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Biomedical subjects

E Sullivan

Publications and source records attributed to E Sullivan.

At least 19 recordsLinked to original sources
PubMed2006

Practitioner reporting of birth defects in children born following assisted reproductive technology: Does it still have a role in surveillance of birth defects?

BACKGROUND: National assisted reproductive technology (ART) data collections that rely on practitioners' reports of birth defects have consistently reported lower proportions of children with birth defects than record linkage studies that link ART infants to birth and malformation registers. METHODS: We compared the birth defect data reported to the national Australian Assisted Conception Data Collection (ACDC) by practitioners at three Western Australian ART clinics with the birth defect data identified on the Western Australian Birth Defects Registry (WABDR) through record linkage of all the pregnancies conceived at these clinics to the WABDR. Cases are reported to the WABDR by multiple statutory and voluntary sources. RESULTS: We found that the national ACDC significantly underestimated the prevalence of birth defects in WA-born ART infants. Less than one-third of ART children identified with a major birth defect on the WABDR were reported to the ACDC. CONCLUSIONS: Although national ART data collections provide valuable information on pregnancy rates and short-term pregnancy outcomes such as multiple birth and birth weight, we strongly recommend that birth defect information used for patient counselling is preferentially drawn from large studies that have used record linkage to high-quality birth defect registers.

Congenital Abnormalities↗
PubMed2006

Optimisation and validation of a medium-throughput electrophysiology-based hERG assay using IonWorks HT.

INTRODUCTION: Regulatory and competitive pressure to reduce the QT interval prolongation risk of potential new drugs has led to focus on methods to test for inhibition of the human ether-a-go-go-related gene (hERG)-encoded K+ channel, the primary molecular target underlying this safety issue. Here we describe the validation of a method that combines medium-throughput with direct assessment of channel function. METHODS: The electrophysiological and pharmacological properties of hERG were compared using two methods: conventional, low-throughput electrophysiology and planar-array-based, medium-throughput electrophysiology (IonWorks HT). A pharmacological comparison was also made between IonWorks HT and an indirect assay (Rb+ efflux). RESULTS: Basic electrophysiological properties of hERG were similar whether recorded conventionally (HEK cells) or using IonWorks HT (CHO cells): for example, tail current V1/2 -12.1+/-5.0 mV (32) for conventional and -9.5+/-6.0 mV (46) for IonWorks HT (mean+/-S.D. (n)). A key finding was that as the number of cells per well was increased in IonWorks HT, the potency reported for a given compound decreased. Using the lowest possible cell concentration (250,000 cells/ml) and 89 compounds spanning a broad potency range, the pIC50 values from IonWorks HT (CHO-hERG) were found to correlate well with those obtained using conventional methodology (HEK-hERG)(r=0.90; p<0.001). Further validation using CHO-hERG cells with both methods confirmed the correlation (r=0.94; p<0.001). In contrast, a comparison of IonWorks HT and Rb+ efflux data with 649 compounds using CHO-hERG cells showed that the indirect assay consistently reported compounds as being, on average, 6-fold less potent, though the differences varied depending on chemical series. DISCUSSION: The main finding of this work is that providing a relatively low cell concentration is used in IonWorks HT, the potency information generated correlates well with that determined using conventional electrophysiology. The effect on potency of increasing cell concentration may relate to a reduced free concentration of test compound owing to partitioning into cell membranes. In summary, the IonWorks HT hERG assay can generate pIC50 values based on a direct assessment of channel function in a timeframe short enough to influence chemical design.

Animals↗
PubMed2004

Oscillations in NF-kappaB signaling control the dynamics of gene expression.

Signaling by the transcription factor nuclear factor kappa B (NF-kappaB) involves its release from inhibitor kappa B (IkappaB) in the cytosol, followed by translocation into the nucleus. NF-kappaB regulation of IkappaBalpha transcription represents a delayed negative feedback loop that drives oscillations in NF-kappaB translocation. Single-cell time-lapse imaging and computational modeling of NF-kappaB (RelA) localization showed asynchronous oscillations following cell stimulation that decreased in frequency with increased IkappaBalpha transcription. Transcription of target genes depended on oscillation persistence, involving cycles of RelA phosphorylation and dephosphorylation. The functional consequences of NF-kappaB signaling may thus depend on number, period, and amplitude of oscillations.

Active Transport, Cell Nucleus↗
PubMed2003

Artificial chromosome vectors and expression of complex proteins in transgenic animals.

Artificial chromosome vectors are autonomous, replicating DNA sequences containing a centromere, two telomeres and origins of replication. Artificial chromosomes have been proposed as possible vectors for transferring very large sequences of DNA into animals. Our goal has been to insert the entire human heavy- and light-chain immunoglobulin loci into cattle as a step in developing a production system for large quantities of human therapeutic polyclonal antibodies. A mitotically stable fragment of chromosome 14, containing the human heavy-chain locus, was identified. A chromosome cloning system was used to transfer the human lambda locus from an unstable chromosome 22 fragment to the chromosome 14 fragment to create a human artificial chromosome (HAC) carrying both immunoglobulin loci. The HAC vector was introduced into bovine primary fibroblasts. Selected fibroblast clones were rejuvenated and expanded by producing cloned fetuses. Cloned fetal cells were selected and recloned to produce 21 healthy, transchromosomic (Tc) calves. Four were analyzed and shown to functionally rearrange both heavy- and light-chain human immunoglobulin loci and produce human polyclonal antibodies. These results demonstrate the feasibility of using HAC vectors for production of transgenic livestock. More importantly, Tc cattle containing human immunoglobulin genes may be used to produce novel human polyclonal therapeutics.

Animals↗
PubMed2001

Drosophila stem loop binding protein coordinates accumulation of mature histone mRNA with cell cycle progression.

Replication-associated histone genes encode the only metazoan mRNAs that lack polyA tails, ending instead in a conserved 26-nt sequence that forms a stem-loop. Most of the regulation of mammalian histone mRNA is posttranscriptional and mediated by this unique 3' end. Stem-loop-binding protein (SLBP) binds to the histone mRNA 3' end and is thought to participate in all aspects of histone mRNA metabolism, including cell cycle regulation. To examine SLBP function genetically, we have cloned the gene encoding Drosophila SLBP (dSLBP) by a yeast three-hybrid method and have isolated mutations in dSLBP. dSLBP function is required both zygotically and maternally. Strong dSLBP alleles cause zygotic lethality late in development and result in production of stable histone mRNA that accumulates in nonreplicating cells. These histone mRNAs are cytoplasmic and have polyadenylated 3' ends like other polymerase II transcripts. Hypomorphic dSLBP alleles support zygotic development but cause female sterility. Eggs from these females contain dramatically reduced levels of histone mRNA, and mutant embryos are not able to complete the syncytial embryonic cycles. This is in part because of a failure of chromosome condensation at mitosis that blocks normal anaphase. These data demonstrate that dSLBP is required in vivo for 3' end processing of histone pre-mRNA, and that this is an essential function for development. Moreover, dSLBP-dependent processing plays an important role in coupling histone mRNA production with the cell cycle.

Amino Acid Sequence↗
PubMed2001

Outcomes of child sexual contacts: patterns of incarcerations from a national sample.

OBJECTIVE: In a test of the relationships between sexual touching before puberty and later incarcerations during adolescence and adulthood, two theoretical models were examined. These models focus on examination of crime from the developmental origins of criminals and the adaptive and maladaptive outcomes of early experiences. METHOD: Data were taken from the National Health and Social Life Survey to study the sexual touching and social origin variables in childhood and incarceration variable during teen years. The sample was a stratified, random sample of 3,362 adults (18 to 59 years of age) throughout the United States. RESULTS: Data support inferences from the two interrelated models. Respondents reporting touching before puberty were significantly more likely to experience incarceration. They were also more likely to engage in behaviors as teenagers that were associated with an increased probability of jailing. Such behaviors include sexual promiscuity and early departure from the parental family. CONCLUSIONS: These findings are consistent for first jailing as a teenager and as an adult, as well as for those with short (less than a week) or longer (a week or more) spells of incarceration. Prepubertal sexual touching has a significant and enduring effect on later adolescent and adult incarcerations.

Adaptation, Psychological↗
PubMed2001

Sex differences in the effects of alcohol on brain structure.

OBJECTIVE: This study investigated whether alcoholic women manifest deficits in cortical gray and white matter volumes and ventricular enlargement similar to those seen in alcoholic men. METHOD: Volumetric measures of intracranium, cortical gray matter, white matter and sulci, and lateral and third ventricles were obtained from magnetic resonance images of 42 women and 44 men with DSM-III-R alcoholism and age-matched healthy comparison groups (37 women and 48 men). Groups of alcoholic men and women were matched on age and length of sobriety, but men had a 2.5 times higher lifetime alcohol consumption than women. RESULTS: Women, regardless of diagnosis, had less cortical gray and white matter and smaller third ventricles than men, consistent with sex-related differences in intracranial volume. Alcoholics had larger volumes of cortical sulci and lateral and third ventricles than comparison subjects. Diagnosis-by-sex interactions for cortical white matter and sulcal volumes were due to abnormalities in alcoholic men but not alcoholic women, relative to same-sex comparison subjects. This interaction persisted for cortical sulci after covarying for lifetime alcohol consumption. Slopes relating cortical gray matter and sulcal volumes to age were steeper in alcoholic than in comparison men. Slopes relating lateral ventricle volume to age were steeper in alcoholic than in comparison women. In alcoholic women, longer sobriety was associated with larger white matter volumes. CONCLUSIONS: Alcoholic men and women show different brain morphological deficits, relative to same-sex comparison subjects. However, age and alcoholism interact in both sexes, which puts all older alcoholics at particular risk for the negative sequelae of alcoholism.

Adult↗
PubMed2000

A method for detecting errors in discounted fee-for-service payments by insurance companies.

In order to discover and correct inaccurate payments received from insurance companies, a practice requires a plan for the systematic, efficient, and prompt monitoring of receipts. When any such discrepancies are detected, the physician can query the insurance company and correct the problem. Once the system is in place, it behooves each physician to look at the results at least weekly. Monitoring receipts requires interest, know-how, and persistence in the face of ever-confusing payment methodologies. This paper explains one such plan for detecting and correcting inaccurate insurance company payments.

Connecticut↗
PubMed1999

Effects of endorectal ultrasonography in the surgical management of rectal adenomas and carcinomas.

BACKGROUND: Accurate preoperative staging of rectal lesions can help select patients for treatment options. This prospective study examines the effects of endorectal ultrasonography (ERUS) in the management of resectable adenomas and adenocarcinomas. METHODS: Between November 1995 and August 1998, 34 patients had resection of their rectal lesions (28 adenocarcinomas, 6 adenomas). Preoperative clinical stage and surgical and adjuvant therapy plans were specified before ERUS staging; then comparisons were made to postoperative pathologic stage and actual treatment. RESULTS: ERUS helped select 7 of 11 patients (64%) for preoperative chemoradiation therapy. Treatments of adenocarcinomas were altered by ERUS to local excision (LOC) in 4 of 9 patients (45%) planned for low anterior resection (LAR), and 2 of 10 patients (20%) planned for abdominoperineal resection (APR). ERUS helped spare 2 patients with adenoma from APR. CONCLUSION: ERUS is a useful modality in the surgical management of patients with rectal adenomas and carcinomas.

Adenocarcinoma↗
PubMed1999

Lay beliefs about the preventability of major health conditions.

Beliefs about the extent to which health problems can be prevented reflect an understanding that preventive measures can reduce adverse health events and the level of control individuals perceive that they hold over the factors that affect their health. A population survey of 1659 people conducted in 1995 in south western Sydney, Australia, found that only child drownings, tooth decay, skin cancer, and burns and scalds were considered all or mostly preventable by more than 50% of the sample. The majority of respondents did not believe that heart attacks, cervical cancer, high blood pressure, serious road injury, lung cancer and asthma deaths were all or mostly preventable. Logistic regression analysis showed that people born in an English speaking country, those with more than 10 years of education and men were significantly more likely to recognize a number of key conditions as highly preventable. The findings suggest that, in spite of the range of prevention efforts in Australia to date, these are not matched by strong beliefs within the community that prevention is possible. Communication of the opportunities and methods for prevention needs to be improved, particularly among certain population groups. The findings also indicate a need to examine social and environmental factors which are potentially reducing confidence, and subsequently and adoption of preventive behaviours.

Adolescent↗
PubMed1999

Persistent infection promotes cross-species transmissibility of mouse hepatitis virus.

Persistent infection with mouse hepatitis virus (MHV) strain A59 in murine DBT (delayed brain tumor) cells resulted in the emergence of host range variants, designated V51A and V51B, at 210 days postinfection. These host range mutants replicated efficiently in normally nonpermissive Chinese hamster ovary (CHO), in human hepatocarcinoma (HepG2), and to a lesser extent in human breast carcinoma (MCF7) cell lines. Little if any replication was noted in baby hamster kidney (BHK), green African monkey kidney (COS-7), feline kidney (CRFK), and swine testicular (ST) cell lines. By fluorescent antibody (FA) staining, persistent viruses V10B and V30B, isolated at days 38 and 119 days postinfection, also demonstrated very low levels of replication in human HepG2 cells. These data suggest that persistence may rapidly select for host range expansion of animal viruses. Pretreatment of HepG2 cells with a polyclonal antibody directed against human carcinoembryonic antigens (CEA) or with some monoclonal antibodies (Col-1, Col-4, Col-12, and Col-14) that bind human CEA significantly inhibited V51B infection. Under identical conditions, little or no blockade was evident with other monoclonal antibodies (kat4c or Col-6) which also bind the human CEA glycoproteins. In addition, an antibody (EDDA) directed against irrelevant antigens did not block V51B replication. Pretreatment with the Col-4 and Col-14 antibodies did not block Sindbis virus replication in HepG2 cells or MHV infection in DBT cells, suggesting that one or more CEA glycoproteins likely functioned as receptors for V51B entry into human cell lines. To test this hypothesis, the human biliary glycoprotein (Bgp) and CEA genes were cloned and expressed in normally nonpermissive BHK cell lines by using noncytopathic Sindbis virus replicons (pSinRep19). By growth curves and FA staining, human CEA and to a much lesser extent human Bgp functioned as receptors for V51B entry. Furthermore, V51B replication was blocked with polyclonal antiserum directed against human CEA and Bgp. Under identical conditions, the parental MHV strain A59 failed to replicate in BHK cells expressing human Bgp or CEA. These data suggest that MHV persistence may promote virus cross-species transmissibility by selecting for virus variants that recognize phylogenetic homologues of the normal receptor.

Animals↗
PubMed1998

Pulmonary vascular pressures of strenuously exercising Thoroughbred horses after administration of phenylbutazone and frusemide.

The present study was carried out to examine the effects of phenylbutazone treatment on the pulmonary haemodynamic effects of frusemide in strenuously exercising horses. Using catheter mounted manometers, whose in vivo signals were referenced at the point of the shoulder, heart rate, right atrial, right ventricular and pulmonary vascular pressures were measured in 3 different sets of experiments. Seven Thoroughbreds were subjected to 1) control (no medications), 2) frusemide control and 3) phenylbutazone + frusemide. The experiments were carried out in random order and were separated by 7 days. Measurements were made at rest and during incremental exercise performed on a treadmill set at 3.5% uphill grade. In the frusemide control experiment, horses received frusemide 250 mg i.v., 4 h pre-exercise. In the phenylbutazone + frusemide experiment, horses received 4 i.v. injections of phenylbutazone (4.4 mg/kg bwt) at 12 h intervals. Twenty-four hours after the last phenylbutazone injection, horses received frusemide 250 mg i.v. and exercise was performed 4 h later. This latter regimen mimics prevailing veterinary practice at Illinois racetracks. The highest work intensity (14.2 m/s, 3.5% uphill grade) elicited maximal heart rate of horses. Significant right atrial, as well as pulmonary arterial, capillary and venous hypertension occurred with exertion in all 3 experiments. However, in the frusemide-control and the phenylbutazone + frusemide studies, the exercise induced rise in mean right atrial and pulmonary vascular pressures was significantly (P<0.05) attenuated in comparison with that in the control experiments. Statistically significant differences were not found between the frusemide control study and the phenylbutazone + frusemide study either at rest or during any level of exertion. Therefore, it was concluded that the phenylbutazone treatment in our study did not mitigate the pulmonary haemodynamic effects of frusemide in strenuously exercising Thoroughbred horses.

Animals↗
PubMed1997

Pulmonary vascular pressures of strenuously exercising Thoroughbreds after administration of varying doses of frusemide.

The frusemide dose-response for attenuation of exercise-induced pulmonary capillary hypertension was studied in 7 healthy, exercise-conditioned Thoroughbred horses using previously described haemodynamic procedures. Four different doses of frusemide were tested: 250 mg regardless of bodyweight (amounting to 0.56 +/- 0.03 mg/kg bwt), 1.0 mg/kg bwt, 1.5 mg/kg bwt and 2.0 mg/kg bwt. Frusemide was administered i.v., 4 h before exercise. Haemodynamic data were obtained at rest and during treadmill exercise performed at 14.2 m/s on a 3.5% uphill grade; this workload elicited maximal heart rate of horses. Airway endoscopy was performed post exercise to detect exercise-induced pulmonary haemorrhage (EIPH). In standing horses, frusemide administration resulted in a significant (P<0.05) decrease in mean pulmonary arterial, pulmonary capillary and pulmonary artery wedge pressures, but significant differences among the various frusemide doses were not observed. In the control experiments, exercise caused significant increments in the right atrial as well as pulmonary arterial, wedge, and capillary pressures, and all horses experienced EIPH. Following frusemide administration, the exercise-induced rise in right atrial and pulmonary vascular pressures was significantly attenuated, but significant differences between the frusemide doses of 250 mg, 1.0 mg/kg, and 1.5 mg/kg were not discerned and all horses remained positive for EIPH. Although a further significant (P<0.05) attenuation of the exercise-induced rise in pulmonary capillary blood pressure occurred when frusemide dose increased from 250 mg to 2.0 mg/kg bwt, all horses still experienced EIPH. It is concluded that a linear response to increasing frusemide dosage in terms of attenuation of the pulmonary capillary hypertension does not exist in strenuously exercising Thoroughbred horses.

Animals↗