Search PubMed⌕ Search

Biomedical subjects

J A Epstein

Publications and source records attributed to J A Epstein.

At least 19 recordsLinked to original sources
PubMed2001

Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects.

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital anomaly disorder associated with hemizygous 22q11 deletions. We previously showed that bacterial artificial chromosome (BAC) transgenic mice overexpressing four transgenes, PNUTL1, (CDCrel-1), GP1B beta, TBX1 and WDR14, had reduced viability, cardiovascular malformations and thymus gland hypoplasia. Since these are hallmark features of VCFS/DGS, we analyzed the mice for additional anomalies. We found that the mice have important defects in the middle and inner ear that are directly relevant to the disorder. The most striking defect was the presence of chronic otitis media, a common finding in VCFS/DGS patients. In addition, the mice had a hyperactive circling behavior and sensorineural hearing loss. This was associated with middle and inner ear malformations, analogous to Mondini dysplasia in humans reported to occur in VCFS/DGS patients. We propose that overexpression of one or more of the transgenes is responsible for the etiology of the ear defects in the mice. Based upon its pattern of expression in the ear and functional studies of the gene, TbX1 likely plays a central role. Haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients.

Abnormalities, Multiple↗
PubMed2001

Characterization of the murine Lbx2 promoter, identification of the human homologue, and evaluation as a candidate for Alström syndrome.

The murine Lbx2 gene is a member of the ladybird family of homeobox genes, which is expressed in the developing urogenital system, eye, and brain. Using transgenic mice, we demonstrate that 9 kb of the 5' flanking region of mouse Lbx2 is able to direct expression of a reporter gene in a tissue-specific manner recapitulating the endogenous expression pattern. This regulatory region provides a novel reagent allowing for transgenic expression in the developing urogenital ridge. In addition, we describe the identification of the human homologue, LBX2. Comparison of the human LBX2 and mouse Lbx2 sequences upstream of the coding regions reveals sequence conservation suggesting conserved regulatory regions. Both the human LBX2 and the mouse Lbx2 genes have similar genomic structures and are composed of two exons separated by an intron. We mapped the mouse Lbx2 gene to 35 cM on chromosome 6 and the human LBX2 gene to a homologous region of chromosome 2p13. This is a candidate region for several inherited disorders, including Alström syndrome, a disorder that includes ocular, urogenital, and renal abnormalities. Given the expression pattern of Lbx2, the chromosomal location in humans, and the potential function of mammalian ladybird genes, we have begun to analyze patients with ocular disorders and those with Alström syndrome for mutations in LBX2. Although polymorphisms were identified, our results indicate that mutations in the coding region of LBX2 do not account for Alström syndrome in the six kindreds analyzed.

Amino Acid Sequence↗
PubMed2001

TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome.

Velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a human disorder characterized by a number of phenotypic features including cardiovascular defects. Most VCFS/DGS patients are hemizygous for a 1.5-3.0 Mb region of 22q11. To investigate the etiology of this disorder, we used a cre-loxP strategy to generate mice that are hemizygous for a 1.5 Mb deletion corresponding to that on 22q11. These mice exhibit significant perinatal lethality and have conotruncal and parathyroid defects. The conotruncal defects can be partially rescued by a human BAC containing the TBX1 gene. Mice heterozygous for a null mutation in Tbx1 develop conotruncal defects. These results together with the expression patterns of Tbx1 suggest a major role for this gene in the molecular etiology of VCFS/DGS.

Animals↗
PubMed2001

A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression.

Germline mutations of the human BRCA2 gene confer susceptibility to breast cancer. Although the function of the BRCA2 protein remains to be determined, murine cells homozygous for BRCA2 inactivation display chromosomal aberrations. We have isolated a 2 MDa BRCA2-containing complex and identified a structural DNA binding component, designated as BRCA2-Associated Factor 35 (BRAF35). BRAF35 contains a nonspecific DNA binding HMG domain and a kinesin-like coiled coil domain. Similar to BRCA2, BRAF35 mRNA expression levels in mouse embryos are highest in proliferating tissues with high mitotic index. Strikingly, nuclear staining revealed a close association of BRAF35/BRCA2 complex with condensed chromatin coincident with histone H3 phosphorylation. Importantly, antibody microinjection experiments suggest a role for BRCA2/BRAF35 complex in modulation of cell cycle progression.

Amino Acid Sequence↗
PubMed2001

Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2.

The transition to pulmonary respiration following birth requires rapid alterations in the structure of the mammalian cardiovascular system. One dramatic change that occurs is the closure and remodeling of the ductus arteriosus (DA), an arterial connection in the fetus that directs blood flow away from the pulmonary circulation. A role for prostaglandins in regulating the closure of this vessel has been supported by pharmacological and genetic studies. The production of prostaglandins is dependent on two cyclooxygenases (COX-1 and COX-2), which are encoded by separate genes. We report here that the absence of either or both COX isoforms in mice does not result in premature closure of the DA in utero. However, 35% of COX-2(-/-) mice die with a patent DA within 48 h of birth. In contrast, the absence of only the COX-1 isoform does not affect closure of the DA. The mortality (35%) and patent DA incidence due to absence of COX-2 is, however, significantly increased (79%) when one copy of the gene encoding COX-1 is also inactivated. Furthermore, 100% of the mice deficient in both isoforms die with a patent DA within 12 h of birth, indicating that in COX-2-deficient mice, the contribution of COX-1 to DA closure is gene dosage-dependent. Together, these data establish roles for COX-1, and especially for COX-2, in the transition of the cardiopulmonary circulation at birth.

Animals↗
PubMed2001

Developing models of DiGeorge syndrome.

DiGeorge syndrome is a common congenital disorder characterized by neural-crest-related developmental defects. Mouse models of DiGeorge syndrome have been created that recapitulate defects seen in human patients. Here, the genetic pathways regulating cardiac neural crest development are reviewed and the evidence implicating TBX1 and other genes on chromosome 22q11 in the pathogenesis of DiGeorge syndrome is summarized.

Animals↗
PubMed2001

Risk taking and refusal assertiveness in a longitudinal model of alcohol use among inner-city adolescents.

Risk taking and refusal assertiveness have been shown to be important determinants of adolescent alcohol use. However, it remains unclear whether youth predisposed to risk taking would be less likely to assertively refuse. This study examined the relationships among risk taking, refusal assertiveness, and alcohol use in a sample of inner-city minority students (N = 1,459), using a cross-lagged longitudinal structural equation model. Data collectors administered the questionnaire to students following a standardized protocol during a 40-min class period. Based on the tested model, risk taking was more stable over time than refusal assertiveness. Furthermore, high risk takers reported less frequent subsequent refusal assertiveness, and less frequent refusal assertiveness predicted greater drinking. A predisposition toward risk taking appears to be an enduring characteristic that is associated with low refusal assertiveness and increased alcohol use. These findings suggest that alcohol prevention programs that emphasize refusal skills training may be less effective for high risk takers. But programs that focus on enhancing competence or reducing normative expectations for peer alcohol use might be more effective for high risk-taking youth.

Adolescent↗
PubMed2001

Linguistic acculturation associated with higher marijuana and polydrug use among Hispanic adolescents.

Hispanic sixth and seventh graders in 22 New York City middle schools (mean age: 12.66 years) completed self-report questionnaires with items related to drug use (cigarette smoking, alcohol use, and marijuana) use and linguistic acculturation at two assessments (N = 1299 at baseline; N = 1038 at 1-year follow-up). Adolescents who spoke English with their parents smoked marijuana more frequently than those who spoke Spanish with their parents at both surveys. By the 1-year follow-up, students who spoke English with their parents and bilingual students who spoke English and Spanish with their parents engaged in greater polydrug use than those who spoke Spanish with their parents.

Acculturation↗
PubMed2001

Alcohol use among Dominican and Puerto Rican adolescents residing in New York City: role of Hispanic group and gender.

Hispanic groups are often aggregated when examining adolescent drinking. The objective of this study was to determine the roles of Hispanic group (Puerto Rican versus Dominican) and gender in alcohol use among inner-city youth. Sixth and seventh graders in 22 New York City schools who identified themselves as Puerto Rican or Dominican completed self-report questionnaires at two assessments (N = 849 at baseline; N = 678 at 1-year follow-up). Dominican adolescents generally engaged in more alcohol use than Puerto Rican adolescents. In a number of cases, gender moderated the effect of Hispanic group on drinking. Specifically, Dominican boys reported greater use than Dominican girls, but use was similar across gender for Puerto Rican adolescents. These findings highlight the importance of considering Hispanic group and gender when examining adolescent drinking.

Adolescent↗
PubMed2001

Seesaw nystagmus following whole brain irradiation and intrathecal methotrexate.

A patient developed pendular seesaw nystagmus after receiving radiation and intrathecal methotrexate treatment for central nervous system lymphoma. Nystagmus developed without evidence of a brainstem lesion on magnetic resonance imaging. This case expands the causes of seesaw nystagmus and lends further support to the notion that midbrain lesions are not a prerequisite for its development.

Antimetabolites, Antineoplastic↗
PubMed2001

A gene expression screen in zebrafish embryogenesis.

A screen for developmentally regulated genes was conducted in the zebrafish, a system offering substantial advantages for the study of the molecular genetics of vertebrate embryogenesis. Clones from a normalized cDNA library from early somitogenesis stages were picked randomly and tested by high-throughput in situ hybridization for restricted expression in at least one of four stages of development. Among 2765 clones that were screened, a total of 347 genes with patterns judged to be restricted were selected. These clones were subjected to partial sequence analysis, allowing recognition of functional motifs in 163 among them. In addition, a portion of the clones were mapped with the aid of the LN54 radiation hybrid panel. The usefulness of the in situ hybridization screening approach is illustrated by describing several new markers for the characteristic structure in the fish embryo named the yolk syncytial layer, and for different regions of the developing brain.

Animals↗
PubMed2001

Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption.

Semaphorin 3C is a secreted member of the semaphorin gene family. To investigate its function in vivo, we have disrupted the semaphorin 3C locus in mice by targeted mutagenesis. semaphorin 3C mutant mice die within hours after birth from congenital cardiovascular defects consisting of interruption of the aortic arch and improper septation of the cardiac outflow tract. This phenotype is similar to that reported following ablation of the cardiac neural crest in chick embryos and resembles congenital heart defects seen in humans. Semaphorin 3C is expressed in the cardiac outflow tract as neural crest cells migrate into it. Their entry is disrupted in semaphorin 3C mutant mice. These data suggest that semaphorin 3C promotes crest cell migration into the proximal cardiac outflow tract.

Amino Acid Sequence↗
PubMed2001

PlexinA2 and semaphorin signaling during cardiac neural crest development.

Classic studies using avian model systems have demonstrated that cardiac neural crest cells are required for proper development of the cardiovascular system. Environmental influences that perturb neural crest development cause congenital heart defects in laboratory animals and in man. However, little progress has been made in determining molecular programs specifically regulating cardiac neural crest migration and function. Only recently have complex transgenic tools become available that confirm the presence of cardiac neural crest cells in the mammalian heart. These studies have relied upon the use of transgenic mouse lines and fate-mapping studies using Cre recombinase and neural crest-specific promoters. In this study, we use these techniques to demonstrate that PlexinA2 is expressed by migrating and postmigratory cardiac neural crest cells in the mouse. Plexins function as co-receptors for semaphorin signaling molecules and mediate axon pathfinding in the central nervous system. We demonstrate that PlexinA2-expressing cardiac neural crest cells are patterned abnormally in several mutant mouse lines with congenital heart disease including those lacking the secreted signaling molecule Semaphorin 3C. These data suggest a parallel between the function of semaphorin signaling in the central nervous system and in the patterning of cardiac neural crest in the periphery.

Animals↗
PubMed2000

Rnf4, a RING protein expressed in the developing nervous and reproductive systems, interacts with Gscl, a gene within the DiGeorge critical region.

A yeast 2-hybrid screen was performed to identify possible transcriptional modulators interactive with goosecoid-like (gscl), a transcription factor with suppressive activity, expressed during early brain and gonad development. The screen resulted in the identification of a RING protein known as rnf4 or snrf. Gscl/rnf4 interactions were confirmed by affinity chromatography and by immunoprecipitation. Northern analysis confirmed earlier reports of ubiquitous rnf4 expression in adult tissues. Immunohistochemical analysis of mouse embryos revealed expression primarily in the developing nervous system, with strong expression in the dorsal root ganglia and developing gonads. In contrast to previous reports, both cytoplasmic and nuclear expression of rnf4 was documented. The results reported here confirm and extend earlier reports of rnf4 expression. They suggest for the first time, that in addition to acting as a modulator of transcriptional activity, rnf4 may function, as do other RING proteins, to promote the formation of intracytoplasmic complexes involved in shuttling information between the cytoplasm and the nucleus.

Animals↗
PubMed2000

A model of smoking among inner-city adolescents: the role of personal competence and perceived social benefits of smoking.

BACKGROUND: Based on current trends, smoking will remain a major public health problem in the 21st century. Effective smoking prevention approaches offer the best hope for decreasing the rise in adolescent smoking rates. Competence enhancement approaches to smoking prevention are among the most successful. Yet, there is not a full understanding of how effective prevention approaches work. This study tests whether a deficiency in competence (poor decision-making skills and low personal efficacy) is linked to acquiring beliefs in the perceived benefits of smoking and whether these perceived benefits are then related to subsequent smoking. METHODS: A sample of 1459 students attending 22 middle and junior high schools in New York City participated. Students completed surveys at baseline, 1-year follow-up and 2-year follow-up during a regular class period. They self-reported smoking, decision-making skills, personal efficacy and beliefs in the perceived benefits of smoking. RESULTS: The tested structural equation model had a good fit and was parsimonious and consistent with the theory underlying the competence approach to smoking prevention. CONCLUSIONS: This research highlights the importance of addressing decision-making skills, personal efficacy, and beliefs in the social benefits of smoking within adolescent smoking prevention programs.

Adolescent↗