Biomedical subjects

E Lai

Publications and source records attributed to E Lai.

At least 37 records · Page 2Linked to original sources

PubMed1999

Dynamics of placodal lineage development revealed by targeted transgene expression.

Examination of the expression pattern of the winged-helix transcription factor BF-1 outside of the neural tube in mouse embryos suggests that BF-1 is restricted to a population of cells that gives rise to the ectodermal placodes and their derivatives. Within the sensory cranial nerve ganglia, the expression of BF-1 distinguishes cells that arise from the placodes from those derived from the neural crest. Expression of a lacZ transgene targeted to the BF-1 locus was used to follow the placodal lineage during mouse development. Analysis of placodal development in mice with a targeted deletion of BF-1 reveals that, although BF-1 is required for proliferation of the cells arising from the nasal placode, it is not required for the proliferation, survival, or both, of placode-derived cells in the sensory cranial nerve ganglia. Dev Dyn 1999;215:332-343.

Animals↗

PubMed1999

Unilateral neglect and disambiguation of the Necker cube.

Three groups of patients (right brain-damaged patients with or without left neglect, and left brain-damaged patients) and a group of healthy subjects, matched for age and educational level to the three groups of patients, were asked to report which of the two frontal surfaces of Necker cubes oriented in four different ways looked, at first sight, nearer to the viewer. The extent to which, and the way in which, disambiguation of the apparent perspective of Necker cubes occurred was found to vary across the four orientations and to be different in left-neglect patients compared with subjects of the other three groups. With normal subjects, the disambiguating factor is suggested to be a disposition to perceive the upper surface, which is nearly orthogonal to the frontal plane, as external to the cube. This would result from a navigation of the observer's spatial attention towards its target along a particular path that is altered in patients suffering from left neglect. It is suggested that comparison of the paths followed by the attentional vectors of normal subjects and left-neglect patients is potentially fruitful for a better understanding of the brain's normal mechanisms of spatial attention and of unresolved issues concerning the perception of the Necker cube.

Adult↗

PubMed1999

Dual role of brain factor-1 in regulating growth and patterning of the cerebral hemispheres.

Brain factor-1 (BF-1) is a winged-helix (WH) transcription factor with a restricted pattern of expression in the neural tube. In the embryo, BF-1 is localized to the progenitor cells of the most rostral neural tube, the telencephalic neuroepithelium. Expression of BF-1 persists in the adult brain in the structures derived from the telencephalon, including the cerebral cortex, the hippocampus, the olfactory bulbs and the basal ganglia. Targeted disruption of the BF-1 gene in mice results in hypoplasia of the cerebral hemispheres. Proliferation of the telencephalic neuroepithelium is decreased and neuronal differentiation occurs prematurely. The forebrain of the BF-1 (-/-) mutant also displays dorsal-ventral patterning defects. Development of the ventral (basal) region of the telencephalon is more severely affected than the dorsal region. These anomalies are associated with the ectopic expression of BMP4 in the dorsal telencephalic neuroepithelium and the loss of shh in the ventral telencephalon. These results raise the possibility that BF-1 may modulate both progenitor cell proliferation and regional patterning by regulating the expression or activity of inductive signals which act on the telencephalic neuroepithelium.

Animals↗

PubMed1999

FAST-2 is a mammalian winged-helix protein which mediates transforming growth factor beta signals.

The mechanisms by which transforming growth factor beta (TGF-beta) and related ligands regulate transcription remain poorly understood. The winged-helix (WH) transcription factor fork head activin signal transducer 1 (FAST-1) was identified as a mediator of activin signaling in Xenopus embryos (X. Chen, M. J. Rubock, and M. Whitman, Nature 383:691-696, 1996). We have cloned a novel WH gene from the mouse which shares many properties with FAST-1. We find that this gene, which we call FAST-2, is able to mediate transcriptional activation by TGF-beta. FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-beta, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1. Analysis of the sequences of FAST-1 and FAST-2 reveals substantial protein sequence divergence compared to known vertebrate orthologs in the WH family. This suggests that FAST-2 represents a new WH gene related to FAST-1, which functions to mediate TGF-beta signals in mammals. We have also examined the structure of the FAST-2 gene and find that it overlaps with a kinesin motor protein gene. The genes are transcribed in opposite orientations, and their transcripts overlap in the 3' untranslated region.

Activins↗

PubMed1999

Co-inherited Gilbert's syndrome: a factor determining hyperbilirubinemia in homozygous beta-thalassemia.

BACKGROUND AND OBJECTIVE: Patients with thalassemia major and intermedia show a marked variability of serum indirect bilirubin levels. In this paper we tested the hypothesis related to the variability of the glucuronidation bilirubin rate which depends on the configuration of the A(TA)nTAA motif of the UGT1*1 glucuronosyltransferase gene promoter. DESIGN AND METHODS: We studied the configuration of the A(TA)nTAA motif in 26 patients with thalassemia major and 34 with thalassemia intermedia. RESULTS: In patients with thalassemia major and in those with thalassemia intermedia significantly higher bilirubin levels were found in patients with the (TA)7/(TA)7 genotype, than in those with the (TA)7/(TA)6 or (TA)6/(TA)6 genotype. INTERPRETATION AND CONCLUSIONS: These results indicate that the (TA)7/(TA)7 genotype, the configuration found in patients with Gilbert's syndrome, is capable of modifying the clinical phenotype of homozygous beta-thalassemia. This is an example of the role played by co-inherited modifying gene(s) on the extent of clinical heterogeneity of monogenic disorders.

Gilbert Disease↗

PubMed1998

A 4-Mb high-density single nucleotide polymorphism-based map around human APOE.

Whole-genome association studies using single-nucleotide polymorphisms (SNPs) are the proposed method of choice for the identification of loci associated with complex diseases. In this report, we address the feasibility of generating high-density SNP maps (with <100-kb spacing). As a pilot study, we concentrated on a 4-Mb region around the human APOE locus on chromosome 19. We compared the efficiency of SNP detection using YAC-based versus BAC/PAC-based maps, sequencing individual DNAs versus a pooled DNA sample, and we evaluated three different software applications for polymorphism detection. A total of 121 SNPs (25 in coding regions) were identified. The frequency of SNP detection was 1 SNP/1.1 kb of genomic sequence. From APOE to CALM3 (approximately 2 Mb), the average marker spacing was approximately 30 kb. Fifty-one SNPs were genotyped in five populations, and 10 SNPs showed an allele frequency differential greater than 0.5 between populations. Our results demonstrated that high-density SNP maps can be efficiently generated using existing technologies and that a genome-wide map with 60,000-100,000 SNPs is achievable in a reasonable time frame.

Alleles↗

PubMed1998

Telencephalic progenitors maintain anteroposterior identities cell autonomously.

Grafting experiments have demonstrated that determination of anteroposterior (AP) identity is an early step in neural patterning that precedes dorsoventral (DV) specification [1,2]. These studies used pieces of tissue, however, rather than individual cells to address this question. It thus remains unclear whether the maintenance of AP identity is a cell-autonomous property or a result of signaling between cells within the grafted tissue. Previously, we and others [3-5] have used transplants of dissociated brain cells to show that individual telencephalic precursor cells can adopt host-specific DV identities when they integrate within novel regions of the telencephalon. We have now undertaken a set of transplantations during the same mid-neurogenic period used in the previous studies to assess the ability of telencephalic progenitors to integrate and differentiate into more posterior regions of the neuraxis. We observed that telencephalic progenitors were capable of integrating and migrating within different AP levels of the central nervous system (CNS). Despite this, we found that telencephalic progenitors that integrated within the diencephalon and the mesencephalon continued to express a telencephalic marker until adulthood. We speculate that during neurogenesis individual progenitors are determined in terms of their AP but not their DV identity. Hence, AP identity is maintained cell autonomously within individual progenitors.

Animals↗

PubMed1998

Gene structure and chromosomal localization of the human P2X7 receptor.

The genomic organization for the human P2X7 receptor gene was determined to comprise 13 exons. Alignment of the exon-intron junctions with those for the rat P2X2 gene demonstrated a precise conservation of the boundaries for the first 10 introns. The human P2X7 receptor gene was localized by in situ hybridization to chromosome 12q24. Radiation hybrid mapping indicated that this is within 130 kb of the gene for the homologous P2X4 receptor.

Animals↗

PubMed1997

Use of testosterone to prevent cyclophosphamide-induced azoospermia.

BACKGROUND: Prepubertal patients receiving chemotherapy are relatively resistant to cyclophosphamide-induced germinal cell alterations. OBJECTIVE: To study the possible protective effect of testosterone used to inhibit germinal cell activity in men who are receiving cyclophosphamide. DESIGN: Randomized, clinical trial. SETTING: University medical center. PATIENTS: 15 patients with the nephrotic syndrome who were treated with cyclophosphamide for 6 to 8 months. INTERVENTION: Five patients received daily oral cyclophosphamide, five received cyclophosphamide in monthly bolus injections, and five received monthly intravenous boluses of cyclophosphamide plus testosterone (100 mg intramuscularly every 15 days). MEASUREMENTS: Sperm counts, serum follicle-stimulating hormone levels, and serum luteinizing hormone levels were measured before, during, and after treatment with cyclophosphamide alone or cyclophosphamide plus testosterone. RESULTS: The 10 patients who did not receive testosterone became azoospermic during cyclophosphamide therapy. In only 1 of the 10 patients did the sperm count return to normal 6 months after discontinuation of therapy. Follicle-stimulating hormone levels were elevated in these patients (mean +/- SE, 19.20 +/- 1.28 IU/L in patients receiving oral cyclophosphamide and 16.04 +/- 2.22 IU/L in patients receiving intravenous cyclophosphamide alone). All 5 patients who received testosterone became azoospermic or severely oligospermic during treatment but had a normal sperm count 6 months after the discontinuation of therapy. In these patients, the mean sperm count was 45.78 +/- 3.89 x 10(6)/mL and follicle-stimulating hormone levels were normal (5.08 +/- 0.56 IU/L). CONCLUSION: Testosterone given to men before and during an 8-month cycle of cyclophosphamide therapy for the nephrotic syndrome may preserve fertility.

Adult↗

PubMed1997

The distribution of total and specific serum IgE in the European Community Respiratory Health Survey.

BACKGROUND: Variations in the prevalence of atopy could provide important clues to the etiology of atopy and asthma. Although estimates of prevalence are available from different studies, a lack of standardization makes comparisons difficult. OBJECTIVE: This study was conducted to estimate the variation of geometric mean levels of serum IgE and the prevalence of specific IgE to common allergens between populations as part of the European Community Respiratory Health Survey (ECRHS), a multicenter survey of asthma and risk factors for asthma. METHODS: Random samples of subjects living in 37 centers in 16 countries who had answered a questionnaire about their respiratory symptoms were invited for further assessment including total serum IgE and the presence of specific IgE against house dust mite (Dermatophagoides pteronyssinus), timothy grass, cat, Cladosporium herbarum, and a local allergen. Sera were tested from 13,883 persons. RESULTS: The estimated prevalence of atopy, defined as the presence of at least one positive specific IgE, ranged from 16% in Albacete (Spain) to 45% in Christchurch (New Zealand). The geometric mean total serum IgE varied from 13 kU/L in Reykjavik (Iceland) to 62 kU/L in Bordeaux (France). There was no relation between the geometric mean total serum IgE in a center and the prevalence of atopy. CONCLUSIONS: There are substantial variations in the prevalence of atopy and the level of serum IgE. These variations are independent of each other and likely to be largely environmental in origin.

Allergens↗

PubMed1997

TWH regulates the development of subsets of spinal cord neurons.

Thymocyte winged helix (TWH) is a putative transcription factor expressed in the developing neural tube. At midgestation, TWH expression identifies subsets of spinal cord motor neurons and interneurons. TWH-expressing motor neurons were restricted to specific spinal cord levels, distinguishing motor neurons at lumbar from those at cervical levels. To understand the developmental role of TWH, we replaced the TWH gene with the lacZ reporter gene and generated mice with a homozygous disruption of the TWH gene. TWH(-/-) mutant mice had increased perinatal mortality, retarded postnatal growth, and motor weakness. The TWH(-/-) mutation resulted in alterations in the sizes and position of different neuronal populations. Our results demonstrate that TWH plays a critical role in neuronal development and suggest that TWH regulates the early differentiation of neural progenitors.

Animals↗

PubMed1997

Pulse oximeter performance during desaturation and resaturation: a comparison of seven models.

STUDY OBJECTIVE: To compare pulse oximeter performance during induced hypoxemia. DESIGN: Prospective investigation in human volunteers. SETTING: Laboratory facility at a university medical center. PATIENTS: 8 unanesthetized, healthy ASA physical status I volunteers. INTERVENTIONS: We evaluated the accuracy and response times of seven popular pulse oximeters during induced hypoxemia. Arterial blood fractional oxygen saturation (SaO2) measurements were performed simultaneously and considered a gold standard. MEASUREMENTS AND MAIN RESULTS: All oximeters were accurate (+/-2%) while subjects were breathing room air. During maximal hypoxemia (induced by breathing a FIO2 = 10% in nitrogen), large differences were noted between oxygen saturation as measured by pulse oximetry (SpO2) and SaO2 values, with pulse oximeters consistently underreporting SpO2 when actual SaO2 values were 75% or less. The Ohmeda 3740 (Ohmeda, Boulder, CO) using an ear probe was the first to detect desaturation (change in SpO2 > 3%) in 4 of 8 subjects (p < 0.05), and the Nellcor N200 reflectance oximeter (Nellcor, Inc., Pleasanton, CA) was first in 3 of 8 subjects (p < 0.05). During resaturation (after administering 100% oxygen), the Novametrix Oxypleth (Novametrix, Wallingford, CT) was significantly faster than other oximeters (p < 0.05) to return to baseline (SpO2 = 98%). CONCLUSION: Most models of oximeters tested performed well when hemoglobin oxygen saturation was high, but all were inaccurate when SaO2 was approximately 75%. During induced hypoxemia, there were significant differences in the response times of oximeters tested, with no model demonstrably superior to others in all measures of performance.

Adult↗

PubMed1997

Effects of motion, ambient light, and hypoperfusion on pulse oximeter function.

STUDY OBJECTIVE: To compare the performance of five pulse oximeters during hypoperfusion, probe motion, and exposure to ambient light interference. DESIGN: Prospective study. SETTING: Laboratory facility at a university medical center. PATIENTS: 8 unanesthetized, ASA physical status I volunteers. INTERVENTIONS: We evaluated five common pulse oximeters with respect to three scenarios: (1) an operating room light was shone on oximeter probes, (2) a motion generator was used to generate 2 Hz and 4 Hz hand motion, and (3) a pneumatic compression device overlying the brachial artery was used to simulate hypoperfusion. Electrocardiographic (ECG) and arterial blood gas values were considered gold standards for heart rate (HR) and oxygen saturation (SpO2) respectively. SpO2 nondisplay and values greater than 4% from simultaneous arterial SaO2-oximeter values were defined as errors. Nondisplay of HR, or HR greater than 5% from ECG values, were also considered errors. MEASUREMENTS AND MAIN RESULTS: The Ohmeda and Nellcor N200 with finger probe had the highest total failure rates with respect to both SpO2 and HR due to ambient light interference (p < 0.05). The Nellcor N200 with finger probe and N200 with C lock were the most accurate with regard to SpO2 during 2 Hz and 4 Hz motion (p < 0.05). However, all oximeters failed dramatically during 4 Hz motion when measuring HR. In the hypoperfusion model, the Nellcor N200 with finger probe and the Nellcor C Lock oximeters performed significantly better than all others in terms of both HR and SpO2 (P < 0.05), while the Criticare oximeter failed 100% of the time. CONCLUSION: There are significant differences in the accuracy of commercially available pulse oximeters during nonideal circumstances, with failure rates varying from approximately 5% to 50% depending on the oximeter and source of interference. Furthermore, no single oximeter performed the best under all conditions.

Adult↗

PubMed1997

IMAGE cDNA clones, UniGene clustering, and ACeDB: an integrated resource for expressed sequence information.

In this study we describe a new information resource that provides integrated access to information on IMAGE (integrated molecular analysis of genomes and their expression) cDNA library clones and derived expressed sequence tags (ESTs). We have developed an automated procedure that collates data from various public sources into a single ACeDB database. This database is a valuable tool for electronic cloning experiments and gene expression studies. It allows researchers to find information about cDNA libraries, plate addresses, insert sizes, and sequence data for IMAGE clones, the assignment of ESTs to UniGene clusters, and the chromosomal location of those genes in an efficient, graphically oriented manner.

Cloning, Molecular↗

PubMed1996

Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2.

Metanephric mesenchyme gives rise to both the epithelial cells of the nephron and the stromal cells of the mature kidney. The function of the stroma. in kidney morphogenesis is poorly understood. We have generated mice with a null mutation in the Winged Helix (WH) transcription factor BF-2 to examine its function during development. BF-2 expression within the developing kidney is restricted to the stromal cell lineage. Homozygotes die within the first 24 hr after birth with abnormal kidneys. Mutant kidneys are small, fused longitudinally, and rotated 90 degrees ventrally. Histological examination reveals a smaller collecting system, numerous large condensations of mesenchyme, and a decrease in the number of nephrons. Using molecular markers we show that induction and condensation of the nephrogenic mesenchyme occurs normally in mutant. The disruption of BF-2 reduces the rate of differentiation of the condensed mesenchyme into tubular epithelium, as well as the rate of growth and branching of the ureter and collecting system. Our findings demonstrate that BF-2 and stromal cells have essential functions during kidney morphogenesis. Furthermore, they suggest that BF-2 controls the production, by the stroma, of signals or factors that are required for the normal transition of induced mesenchyme into tubular epithelium and full growth and branching of the collecting system.

Animals↗

PubMed1996

The brain-specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons.

Cell cycle withdrawal in postmitotic cells involves cyclin-dependent kinase (Cdk) inhibitors that repress cell cycle Cdk activity. During mouse neurogenesis, cortical postmitotic neurons are shown here to accumulate high levels of the p27 Cdk inhibitor compared with their progenitor neuroblasts. Elevated p27 levels in staged embryo brain extracts correlate with p27 binding to Cdk2, and Cdk inactivation. Yet, Cdk5, which is associated with the noncyclin activator p35 in neurons, remains active in the presence of high p27 levels. Both in vitro and in vivo, p27 and related inhibitors can recognize a cyclin D-Cdk5 complex but not a p35-Cdk5 complex. The results indicate that the choice of activator determines the susceptibility of Cdk5 to p27 and related Cdk inhibitors, and thus its ability to act in postmitotic cells.

Animals↗

PubMed1996

Measuring atopy in a multi-centre epidemiological study.

Skin prick tests are used as a measure of atopy in epidemiological studies, but results may be influenced by the fieldworker performing the test. In a multi-centre epidemiological study the method of reporting the results should consider the need for comparability of findings from different centres. Data on over 1000 subjects from three English centres of the European Community Respiratory Health Survey were analysed to determine whether allergen wheal should be adjusted for histamine wheal, and what cutoff diameter gave the most comparable results. No consistent relation between allergen wheal diameter and histamine wheal diameter was found for any fieldworker or allergen. A cutoff of > 0 mm for a positive result gave a more consistent relation with the corresponding specific IgE value between fieldworkers than either a cutoff of > or = 3 mm or the use of the mean wheal diameter. While this result is not immediately generalisable to studies using different skin prick test reagents, the method of analysis to determine the appropriate criterion of reporting can be used in other epidemiological studies.

Adult↗

PubMed1996

Characterization of the structure and function of the gene for transcription factor BF-1, an essential regulator of forebrain development.

Brain factor-1 (BF-1) is a winged-helix transcription factor which has been shown to be essential for the development of the cerebral hemispheres. We report here the cloning and characterization of the mouse BF-1 gene. We have identified two classes of alternatively spliced mouse BF-1 cDNA which are transcribed from distinct promoters. Both classes of cDNA encode identical BF-1 proteins. The class 1 mouse cDNA is the homolog of the previously reported rat and human BF-1 cDNAs, and accounts for about 90-95% of BF-1 expression in brain. Primer extension analyses show that the major promoter, P1, is TATA-less and has multiple transcription start sites. We identified neural cell lines which express BF-1 primarily from the P1 promoter, including the OBL21a and OBL21 cell lines derived from the olfactory bulb. Expression of BF-1 is highest in proliferating OBL21 cells, declining as the cells differentiate in vitro. This correlates well with the reduction of BF-1 expression as the cells of the telencephalic neuroepithelium differentiate. Using these cells, we demonstrate that the genomic region between -3.7kb and -79 bp upstream of the P1 promoter contains cell-specific enhancer activity in transient transfection assays.

Animals↗