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Biomedical subjects

A L Brown

Publications and source records attributed to A L Brown.

At least 37 records · Page 2Linked to original sources
PubMed1999

Monitoring the prevalence of congenital hypothyroidism for 20 years near the Savannah River site.

OBJECTIVES: The main objectives were to describe the epidemiology of primary congenital hypothyroidism (CH) in Georgia during the past 20 years and specifically to determine whether there was a significant increase in CH prevalence proximal to the Savannah River Site (SRS), a nuclear plant. METHODS: Data were derived from the Georgia Newborn Screening Program. Frequencies were determined for race, sex, birth weight and birth month. Seasonality effects were investigated and the prevalence was determined and mapped by health district. RESULTS: The majority of the CH cases were female, white and of average birth weight. The sex ratio varied by race/ethnicity. There was not a statistically significant increase in the prevalence in the eastern districts that were in close proximity to the SRS. CONCLUSIONS: Although there were differences in the prevalence between health districts, we found no increased prevalence of CH in those health districts proximal to the SRS.

Congenital Hypothyroidism↗
PubMed1998

T1-weighted magnetic resonance imaging in breast cancer vertebral metastases: changes on treatment and correlation with response to therapy.

PURPOSE: To document the MR appearances of vertebral metastases in breast cancer on treatment and to determine whether a single T1-weighted (T1-W) sequence of the spine could provide a quick and effective method of response assessment. PATIENTS AND METHODS: One-hundred and nine spinal magnetic resonance (MR) examinations in 41 metastatic breast cancer patients on treatment were reviewed. The changes in number, size and signal intensity of vertebral metastases during 68 intervals (mean length 6.9 months) were documented. T1-W signal intensity (SI) before and after treatment was assigned to three patterns: (A) low homogeneous SI; (B) low heterogeneous SI; and (C) high homogeneous SI. For each interval between MR examinations, an objective assessment of the overall response (disease regression, no change, disease progression) to treatment of metastases was made based on standard assessment criteria. RESULTS: The number and size of treated vertebral metastases increased in 47% and 43% of cases and showed no change in 53% and 54% of cases, respectively. A reduction in size of lesions was seen in 3% of cases only and no reduction in the number of lesions was seen. T1-W [corrected] signal intensity changes occurred in approximately one-third of cases documented. The most commonly observed SI change in 25% of all intervals (17 of 68) was from type A to type B. There was no correlation between SI change and response to therapy. T1-W [corrected] MR response assessment, based on changes in size and number of vertebral metastases, accurately predicted progression of disease in 79% of cases and stable disease in 75% of cases. It did not predict regression of disease. CONCLUSION: A T1-W MR spinal assessment is a simple and effective method of evaluation of therapeutic response of lytic and sclerotic vertebral metastases in breast cancer being able to distinguish patients with progressive disease from those with a favourable response (no change or disease regression) to therapy. These findings have important clinical implications.

Breast Neoplasms↗
PubMed1997

Population study of congenital hypothyroidism and associated birth defects, Atlanta, 1979-1992.

Very little data are available from population-based studies on congenital hypothyroidism (CH) epidemiology and patterns of associated birth defects. By linking data from two population-based registries, we describe the epidemiology of CH and associated defects in Atlanta from 1979-1992. Cases included all infants with CH born from 1979-1992 to mothers residing in the metropolitan Atlanta area at the time of birth. We ascertained CH cases by reviewing newborn screening records and records of the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based registry of all serious birth defects diagnosed during a child's first year of life. We linked CH cases with MACDP records to ascertain the presence of serious birth defects among infants with CH. Of 97 infants identified with CH through newborn screening and/or MACDP (1:5,000 live births), 87 had primary CH and 10 had secondary. The rate of primary CH was higher among non-hispanic whites than among blacks (1:4,400 vs. 1:10,000) and among females compared with males (1:4,000 vs. 1:7,700). Among infants with primary CH, 77 had isolated CH, 3 had Down syndrome, and 7 had unrelated major structural defects. Based on Atlanta population rates of Down syndrome and major structural anomalies, we infer i) infants with Down syndrome have a 35-fold increased risk for primary CH compared with infants in the general population (P < .0001); ii) infants with primary CH have a 2.2-fold increased risk for major structural anomalies (P < .05). Because this is the first population study of CH in the United States in which data from two population-based registries were linked, the epidemiologic patterns and associated defects are more representative than those found in studies based on newborn screening records only.

Adult↗
PubMed1997

The ETS-domain transcription factor family.

During recent years, several significant discoveries have been made concerning the function of ETS-domain transcription factors. This family of transcription factors was originally defined on the basis of the conserved primary sequence of their DNA-binding domains. The ETS DNA-binding domain is also conserved at the structural level and is a divergent member of the winged helix-turn-helix superfamily of DNA binding proteins. This sequence conservation is reflected by their overlapping DNA-binding specificities based on the central GGAA/T motif. In addition to DNA-protein interactions, protein-protein interactions with partner proteins often play major roles in targeting ETS-domain proteins to specific promoters. Several such partner proteins have been identified. ETS-domain proteins function as either transcriptional activators or repressors and their activities are often regulated by signal transduction pathways, including the MAP kinase pathways. Specific links between such pathways and ETS-domain proteins have been established in several different experimental systems. ETS-domain transcription factors regulate a diverse array of biological functions including mammalian haematopoiesis and Drosophila eye development. In vertebrates, many ETS-domain proteins regulate embryonic and adult haematopoiesis. Deregulation of ETS-domain protein activity often leads to tumorigenesis. Future work will uncover further details of how these transcription factors work at the molecular level to regulate specific biological processes.

Adult↗
PubMed1997

Transforming schools into communities of thinking and learning about serious matters.

In this article, a program of research known as Fostering Communities of Learners is described. This program is in place in several schools and classrooms serving inner-city students from 6 to 12 years of age. Based on theoretical advances in cognitive and developmental psychology, the program is successful at improving both literacy skills and domain-area subject matter knowledge (e.g., environmental science and biology). Building on young children's emergent strategic and metacognitive knowledge, together with their skeletal biological theories, the program leads children to discover the deep principles of the domain and to develop flexible learning and inquiry strategies of wide applicability.

Child↗
PubMed1996

Linkage between reovirus-induced apoptosis and inhibition of cellular DNA synthesis: role of the S1 and M2 genes.

The mammalian reoviruses are capable of inhibiting cellular DNA synthesis and inducing apoptosis. Reovirus strains type 3 Abney (T3A) and type 3 Dearing (T3D) inhibit cellular DNA synthesis and induce apoptosis to a substantially greater extent than strain type 1 Lang (T1L). We used T1L x T3A and T1L x T3D reassortant viruses to identify viral genes associated with differences in the capacities of reovirus strains to elicit these cellular responses to viral infection. We found that the S1 and M2 genome segments determine differences in the capacities of both T1L x T3A and T1L x T3D reassortant viruses to inhibit cellular DNA synthesis and to induce apoptosis. These genes encode viral outer-capsid proteins that play important roles in viral attachment and disassembly. To extend these findings, we used field isolate strains of reovirus to determine whether the strain-specific differences in inhibition of cellular DNA synthesis and induction of apoptosis are also associated with viral serotype, a property determined by the S1 gene. In these experiments, type 3 field isolate strains were found to inhibit cellular DNA synthesis and to induce apoptosis to a greater extent than type 1 field isolate strains. Statistical analysis of these data indicate a significant correlation between the capacity of T1L x T3A and T1L x T3D reassortant viruses and field isolate strains to inhibit cellular DNA synthesis and to induce apoptosis. These findings suggest that reovirus-induced inhibition of cellular DNA synthesis and induction of apoptosis are linked and that both phenomena are induced by early steps in the viral replication cycle.

Animals↗
PubMed1996

Chimeric hepatitis B virus core particles as probes for studying peptide-integrin interactions.

An RGD-containing epitope from the foot-and-mouth disease virus (FMDV) VP1 protein was inserted into the e1 loop of the hepatitis B virus core (HBc) protein. This chimeric protein was expressed at high levels in Escherichia coli and spontaneously assembled into virus-like particles which could be readily purified. These fusion particles elicited high levels of both enzyme-linked immunosorbent assay- and FMDV-neutralizing antibodies in guinea pigs. The chimeric particles bound specifically to cultured eukaryotic cells. Mutant particles carrying the tripeptide sequence RGE in place of RGD and the use of a competitive peptide, GRGDS, confirmed the critical involvement of the RGD sequence in this binding. The chimeric particles also bound to purified integrins, and inhibition by chain-specific anti-integrin monoclonal antibodies implicated alpha 5 beta 1 as a candidate cell receptor for both the chimeric particle and FMDV. Some serotypes of FMDV bound to beta 1 integrins in solid- phase assays, and the chimeric particles competed with FMDV for binding to susceptible eukaryotic cells. Thus, HBc particles may provide a simple, general system for exploring the interactions of specific peptide sequences with cellular receptors.

Animals↗
PubMed1996

Withdrawal of renal replacement therapy in Newcastle upon Tyne: 1964-1993.

BACKGROUND: Termination of renal replacement therapy (RRT) is common in North America and Australia but is considered to be rare in Europe. METHODS: In order to review the phenomenon of RRT termination in all patients treated in Newcastle upon Tyne between 1964 and 1993 a retrospective study of clinical case notes was undertaken. In all RRT patients sex, age at start of RRT, renal diagnosis and history of RRT were recorded. In addition, mortality data and marital and residential status were recorded in all patients who died, and Karnofsky index, bodyweight, complications, history of bereavement, place of death, overall survival, survival after withdrawal of treatment, other medical problems, higher mental function and surgical history in all patients stopping treatment. RESULTS: 1639 patients started RRT between 1964 and September 1993 inclusive. Eighty-eight patients were identified in whom death was a result of treatment being stopped (17% of all deaths). The first was in 1985. In these patients, age was greater (62 vs 47 years, P < 0.001) and diabetes was more prevalent (15 vs 7%, P < 0.03) than in the total RRT population. The Karnofsky index was 70 at the start and 33 at withdrawal of treatment (P < 0.001). The Karnofsky index at the start of RRT was weakly related to that at withdrawal and overall survival (r = 0.36 and 0.28 respectively, P < 0.01). The Karnofsky index at treatment withdrawal correlated with the following survival (r = 0.40, P < 0.001). The median survival of patients stopping treatment was significantly lower than in all RRT patients (16 vs 74 months, P < 0.001) and the majority survived less than 2 years. After dialysis withdrawal the median survival was 8 days, 15 patients survived 3 days or less and 19 more than 10 days. The majority (80%) received terminal care in hospital. At treatment withdrawal 11 patients were demented and 34 showed signs of early dementia. Seventy-eight patients (89%) stopped treatment as a consequence of multiple medical problems. The possibility of dialysis withdrawal was raised by physicians in 50.5%, the patient in 23.8% and the patients' relatives in 21.9% of cases. Four patients (3.8%) committed suicide. CONCLUSIONS: Death from dialysis termination is a relatively common cause of death in RRT patients in Newcastle upon Tyne. These patients are older with a higher prevalence of diabetes. In 89% of cases the decision to stop treatment was related to multiple medical problems with a recent deterioration. Physicians raised the issue of withdrawal in the majority of cases and most patients subsequently received terminal care in hospital.

Decision Making↗
PubMed1995

Immunogenic HIV variant peptides that bind to HLA-B8 can fail to stimulate cytotoxic T lymphocyte responses.

Cytotoxic T lymphocyte responses in HIV infection can be impaired through variation in the epitope regions of viral proteins such as a gag. We report here an analysis of variant epitope peptides in three gag epitopes presented by HLA B8. Fifteen variant peptides were examined for their binding to HLA-B8; all but one bound at concentrations comparable to known epitopes. All except two of those that bound could be recognized by CTL from an HLA-B8 positive HIV-1-infected patient and were therefore immunogenic. However, in a hemophiliac patient studied in detail, there was a failure to respond to two immunogenic peptide epitopes representing virus present as provirus in the patient's peripheral blood. In one case, the patient's CTL had previously responded to the peptide; in the other case, there was a good response to a peptide of closely related sequence. Thus there was a selective failure of the CTL response to some proviral epitopes. This impaired reaction to new variants could contribute to the loss of immune control of the infection.

Animals↗
PubMed1995

Use of reverse ligation-PCR to identify transcriptional start sites in GC-rich TATA-less genes: application to the rat IGFBP-2 gene.

TATA-less genes are often GC-rich in the region of transcriptional initiation and the corresponding mRNAs are prone to the formation of secondary structure. These properties have made it difficult to determine unambigously the start sites of transcription for some of these genes by conventional assays such as primer extension and nuclease protection. Using the TATA-less rat IGFBP-2 gene, we demonstrate that tobacco acid pyrophosphatase-reverse ligation polymerase chain reaction (TAP-RLPCR), a novel and sensitive assay, can be used to map the start sites of these genes. First, the validity of TAP-RLPCR was demonstrated by mapping the transcription start site of the rat insulin-like growth factor 1 (IGFBP-1) gene to the correct position (nucleotides -173 relative to ATG, +1). Using total RNA obtained from the rat liver cell line BRL-3A, the transcription start sites of the rat IGFBP-2 gene were mapped to a narrow cluster extending from nucleotides -86 to -90 (ATG, +1), 39 bp downstream of three adjacent GC boxes that are essential to the transcriptional activity of the gene. The assay was also used to map the start sites of a luciferase reporter gene driven by the fragment -1,295 to -32 of the rat IGFBP-2 promoter after transfection in the human embryonic kidney cell line 293. The hybrid gene utilized the same transcription start sites as the rat IGFBP-2 gene, indicating that the elements required for positioning of the transcription initiation complex are contained within the 3' end terminating at nucleotide -32.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Widening of the tracheal bifurcation on chest radiographs: value as a sign of left atrial enlargement.

OBJECTIVE: This study evaluated widening of the tracheal bifurcation (subcarinal and interbronchial) angle on posteroanterior chest radiographs as a sign of left atrial enlargement. The purpose was to determine the diagnostic sensitivity and specificity of the sign. MATERIALS AND METHODS: The chest radiographs and echocardiograms of 122 clinically stable patients were retrospectively reviewed. The mean interval between examinations was 10 days (range, 0-30 days). The left atrial dimension was measured on the two-dimensional echocardiograms. Sixty-five patients had a normal left atrial dimension (mean, 34 mm), and 45 patients had an enlarged atrium (mean, 47 mm) on echocardiography. Subcarinal and interbronchial angles were jointly measured by two observers who were unaware of the echocardiographic findings. Correlation analysis was used to determine which angle measurement best predicted the left atrial size. Discriminant analysis was used to derive a threshold angle that predicted left atrial enlargement. RESULTS: The carina was inadequately seen on 14 radiographs. Left atrial size correlated poorly with both the interbronchial (r = .33) and the subcarinal (r = .25) angel values. An interbronchial angle of 76.4 degrees and a subcarinal angle of 65.4 degrees were the best discriminators between patients with normal and those with enlarged left atrial dimensions (sensitivities, 61% and 51%, respectively; specificities, 63% and 66%). CONCLUSION: Our findings show that widening of the tracheal bifurcation angle on chest radiographs is an insensitive and nonspecific sign of left atrial enlargement. This sign is of little value in diagnosing left atrial enlargement.

Adult↗
PubMed1994

The effect of inhibition of glutathione S-transferase P on the growth of the Jurkat human T cell line.

To investigate the possible role of glutathione S-transferase P (GSTP) in carcinogenesis and cell proliferation, ethacrynic acid (EA) was used to inhibit GSTP in the human Jurkat T cell line. At lower doses (0-30 microM), EA led to a decreased rate of proliferation as assessed by the MTT assay. This was associated with a decreased DNA S+G2/M phase population and also a dose-dependent increase in apoptosis. At concentrations of EA > 30 microM, cells suffered non-specific cytotoxic injury and underwent necrosis. The total cell number fell over the time course of the experiment. A resistant subculture of cells which proliferated in the presence of EA at 30 microM was selected by continuous growth in the presence of EA. Although this had a higher basal rate of apoptosis than control cells, it also showed a significantly larger growth fraction as assessed by flow cytometry. GSTP is frequently overexpressed in human tumours and animal models of carcinogenesis, and is regarded as a marker of the 'drug-resistant phenotype' of initiated cells. Our findings suggest that the role of GSTP in models of chemical carcinogenesis and in tumours may be its permissive effect on cell cycle activity and downregulation of apoptosis, thus allowing expansion of a population of initiated cells.

Apoptosis↗
PubMed1994

Percutaneous aspiration thromboembolectomy: a preliminary experience.

Percutaneous aspiration thromboembolectomy (PAT) is a radiological alternative to surgical embolectomy or thrombolysis in the treatment of acute arterial thromboembolic disease. We report our experience in eight patients aged 63-83 years (mean 71 years). Indications were graft thrombosis (1) or emboli from atrial fibrillation (3), abdominal aneurysm (2) or proximal angioplasty (2). PAT was performed at 10 arterial sites; common iliac (1), profunda femoris (1), superficial femoral (2), femoro-popliteal graft (1), popliteal (2) and arteries of the trifurcation (3). PAT was used as an adjunct to thrombolysis or angioplasty in five patients and as the sole procedure in three patients. It was successful in six patients (seven sites) with mean ABI rising from 0.4 pre- to 0.8 post-procedure. Two of the failures required amputations. One of these was a completely thrombosed dacron femoro-popliteal graft with poor run-off, and the second case had a failed surgical embolectomy prior to amputation. There were no major complications, and no mortality on follow-up at 1 month. PAT is a useful adjunct to thrombolysis and balloon angioplasty in the radiological treatment of acute thromboembolic disease. In patients in whom thrombolysis is contraindicated, it offers an alternative to surgical embolectomy.

Aged↗
PubMed1994

Recombinant human insulin-like growth factor (IGF)-binding protein-6 inhibits IGF-II-induced differentiation of L6A1 myoblasts.

Insulin-like growth factor-binding protein-6 (IGFBP-6) is an O-linked glycoprotein that binds insulin-like growth factor-II (IGF-II) with marked preferential affinity over IGF-I. Recombinant human IGFBP-6 (rhIGFBP-6) was synthesized by COS-7 monkey kidney cells that were transiently transfected with a eukaryotic expression vector into which a complementary DNA for IGFBP-6 modified for optimal translation had been inserted. rhIGFBP-6 was similar to IGFBP-6 purified from human cerebrospinal fluid with respect to IGF binding and O-glycosylation. The effect of rhIGFBP-6 on IGF-induced L6A1 myoblast differentiation was studied using creatine kinase activity as an index of differentiation. rhIGFBP-6 inhibited differentiation initiated by IGF-II in a dose-dependent manner, inhibition was complete when rhIGFBP-6 was present in a slight molar excess. In contrast, rhIGFBP-6 had no effect on IGF-I-induced differentiation, even when coincubated in a 5-fold molar excess. These results are consistent with the preferential affinity of IGFBP-6 for IGF-II. As cell association and proteolysis have been associated with the potentiation, rather than the inhibition, of IGF action by IGFBPs, we investigated whether they occurred in the L6A1 myoblast system. After incubation of L6A1 myoblasts with rhIGFBP-6, IGFBP-6 was recovered from the medium, but not from cell lysates or extracellular matrix. In addition, [125I]IGFBP-6 did not bind to myoblast monolayers, and there was no evidence that proteolysis had occurred. Together, these results indicate that rhIGFBP-6 remains intact and soluble and, hence, inhibits IGF-II-induced differentiation. The fidelity of the IGFBP-6 expression system used for these studies will enable us to use this system to determine how structural modifications of the protein affect the modulation of IGF action by IGFBP-6.

Animals↗