Biomedical subjects
L Steele
Publications and source records attributed to L Steele.
Sphingomyelin-derived lipids differentially regulate the extracellular signal-regulated kinase 2 (ERK-2) and c-Jun N-terminal kinase (JNK) signal cascades in airway smooth muscle.
In ASM cells platelet-derived growth factor stimulates rapid transient sphingosine phosphate formation, the activation of extracellular signal-regulated kinase 2 (ERK-2), the phosphorylation of p70(56K), and a ninefold increase in DNA synthesis. In contrast, this growth factor fails to activate c-Jun N-terminal kinase (JNK). Based upon these findings, we have tested whether the sphingomyelin-derived sphingolipids play a role in growth factor signalling by assessing their effect on ERK-2, JNK, and p70(56K). We demonstrate that sphingosine phosphate induces the activation of ERK-2, is ineffective against JNK, and fails to induce the phosphorylation of p70(56K). The latter may explain why it is a poor mitogen when added directly to ASM cells. In contrast, sphingosine and cell-permeable ceramides elicit the prominent tyrosyl phosphorylation and activation of JNK, are poor stimulators of ERK-2, and do not induce the phosphorylation of p70(56K). Therefore, the specificity of signalling through either ERK-2 or JNK cascades may be determined by the rapid agonist-dependent interconversion of these sphingomyelin-derived lipids. This may also provide a dynamic mechanism that enables growth factors and cytokines to elicit pleiotropic cell responses, such as proliferation and cell survival. For instance, both ceramide and sphingosine will elicit growth arrest via activation of JNK, whereas sphingosine phosphate will potentiate growth-factor-stimulated DNA synthesis, a consequence of the activation of ERK-2, Furthermore, under certain conditions, sphingosine and ceramide stimulate cAMP formation, a negative modulator of cell growth, whereas sphingosine phosphate depresses cAMP, thereby enhancing its own growth-promoting properties. From these studies, it is evident that sphingosine phosphate displays a signalling profile that is consistent with it mediating part of the action of platelet-derived growth factor.
M-mode echocardiographic evaluation of fetal and infant hearts: longitudinal follow-up study from intrauterine life to year one.
OBJECTIVE: Our purpose was to evaluate cardiac variables, including right and left end-diastolic and end-systolic dimensions by use of M-mode echocardiography during fetal, neonatal (transitional), and infancy periods to understand hemodynamic adaptation during these periods. STUDY DESIGN: Fifty-three fetuses were enrolled in this study. Echocardiography evaluations were started as early as the sixteenth week of gestation and were repeated every 4 to 6 weeks until term, on postnatal days 1 and 2, and at 6 weeks, 6 months, and 12 months of age. End-diastolic and end-systolic measurements were made according to published standards. Mean and SEM for each of the end-diastolic and end-systolic measurements were calculated for each of 11 study periods. Data were analyzed by one-way analysis of variance, corrected for repeated measures, and in the case of right and left ventricular differences paired t tests were used for significance. RESULTS: Left ventricular end-diastolic and end-systolic correlated positively with advancing age (R2 = 0.93, p < 0.0001), right ventricular end-diastolic also correlated with advancing age (R2 = = 0.361, p < 0.05), and right ventricular end-diastolic was significantly larger than left ventricular end-diastolic in utero (p < 0.01), whereas the opposite was true after birth (p < 0.0001). Heart rate significantly decreased with advancing age (p < 0.001), whereas ejection fraction for either the right or the left ventricle did not change significantly with advancing age. CONCLUSION: This suggests that under basal conditions the ventricles can meet the increased demands in cardiac output by increasing ventricular dimensions without having to increase contractility reserve.
The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.
Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.
The anti-proliferative effect of alpha-1-acid glycoprotein from HepG2 cell line on mononuclear leucocytes.
Explore the source record for details and available documents.
The identification of DL-threo dihydrosphingosine and sphingosine as novel inhibitors of extracellular signal-regulated kinase signalling in airway smooth muscle.
We present entirely novel evidence that DL-threo dihydrosphingosine and sphingosine are inhibitors of the extracellular signal-regulated kinase (ERK) signalling cassette in mammalian cells. We show that DL-threo dihydrosphingosine is effective against both growth factor- and G-protein-dependent activation of ERK. We conclude that DL-threo dihydrosphingosine may represent an important pharmacological cell-permeable agent that may be usefully employed to block smooth muscle cell proliferation.
Seroepidemiology of chronic fatigue syndrome: a case-control study.
We performed serological testing for a large number of infectious agents in 26 patients from Atlanta who had chronic fatigue syndrome (CFS) and in 50 controls matched by age, race, and sex. We did not find any agent associated with CFS. In addition, we did not find elevated levels of antibody to any of a wide range of agents examined. In particular, we did not find elevated titers of antibody to any herpesvirus, nor did we find evidence of enteroviral exposure in this group of patients.
Home health care for cancer patients. Insights from the American Indian community.
Explore the source record for details and available documents.
. . . Insidious disease.
Explore the source record for details and available documents.
A 45-year follow-up of kindred 107 and the search for BRCA2.
Interest in the genetics of breast cancer has intensified with the discovery of a breast cancer susceptibility locus, BRCA1, on chromosome 17q. In this paper, we describe updated information on a large breast cancer kindred (K107) that has been extensively studied since 1948. Specifically, we have identified many new cases of cancer in the family and have shown that this family is unlinked to BRCA1 as well as a number of other genes considered as candidates for breast cancer. In a collaborative study between the University of Utah and the Institute of Cancer Research in the United Kingdom, we have collected a set of families with a predisposition to breast and ovarian cancers that have been reliably excluded from linkage to BRCA1 and evaluated their usage in a genomic search for other breast cancer loci. This effort led to the discovery of a second breast cancer locus located on chromosome 13q, BRCA2, which is responsible for the increased incidence of breast cancer in Kindred 107.
Promoting the health of aging adults in the community.
Explore the source record for details and available documents.
Specific labeling of Candida tropicalis peroxisomal proteins with photoreactive fatty-acid derivatives.
The labeling of Candida tropicalis peroxisomal proteins with photoreactive fatty-acid derivatives was investigated. Proteins having molecular masses of 70 kDa, 48 kDa and 15 kDa were labeled with 11-m-diazirinophenoxy-[11-3H]undecanoate while 11-m-diazirinophenoxy-[11-3H]undecanoyl-CoA labeled proteins of 70 kDa and 55 kDa. The 70 kDa protein labeled with both photoreactive probes was resolved into two bands by electrophoresis on a gradient polyacrylamide gel; immunoprecipitation with anti-fatty acyl-CoA oxidase showed that these proteins are fatty-acyl-CoA oxidases. In purified peroxisomal membranes, two proteins of 36 kDa and 25 kDa were labeled with the photoreactive fatty-acid probe, whereas very little labeling of the above proteins or other proteins was observed with the fatty-acyl-CoA probe. The photoaffinity labeling method described is, thus, clearly capable of identifying and distinguishing between proteins having an affinity for fatty acid or fatty-acyl-CoA. The labeling also identified a fatty-acid-binding site on the 16 kDa peroxisomal matrix protein as well as on two peroxisomal acyl-CoA oxidases. This approach thus provides a general means for the identification of fatty-acid metabolizing enzymes, as well as for the identification of fatty-acid-binding sites on known enzymes.
Identification of phospholipase D (PLD) activity in mouse peritoneal macrophages.
It is now believed that PLD may contribute to the sustained generation of diacylglycerol (DAG) within activated cells. DAG can be formed from phosphatidylcholine by the sequential actions of PLD and phosphatidic acid phosphohydrolase. Phorbal myristate acetate (PMA, 1 microM), A23187 (10 microM) or platelet-activating factor (PAF, 100 nM) caused significant enhancement of intracellular 14C-phosphatidic acid levels 2-5 min after the addition of stimulus, in cultures of peritoneal macrophages pre-labelled with 14C-palmitate. Bacterial lipopolysaccharide (LPS) (5 micrograms/ml) or zymosan (375 micrograms/ml) also stimulated the production of 14C-phosphatidic acid, but over a longer time course (15-60 min). In the presence of 1% ethanol each stimulus caused significant production of 4C-phosphatidylethanol at the expense of 14C-phosphatidic acid, thus confirming a contribution of PLD in these reactions. This is the first report of PLD activity in this cell type.
Murine macrophage phospholipase A2.
Explore the source record for details and available documents.
Relationship between number of teeth and periodontal pockets.
The relationship between number of teeth and the prevalence of periodontal disease is an important factor to consider when planning future needs for periodontal care. This is of particular relevance today, when the level of tooth loss is steadily reducing. The aim of the present study was to examine this relationship. Three dependent variables associated with periodontal disease were included in the analysis: 1. The probability of having pockets 4 mm or more. 2. The mean pocket depth for individuals with pockets 4 mm or more. 3. The number of pockets for individuals with pockets 4 mm or more. Age was included in the analysis as a control variable. The study population comprised 2219 individuals in the county of Trøndelag, Norway. The data were analyzed using logistic regression and multiple regression analysis. The probability of having pockets 4 mm or more increased with increasing number of teeth. The average pocket depth decreased with increasing number of teeth. There was no relationship between number of pockets and number of teeth. The increase in the probability of having pockets with a marginal increase in number of teeth was greatest for those aged 53 years and above. It is concluded that this group of people are likely to have the greatest need for periodontal care.
Affinity labeling of mu and kappa receptors with naloxone benzoylhydrazone.
Naloxone benzoylhydrazone (NalBzoH) labels both mu and kappa receptors in standard homogenate binding assays. We now report that [3H]NalBzoH can effectively photoaffinity label opioid receptors. By modifying [3H]NalBzoH binding conditions, we can selectively label either mu or kappa 3 receptors in calf striatal membranes or classical U50,488-sensitive kappa 1 receptors in guinea pig cerebellar membranes. After removal of unbound radioligand, the [3H]NalBzoH-labeled membranes were irradiated with UV light to couple the bound radioligand to its binding site. No specific mu, kappa 1, or kappa 3 binding remained after a 20-hr dissociation at 25 degrees without UV irradiation. In contrast, approximately 45% of mu and 40% of kappa 1 and kappa 3 binding remained after 2 min of UV exposure. In time course studies, increasing the UV exposure from 30 sec to 3 min produced a progressive increase in radioligand incorporation, which did not increase further with UV exposure times up to 5 min. A portion of the binding in irradiated membranes appeared to be covalently coupled to proteins. Following solubilization of irradiated membranes with sodium dodecyl sulfate, approximately 30-40% of the specifically bound radioactivity precipitated with trichloroacetic acid (TCA). These levels of TCA-precipitable binding corresponded to the amount of dissociation-resistant binding described above. No specific binding could be TCA precipitated in samples that were not exposed to UV. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of [3H]NalBzoH-labeled membranes revealed a number of labeled peaks with levels of radioactivity that did not correspond to the intensity of the protein bands, suggesting that this technique was not randomly labeling proteins. This approach may be a useful method to affinity label, characterize, and purify mu and kappa opiate receptor subtypes.
[Changes in hourly rate for dental treatment in the 1980s].
The hourly rate for dental treatment in relation to general price and salary changes in Norway has changed in the period from 1979 to 1988. The results of the present study show that the increase of the hourly rate from 1983 has been less than for the consumer price index, and less than for the index for the average industrial worker's salary. The real price index for dental treatment in 1988 was 87.6. The relationship between the index for the average industrial worker's salary and the nominal price index for dental treatment was 80.5. It is concluded that dental treatment has become cheaper in Norway during the 1980's. The negotiations for dentists' hourly rate cannot be evaluated from these results without taking other factors into consideration.
Longitudinal study of dental health behaviors and other caries predictors in early childhood.
This longitudinal study of 231 preschoolchildren from a medium sized Norwegian town had three aims: firstly, to examine the children's early dental behavior, secondly to study the variation of dental health behavior according to mother's education, mother's dental health, and her dental attendance pattern, and thirdly to identify any behavioral or social predictors of dental caries in 36-month-old children. Data were collected at health centers, using precoded questionnaires and examinations, when the children were 6, 18, and 36 months old. Data about the mothers were collected at the maternity ward. At 36 months of age, 80% of the children were caries free. Favorable dental behaviors were related to toothbrushing and use of fluorides. These behaviors were so well established and consistent at all ages that they can be regarded as norms for this community. The most unfavorable and inconsistent behavior was related to sugar consumption. Dental health education could be most usefully applied to this area, where the greatest potential for improvement in behavior exists. A relationship was found between the children's caries experience and the number of missing teeth of the mother, her dental attendance pattern and her level of education. None of the social or behavioral variables tested had a strong enough association with caries experience to justify their use as caries predictors in this age group.