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Biomedical subjects

L Bradley

Publications and source records attributed to L Bradley.

At least 37 records · Page 2Linked to original sources
PubMed1997

Synthesis and evaluation of trimetoquinol derivatives: novel thromboxane A2/prostaglandin H2 antagonists with diminished beta-adrenergic agonist activity.

Trimetoquinol (TMQ, 1) is a unique catecholamine with a strong stereodependence for agonism at beta-adrenergic (S > > R) and antagonism at thromboxane A2/prostaglandin H2 (TP; R > > S) receptors. Our laboratory has reported the effects of N-alkylation and modification of the trisubstituted benzyl group in these receptor systems. For iodinated derivative 5, maintaining potency in TP receptor systems (112%) was coupled with maintaining limited potency in beta-adrenergic receptor systems (34% for beta 1 and 47% for beta 2). In this study, several diverse TMQ derivatives were prepared to probe for binding interactions specific to a particular receptor system. Planar amidine 2, which was designed to explore the importance of TMQ's chiral center, showed a dramatic loss of potency (< 1%) in each receptor system. Likewise, the homologation of a previously described N-benzyl derivative (3) to the N-phenylethyl derivative 4 also showed reduced potency (< 3%) in both receptor systems. However, modification of the trimethoxybenzyl group of TMQ to a 4-hydroxy-3-nitrobenzyl group (7) provided a unique lead for TMQ derivatives with significant potency in TP receptor systems (91%) and reduced potency in beta-adrenergic receptor systems (4% for beta 1 and 19% for beta 2).

Adrenergic beta-Agonists↗
PubMed1996

A sticky problem: the Xenopus cement gland as a paradigm for anteroposterior patterning.

The cement gland is a mucus-secreting organ found at the extreme anterior of frog embryos. It attaches the embryo to a solid support before swimming and feeding begin, and also serves a related sensory function that stops the embryo from moving once it is attached. Cement gland is an extremely useful anterior marker, whose study continues to yield fundamental information concerning vertebrate axial patterning. Cement gland arises from the outer layer of the embryonic ectoderm and, in Xenopus, forms a cone of columnar epithelium. It is the first ectodermal organ to differentiate, beginning to do so by late gastrula. A battery of genes expressed in the developing and mature cement gland serve as useful markers. Cement gland development can be influenced by both stimulatory and inhibitory cell interactions. Stimulatory signals arise from the anterior neural plate, head endoderm, and the dorsal mesoderm. Inhibitory signals are present in the posterior dorsal mesoderm and in ventral ectoderm and mesoderm. Further, signalling between the ectodermal layers may restrict cement gland differentiation to the outer ectodermal cells. Several secreted molecules are able to induce or repress cement gland formation: these include noggin, follistatin, hedgehog, chordin, retinoic acid, embryonic fibroblast growth factor (eFGF), Bone Morphogenetic Protein-4 (BMP-4), and Xwnt-8. Several of these factors alter expression of the homeodomain gene Xotx2, which may be a transcriptional activator of cement gland differentiation genes. The significance of the cell interactions and factors described in positioning cement gland at the front of the embryo is explored.

Animals↗
PubMed1996

Analysis of perceptual confusions between nine sets of consonant-vowel sounds in normal and dyslexic adults.

It is widely accepted that most developmental dyslexics perform poorly on tasks which assess phonological awareness. One reason for this association might be that the early or "input" phonological representations of speech sounds are distorted or noisy in some way. We have attempted to test this hypothesis directly. In Experiment 1, we measured the confusions that adult dyslexics and controls made when they listened to nine randomly presented consonant-vowel (CV) segments [sequence: see text] under four conditions of increasing white noise masking. Subjects could replay stimuli and were under no obligation to respond quickly. Responses were selected with a computer mouse from a set of nine letter-strings, corresponding to the auditory stimuli, presented on a VDU. While the overall pattern of confusions made by dyslexics and controls was very similar for this stimulus set, dyslexics confused [sequence: see text] significantly more than did controls. In Experiment 2, subjects heard each stimulus once only and were forced to respond as quickly as possible. Under these timed conditions, the pattern of confusions made by dyslexics and controls was the same as before, but dyslexics took longer to respond than controls. The slower responses of dyslexics in Experiment 2 could have arisen because: (a) they were slower at processing the auditory stimuli than controls, (b) they had worse visual pattern memory for letter strings than controls, (c) they were slower than controls at using the computer mouse. In Experiments 3, 4 and 5 subjects carried out control tasks which eliminated each of these possibilities and confirmed that the results from the auditory tasks genuinely reflected subjects' speech perception. We propose that the fine structure of dyslexics' input phonological representations should be further explored with this confusion paradigm by using other speech sounds containing VCs, CCVs and VCCs.

Adult↗
PubMed1996

X linked agammaglobulinaemia with a 'leaky' phenotype.

Typical X linked agammaglobulinaemia (XLA) is characterised by absence of immunoglobulin production and lack of mature B cells. The gene responsible for XLA has recently been identified, and codes for a B cell tyrosine kinase, BTK. A family affected by a B cell immunodeficiency, which is less severe than classical XLA, is described but they had a pedigree suggestive of X linked inheritance. Demonstration of a mutation in the BTK gene confirms that this is a mild form of XLA.

Agammaglobulinemia↗
PubMed1996

Positive and negative signals modulate formation of the Xenopus cement gland.

The cement gland is a simple secretory organ that marks the anterior-most dorsal ectoderm in Xenopus embryos. In this study, we examine the timing of cement gland induction and the cell interactions that contribute to cement gland formation. Firstly, we show that the outer ectodermal layer, from which the cement gland arises, becomes specified as cement gland by mid-gastrula. Curiously, at early gastrula, the inner layer of the dorsal ectoderm, which does not contribute to the mature cement gland, is strongly and transiently specified as cement gland. Secondly, we show that the mid-gastrula dorsoanterior yolky endoderm, which comes to underlie the cement gland primordium, is a potent inducer of cement gland formation and patterning. The cement gland itself has an anteroposterior pattern, with the gene XA expressed only posteriorly. Dorsoanterior yolky endoderm greatly enhances formation of large, patterned cement glands in partially induced anterodorsal ectoderm, but is unable to induce cement gland in naive animal caps. Neural tissue is induced less frequently than cement gland by the dorsoanterior yolky endoderm, suggesting that the endoderm induces cement gland directly. Thirdly, we demonstrate that the ventral ectoderm adjacent to the cement gland attenuates cement gland differentiation late during gastrulation. The more distant ventral mesendoderm is also a potent inhibitor of cement gland formation. These are the first data showing that normal ventral tissues can inhibit cement gland differentiation and suggest that cement gland size and position may be partly regulated by negative signals. Previous work has shown that cement gland can be induced by neural plate and by dorsal mesoderm. Together, these data suggest that cement gland induction is a complex process regulated by multiple positive and negative cell interactions.

Animals↗
PubMed1995

High-pressure near-infrared Raman spectroscopy of bacteriorhodopsin light to dark adaptation.

Near-infrared (NIR) Raman spectroscopy is employed as an in situ probe of the chromophore conformation to study the light to dark-adaptation process in bacteriorhodopsin (bR) at variable pressure and temperature in the absence of undesired photoreactions. In dark-adapted bR deconvolution of the ethylenic mode into bands assigned to the all-trans (1526 cm-1) and 13-cis (1534 cm-1) isomers yields a 13-cis to all-trans ratio equal to 1 at ambient pressure (Schulte et al., 1995, Appl. Spectrosc. 49:80-83). Detailed spectroscopic evidence is presented that at high pressure the equilibrium is shifted toward the 13-cis isomers and that the light to dark adaptation kinetics is accelerated. The change in isomeric composition with temperature and pressure as well as the kinetics support a two-state model activation volumes of -16 ml/mol for the transition of 13-cis to all-trans and -22 ml/mol for the reverse process. These compare with a conformational volume difference of 6.6 ml/mol, which may be attributed to the ionization of one or two residues or the formation of three hydrogen bonds.

Bacteriorhodopsins↗
PubMed1995

Reducing the use of physical restraints in long-term care facilities.

1. There has been increasing recognition of the role of education as a catalyst for changing restraint use practices and policies of long-term care facilities in Canada and other Western countries. 2. Findings of this longitudinal study documented the positive outcome of a structured restraint education program in reducing the use of physical restraints and promoting non-restrictive alternatives. 3. With continuing education and inservice programs, restraint-free elderly care can be attained in a cost-effective manner and without an increase in resident falls and injuries.

Aged↗
PubMed1995

Breaking free.

Explore the source record for details and available documents.

Home Nursing↗
PubMed1994

Hereditary and familial ovarian cancer in southern Ontario.

BACKGROUND: Hereditary ovarian cancer may be site specific or may appear in combination with breast cancer or other cancers in a family. The most common hereditary form is the breast-ovarian cancer syndrome. It is estimated that in 100% of these families, there is linkage to a cancer susceptibility gene on chromosome 17q, BRCA1. METHODS: A positive family history of breast or ovarian cancer was reported for 71 of 450 unselected cases of ovarian cancer identified in Southern Ontario. Detailed pedigrees were completed by telephone interview for 48 of the 71 subjects. RESULTS: Nine families were identified with five or more cases of breast or ovarian cancer, 14 families with four cases of cancer, and eight families with three cases. Breast cancer appeared in 80% of the ovarian cancer families. There were 81 healthy first-degree female relatives of the cancer cases considered to be at high risk for ovarian cancer. CONCLUSIONS: It is feasible to use a simple questionnaire on all incident cases of ovarian cancer in a population to identify families with potential hereditary breast-ovarian cancer. Two point nine percent to 6.9% of cases of ovarian cancer appear to be inherited; the majority of the families also will have an excess number of cases of breast cancer.

Adult↗
PubMed1994

Differences in recovery from constructional apraxia after right and left hemisphere stroke?

Previous comparisons of constructional apraxia after right and left hemisphere damage have not investigated the influence of time since onset. This paper reports some preliminary findings from stroke patients in a physical rehabilitation trial. Fifty-five patients with right hemisphere damage and 65 with left hemisphere damage were assessed on the WAIS-R Block Design test at 1 month and 6 months post stroke. The groups were similar at 1 month but the left hemisphere group showed better average recovery by 6 months. There was great variability in amount of recovery within the left hemisphere group, suggesting individual differences in initial reasons for failing Block Design, and corresponding differences in the recovery process. Compensation by the right hemisphere is discussed as one possible process. Future detailed longitudinal studies may be useful in contrasting the cognitive deficits which underlie constructional apraxia after right-sided and left-sided lesions, and would provide evidence on mechanisms of recovery and adaptation.

Adult↗
PubMed1994

What children see affects how they spell.

The authors predicted that children who have experienced frequent visual confusion of text during their development because of unstable binocular control may be prevented from discovering the rules and patterns of English orthography. The authors compared the spelling errors made by children who had unstable binocular vision with those of children who had stable binocular vision and the same spelling ability. The subjects were drawn from a clinical population of children referred because of suspected reading difficulties; though they were of mixed abilities, they were generally poor spellers and readers. Children with unstable binocular control made spelling errors which were more phonologically plausible than those made by the control group with normal binocular vision.

Child↗
PubMed1994

Enhanced physical therapy for arm function after stroke: a one year follow up study.

Ninety seven patients with stroke who had participated in a randomised trial of conventional physical therapy nu an enhanced therapy for arm function were followed up at one year. Despite the emphasis of the enhanced therapy approach on continued use of the arm in everyday life, the advantage seen for some patients with enhanced therapy at six months after stroke had diminished to a non-significant trend by one year. This was due to some late improvement in the conventional therapy group whereas the enhanced therapy group remained static or fell back slightly. It is recommended that trials should be conducted comparing very intensive therapy for the arm with controls without treatment. This would provide a model of the effects of therapy on intrinsic neural recovery that would be relevant to all areas of neurological rehabilitation.

Aged↗
PubMed1993

A mutant alpha subunit of G12 potentiates the eicosanoid pathway and is highly oncogenic in NIH 3T3 cells.

The discovery of GTPase-inhibiting mutations in genes for alpha subunits of Gs or G(i2) in certain human endocrine tumors has raised the possibility that heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins) might contribute to neoplastic disease. Expression of GTPase-deficient alpha s or alpha i2 polypeptides in rodent fibroblasts increases or decreases cAMP, respectively, and induces certain alterations in cell growth but only a few of the phenotypic changes associated with cellular transformation. In contrast, an analogous mutation in the alpha subunit of Gq, which activates phosphatidylinositol (PI)-specific phospholipase C, is fully oncogenic. However, activated alpha q is cytotoxic and several orders of magnitude less potent as an oncogene than certain G protein-coupled receptors. Thus, G proteins other than those inducing PI hydrolysis might possess high transforming efficiency. In the present study, we explored the G12 family of G proteins for their oncogenic potential. Our results show that whereas overexpression of wild-type alpha 12 in NIH 3T3 cells is itself weakly transforming, an activated alpha 12 behaves as a remarkably potent oncogene. Transformation by alpha 12 correlates with alterations in the eicosanoid pathway but not with PI-specific phospholipase C or other G protein-linked second messengers.

3T3 Cells↗
PubMed1992

Covering one eye affects how some children read.

The Dunlop Test was used to identify unstable binocular control in a group of 32 mixed-ability children. They were compared with 32 reading age-matched controls. The children were then asked to read two lists of single real words of equal linguistic difficulty: one with both eyes open and the other with the left eye occluded. Only children who failed the Dunlop Test made fewer non-word errors when they read with one eye. This result provides additional support for the theory that unstable binocular control can directly affect how children read. In addition, these findings suggest that this effect must be due, at least in part, to some interaction between the images from the two eyes.

Child↗
PubMed1991

Estrogen-stimulation of postconfluent cell accumulation and foci formation of human MCF-7 breast cancer cells.

Foci, nodules of cellular overgrowth, that appear after confluence are an in vitro characteristic of malignant transformation. A well-studied in vitro model of estrogen-dependent tumors is the MCF-7 cell line, derived from a pleural metastasis of a human breast adenocarcinoma. We report that cultivation of MCF-7 cells, using routine methods, results in extensive estrogen-stimulated postconfluent cell accumulation characterized by discrete three-dimensional arrays. Side view Nomarski optical sections revealed these to be principally multicellular foci with occasional domes and pseudoacinar vacuoles. This effect on MCF-7 cell growth occurs in media containing fetal bovine serum but not with calf serum or charcoal-dextran-treated fetal bovine serum unless supplemented with estrogens. Foci formation starts 5-6 days after confluence, and the number of foci generated is a function of the concentration of added estrogens. Foci formation is suppressed by the antiestrogens Tamoxifen and LY 156758. Addition of progesterone, testosterone, or dexamethasone had little or no effect, while various estrogens (ethinyl estradiol, diethylstilbestrol, and moxestrol) induced foci development. Clones derived from single cells of the initial MCF-7 population revealed a wide variance in estrogen-induced foci formation, demonstrating heterogeneity of this tumor cell line. The postconfluent cell growth of the estrogen receptor-deficient cell line, MDA-MB-231, contrasted with MCF-7 by developing an extensive multilayer morphology devoid of discrete structures. The tumorigenic potential of the MCF-7 cells used in our experiments was confirmed by their estrogen-dependent growth in immunosuppressed male BDF1 mice. These data suggest an estrogen receptor-based mechanism for the development of multicellular foci during postconfluent growth of MCF-7 cells. After confluence, foci, in contrast to the quiescent surrounding monolayer, retain proliferating cells. Focus formation, therefore, reflects the heterogeneous responsiveness of these cells to estrogens and should provide a model permitting in vitro comparisons between the progenitor cells of multicellular foci and the monolayer population.

Adenocarcinoma↗
PubMed1991

Prospective evaluation of maternal serum human chorionic gonadotropin levels in 3428 pregnancies.

As part of a multicenter prospective study, second-trimester human chorionic gonadotropin and alpha-fetoprotein concentrations were evaluated. Data included maternal age, human chorionic gonadotropin level, alpha-fetoprotein level, weight, race, and pregnancy outcome of 3428 pregnancies at between 15 and 20 weeks' gestation. The results of the study indicate that human chorionic gonadotropin levels decrease as maternal weight increases, that weight-adjusted human chorionic gonadotropin levels for Oriental and black women are higher than for white or Hispanic women, and that twin pregnancies have higher human chorionic gonadotropin levels than singleton pregnancies. Of 255 pregnancies that did not have normal outcomes, 54 (21.2%) had human chorionic gonadotropin levels greater than 2.0 multiples of the median and 26 (10.2%) had alpha-fetoprotein levels greater than 2.5 multiples of the median. Of 11 pregnancies with fetal aneuploidy, 6 (54.5%) had human chorionic gonadotropin levels greater than 2.0 multiples of the median. It is concluded that in human chorionic gonadotropin screening programs for fetal Down syndrome, weight and race adjustments are necessary for accurate risk assessment.

Aneuploidy↗