied, this new method automatically selects and recovers a set of 36 significant patterns in the iris by the technique of template matching as described by In den Haak et al. Each relocated landmark results in a single estimate of the torsion angle. A robust algorithm estimates OT from this total set of individually determined torsion angles, thereby largely correcting for errors which may arise due to misjudgement of the rotation center. The new method reproduced OT in a prepared set of images of an artificial eye with an accuracy of 0.1 degree. In a sample of 256 images of human eyes, a practical reliability of 0.25 degrees was achieved. To illustrate the method's usefulness, an experiment is described in which ocular torsion was measured during two dynamic conditions of whole-body roll, namely during sinusoidally pendular motion about either an earth horizontal or earth vertical axis (that is "with" and "without" otolith stimulation, respectively).
Assuntos
Movimentos Oculares/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Algoritmos , Humanos , Processamento de Imagem Assistida por Computador/métodos , Processamento de Imagem Assistida por Computador/estatística & dados numéricos , Iris/fisiologia , Pupila/fisiologia , Reprodutibilidade dos Testes , Rotação , Gravação de Videoteipe/instrumentação , Gravação de Videoteipe/métodosRESUMO
In a previous study (1) it was found that in healthy subjects Ocular (Counter) Rotation is mainly due to otolith stimulation and only to a minor extent induced by slanted visual structures. Stimulation of the neck by tilting the trunk laterally upwards did not result in a systematic rotation of the eyes. In the present study it was found that subjects with bilateral loss of vestibular function showed a higher visually induced ocular rotation. Tilting the head (cervical stimulation) or the whole body (somatosensory stimulation) also led to a considerable OCR, demonstrating substitution of other sensory modalities for the loss of vestibular function. Estimates of the subjective horizontal were noisy, demonstrating the lack of an adequate gravitational reference signal.
Assuntos
Movimentos Oculares/fisiologia , Doenças Vestibulares/fisiopatologia , Testes de Função Vestibular/métodos , Percepção Visual/fisiologia , Orelha Interna/fisiopatologia , Humanos , Pessoa de Meia-Idade , Postura , Reflexo Vestíbulo-Ocular/fisiologia , Córtex Somatossensorial/fisiologiaRESUMO
In the present paper a series of experiments will be described in which the postural consequences of long (up to 1.5 h) duration 3G-centrifugation have been subject to investigation. A vestibular model is presented in order to explain for the postural imbalance found in specific conditions after the centrifuge run, and for the often concomitant feelings of motion sickness (50% of the subjects suffer from Sickness Induced by long duration Centrifugation). Finally, the possible relation between SIC and the Space Adaptation Syndrome is discussed.
Assuntos
Postura/fisiologia , Adaptação Fisiológica , Centrifugação , Gravitação , Humanos , Enjoo devido ao Movimento/fisiopatologia , Fatores de Tempo , Vestíbulo do Labirinto/fisiologiaRESUMO
The dynamic contribution of the otolith organs to the human ocular torsion response was examined during passive sinusoidal body roll about an earth-horizontal axis (varying otolith inputs) and about an earth-vertical axis (invariant otolith inputs). Torsional eye movements were registered in 5 subjects by means of video-oculography. At a fixed amplitude of 25 degrees, the stimulus frequency was varied from 0.05 to 0.4 Hz. Additionally, at a fixed frequency of 0.2 Hz, the response was also measured at the amplitudes to 12.5 degrees and 50 degrees. The results showed that the gain and phase of the torsional slow component velocity (SCV) did not depend on stimulus amplitude, indicating a linear response. Contribution of the otoliths affected the ocular torsion response in three different ways. First, the gain of the SCV was slightly, but consistently, higher during rotation about an earth-horizontal axis than during rotation about an earth-vertical axis. With invariant otolith inputs the average gain increased from 0.10 at 0.05 Hz to 0.26 at 0.25 Hz. With varying otolith inputs, the average gain increased from 0.14 to 0.37. Second and more substantially, contribution of the otoliths improved the response dynamics by reducing the phase lead at frequencies up to 0.02 Hz. Third, the nystagmus showed considerably less anticompensatory saccades in upright conditions than in supine conditions, even though the SCV gain was lower in the latter. As a consequence, the average excursion of torsional eye position was highest during earth-horizontal rotation. This effect was observed in the entire frequency range. Thus, the otoliths controlled the human torsional VOR not only at low stimulus frequencies by keeping the slow component in phase with head motion, but also in a wider frequency range by modulating the saccadic behavior as to increase the amplitude of ocular torsion. We conclude that the primary concern of the otolith-oculomotor system during head tilt is to stabilize eye position in space, rather than to prevent retinal blur.
Assuntos
Membrana dos Otólitos/fisiologia , Reflexo Vestíbulo-Ocular/fisiologia , Adulto , Eletroculografia , Oftalmopatias/fisiopatologia , Feminino , Humanos , Masculino , Nistagmo Optocinético/fisiologia , Rotação , Movimentos Sacádicos/fisiologia , Anormalidade Torcional , Gravação em VídeoRESUMO
Previous investigations suggest strong similarities between aftereffects of an 1.5-hour 3 gx centrifuge run (Sickness Induced by Centrifugation; SIC) and the Space Adaptation Syndrome (SAS). Head movements proved to be especially nauseogenic in both cases. Until recently, during SIC experimentation, the performance of head movements was not adequately operationalized, which hampered a statistical evaluation. For this purpose, a test was designed by which head movements in four directions (left, right, up, and down) were provoked and registered, once before and once after a 1-h 3 g centrifuge run. Subjects had to execute these head movements in order to perform well on a psychomotor task. The results indicate that the test described is sensitive in discriminating between subjects who are seriously affected after a long duration centrifugation and those who are not. Because differences in performance were found only on those parts of the task in which head movements were involved, objective evidence is obtained in favour of a vestibular cause in the etiology of SIC.
Assuntos
Cabeça/fisiologia , Hipergravidade , Enjoo devido ao Movimento/fisiopatologia , Movimento/fisiologia , Desempenho Psicomotor/fisiologia , Centrifugação , Feminino , Humanos , Hipergravidade/efeitos adversos , Masculino , Enjoo devido ao Movimento/etiologia , Fatores de Tempo , Vestíbulo do Labirinto/fisiologiaRESUMO
By combining a tilting chair and a tilting room we investigated the subjective horizontal (SH) and ocular counterrotation (OCR) as a function of body tilt, trunk tilt, and tilt of a visual frame. Significant influences of (isolated or combined) vestibular and visual information were found, but no influence of neck proprioception. A second and similar experiment, however, now conducted with subjects devoid of labyrinthine function, suggested a contribution of the neck as well as of somatosensory origin. This made a reinterpretation of our data for normal subjects possible.