PubMed Health⌕ Search

Biomedical subjects

A Nash

Publications and source records attributed to A Nash.

At least 19 recordsLinked to original sources
PubMed2002

Injectable silicone implants as vaccine delivery vehicles.

Injectable silicone implants were assessed as vaccine delivery vehicles in sheep, using either the model antigen avidin or Clostridium tetani and Clostridium novyi toxoids. Two types of implant were compared, the matrix type, that has been shown to deliver antigen in vitro in a first-order profile over approximately 1 month, and the covered rod type, that delivers antigen for several months in a zero-order profile. The implants were prepared using lyophilized antigen and adjuvant (in this case, recombinant ovine interleukin-1beta; rovIL-1beta) and manufactured in the absence of extremes of temperature or pH or the use of organic solvents. Use of the matrix type implant was capable of inducing antibody responses equivalent to those induced by conventional vaccination with aluminium hydroxide adjuvant ("alum"). The use of the covered rod implants, that release very low levels of antigen over a long period, induced responses that were markedly enhanced over the alum control groups. The covered rod implant also favoured production of both IgG1 and IgG2 isotypes in contrast to responses of matrix-vaccinated sheep and conventionally vaccinated control sheep in which IgG1 predominated. Prolonged duration of the antibody response was also observed following vaccination with covered rod implants. Dose-response analysis using the matrix implant demonstrated a trend towards improved responses for lower antigen doses. Clostridial vaccination of sheep showed that protective antibody titres up to 4-fold higher than for alum-adjuvanted groups could be induced by administering the antigen in the covered rod implant. Responses elicited by all implant groups were dependent on the inclusion of adjuvant into the implant formulation.

Adjuvants, Immunologic↗
PubMed2001

Contribution of germline MLH1 and MSH2 mutations to lobular carcinoma in situ of the breast.

Lobular carcinoma in situ (LCIS) is an unusual histological pattern of non-invasive neoplastic disease of the breast occurring predominantly in women aged between 40 and 50 years. LCIS is frequently multicentric and bilateral suggesting a genetic basis to the disease. The high frequency of microsatellite instability in lobular breast cancers, coupled with increased risk of breast cancer associated with germline mismatch repair gene mutations raises the possibility that mutations MSH2 or MLH1 might confer susceptibility to LCIS. To explore this possibility we have examined a series of 71 LCIS patients for germline MSH2 and MLH1 mutations. No mutations were detected in MSH2. Two sequence variants were identified in MLH1. The first was a CTT-->CAT substitution, codon 607 (exon 16) changing leucine to histidine. The other mutation detected in MLH1 was a TAC-->TAA substitution codon 750 (exon 19) creating a stop codon, predicted to generate a truncated protein. These findings suggest that mutations in MLH1 may underlie a subset of LCIS cases.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Lobular carcinoma in situ of the breast is not caused by constitutional mutations in the E-cadherin gene.

Lobular carcinoma in situ (LCIS) is an unusual histological pattern of non-invasive neoplastic disease of the breast occurring predominantly in women aged between 40 and 50 years. LCIS is frequently multicentric and bilateral, and there is evidence that it is associated with an elevated familial risk of breast cancer. Although women with LCIS suffer an increased risk of invasive breast disease, this risk is moderate suggesting that LCIS may result from mutation of a gene or genes conferring a high risk of LCIS, but a lower risk of invasive breast cancer. The high frequency of somatic mutations in E-cadherin in LCIS, coupled with recent reports that germline mutations in this gene can predispose to diffuse gastric cancer, raised the possibility that constitutional E-cadherin mutations may confer susceptibility to LCIS. In order to explore this possibility we have examined a series of 65 LCIS patients for germline E-cadherin mutations. Four polymorphisms were detected but no pathogenic mutations were identified. The results indicate that E-cadherin is unlikely to act as a susceptibility gene for LCIS.

Adult↗
PubMed2000

Effects of prenatal dexamethasone on spatial learning and response to stress is influenced by maternal factors.

The present study investigated the effect of prenatal dexamethasone (Dex) exposure on early perinatal events, hippocampal function, and response to stress. Pregnant rats received Dex in the evening water (2.5 microg/ml) or tap water (Veh) from gestational day 15 until delivery. On the day of parturition, pups were randomized, cross-fostered, and reduced to eight or nine per dam. Four groups resulted: Veh-Veh (offspring exposed to Veh in utero, rearing mother treated with Veh during gestation), Veh-Dex, Dex-Veh, and Dex-Dex. Spatial visual memory was evaluated with the Morris water maze. The corticosterone response to restraint stress was examined, and the expression of hippocampal glucocorticoid and mineralocorticoid receptors mRNA was determined by in situ hybridization. Exposure to Dex caused restlessness in mothers, low birth weights, and poor weight gain in the offspring. The Dex-Dex males had impaired spatial learning, inability to rapidly terminate the adrenocortical response to stress, and decreased hippocampal glucocorticoid receptor (GR) mRNA expression. In contrast, Dex-exposed animals reared by Veh-treated mothers had adequate spatial learning, enhanced glucocorticoid feedback, and increased hippocampal GR mRNA. We conclude that the environment provided by a healthy mother during the postnatal period can prevent the detrimental effects of prenatal Dex administration on cognition, GR mRNA expression of the hippocampus, and the quality of the stress response.

Adrenal Cortex↗
PubMed1999

Suckling defect in mice lacking the soluble haemopoietin receptor NR6.

Cytokines control a variety of cellular responses including proliferation, differentiation, survival and functional activation, via binding to specific receptors expressed on the surface of target cells [1]. The cytokine receptors of the haemopoietin family are defined by the presence of a conserved 200 amino acid extracellular domain known as the haemopoietin domain [2]. We report here the isolation of NR6, a haemopoietin receptor that, like the p40 subunit of interleukin-12 (IL-12) [3] and the EBI3 gene induced by Epstein-Barr virus infection in lymphocytes [4], contains a typical haemopoietin domain but lacks transmembrane and cytoplasmic domains. Although in situ hybridisation revealed NR6 expression at multiple sites in the developing embryo, mice lacking NR6 did not display obvious abnormalities and were born in the expected numbers. Neonatal NR6(-/-) mice failed to suckle, however, and died within 24 hours of birth, suggesting that NR6 is necessary for the recognition or processing of pheromonal signals or for the mechanics of suckling itself. In addition, NR6(-/-) mice had reduced numbers of haemopoietic progenitor cells, suggesting a potential role in the regulation of primitive haemopoiesis.

Amino Acid Sequence↗
PubMed1999

Bicalutamide dosages used in the treatment of prostate cancer.

BACKGROUND: Androgen deprivation is often used for the treatment of patients with prostate cancer. Androgen deprivation can be achieved by surgical castration or medical castration, with or without using an antiandrogen. Each of these treatments may be used alone, or an antiandrogen may be used alongside castration to produce combined androgen blockade therapy. METHODS: The nonsteroidal antiandrogen, bicalutamide (Casodex), has been evaluated as a component in combined androgen blockade and as monotherapy. We review the arguments that indicate why a 50-mg once-daily dose of bicalutamide is appropriate in combined androgen blockade, while ongoing clinical trials evaluate 150-mg once-daily as monotherapy in the treatment of prostate cancer. RESULTS: The choice of the 50-mg dose of bicalutamide when used in combined androgen blockade is supported by four main arguments. First, bicalutamide 50 mg is at least equivalent to, if not better than, flutamide 750 mg in terms of receptor affinity, potency, and favorable plasma concentration profile. Second, the reduction in testosterone concentrations produced by medical or surgical castration decreases the potential competition between bicalutamide and testosterone for androgen receptors in prostate cells, allowing the use of a lower dose of antiandrogen in combined androgen blockade than is necessary in monotherapy. Third, bicalutamide 50 mg has an excellent tolerability profile. Fourth, at the 50-mg dose, bicalutamide plus luteinizing hormone-releasing hormone analogue was equivalent to flutamide plus luteinizing hormone-releasing hormone analogue, although there was a trend towards longer survival with bicalutamide. Furthermore, investigations of higher doses of bicalutamide have justified evaluation of bicalutamide 150 mg as monotherapy. First, pharmacodynamic studies reveal an increasing prostate-specific antigen response with increasing dose, which appears to plateau at a dose of around 150-200 mg. Second, in an analysis with 31% mortality, bicalutamide 150 mg appeared to have equivalent efficacy compared with castration in terms of survival in patients with nonmetastatic prostate cancer. CONCLUSIONS: On the basis of available data, bicalutamide 50 mg is an appropriate dose to use in combined androgen blockade, while 150 mg is being evaluated in ongoing clinical trials as a suitable dose for monotherapy.

Androgen Antagonists↗
PubMed1999

A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity.

Nucleosomal histone modification is believed to be a critical step in the activation of RNA polymerase II-dependent transcription. p300/CBP and PCAF histone acetyltransferases (HATs) are coactivators for several transcription factors, including nuclear hormone receptors, p53, and Stat1alpha, and participate in transcription by forming an activation complex and by promoting histone acetylation. The adenoviral E1A oncoprotein represses transcriptional signaling by binding to p300/CBP and displacing PCAF and p/CIP proteins from the complex. Here, we show that E1A directly represses the HAT activity of both p300/CBP and PCAF in vitro and p300-dependent transcription in vivo. Additionally, E1A inhibits nucleosomal histone modifications by the PCAF complex and blocks p53 acetylation. These results demonstrate the modulation of HAT activity as a novel mechanism of transcriptional regulation.

Acetyltransferases↗
PubMed1998

Murine cerberus homologue mCer-1: a candidate anterior patterning molecule.

Xenopus cerberus (Xcer) is a cytokine expressed in anterior mesendoderm overlapping and surrounding Spemann's gastrula organiser. When misexpressed in blastomeres, Xcer can induce ectopic heads with well-defined brain, cement gland, olfactory placodes, cyclopic eye, and occasionally liver and heart. We report here the identification of mCer-1, a murine gene related to cerberus. Both mCer-1 and Xcer appear to belong to the cystine knot superfamily, which includes TGF beta s and BMPs. In Xenopus animal cap assays, mCer-1 and Xcer induced cement glands and markers of anterior neural tissue and endoderm, characteristic of BMP inhibition. Furthermore, both antagonised the ventrolateral mesoderm-inducing activity of coexpressed BMP4. In mouse embryos, mCer-1 was expressed at early gastrulation in a stripe of primitive endoderm along the future anterior side of the egg cylinder, a region essential for anterior patterning. A second phase of expression was detected in anterior embryonic mesendoderm, and by late-streak stages most of the anterior half of the embryo was positive, except for the node and cardiac progenitors. Expression was later seen in the cranial portion of the two most-recently formed somites and in two stripes within presomitic mesoderm. In embryos lacking Otx2, a homeogene with a demonstrated role in anterior patterning, mCer-1 was still expressed in an anterior zone, although often abnormally. The data suggest that mCer-1 shares structural, functional, and expression characteristics with Xcer and may participate in patterning the anterior of the embryo and nascent somite region, in part, through a BMP-inhibitory mechanism.

Amino Acid Sequence↗
PubMed1998

DAN is a secreted glycoprotein related to Xenopus cerberus.

We report that DAN, a potential cell cycle regulator and tumour suppressor, is a secreted glycoprotein related to Xenopus cerberus. DAN, cerberus, its mouse relative Cer-1/cer-l/Cerberus-like/Cerr1, and the recently described factor DRM/Gremlin, appear to be members of the cystine knot superfamily, which includes TGFbetas and BMPs. Like cerberus and mCer-1, DAN-induced cement glands as well as markers of anterior neural tissue and endoderm in Xenopus animal cap assays, features of BMP signalling blockade. During mouse embryogenesis, Dan was expressed from E8.5 in cranial mesenchyme and somites, then later in limb and facial mesenchyme. The pattern in somites was highly dynamic, with transcripts initially localized to the caudal half of the nascent epithelial somite, then, after maturation, to sclerotomal cells adjacent to the neural tube. Dan was also expressed in the developing myotome. The expression domains include sites in which BMP inhibition is known to be important for development. Thus, DAN appears to be a secreted factor belonging to the cystine knot superfamily, and one of a growing number of antagonists acting to modulate BMP signalling during development.

Amino Acid Sequence↗
PubMed1998

Evaluation of an ultrasonically guided venepuncture technique for the placement of permanent pacing electrodes.

We have evaluated a method of puncturing the subclavian vein in its extrathoracic portion using an ultrasound guidance system. Seventy consecutive patients requiring permanent pacemakers were included in the study. The method was successful in 56 (80%) cases (23 dual chamber systems) and unsuitable or unsuccessful in 14 (20%) cases (2 dual chamber systems). The time taken to achieve a successful cannulation of the vein was similar to that taken with conventional subclavian venepuncture (average time taken for each venepuncture was 31 seconds, range 5-130 seconds). There was a significant "learning curve" in that nearly all of the unsuccessful cases were in the first half of the series. There were no major complications. Computerized Tomography (CT) confirms that the point of entry into the subclavian vein using this technique lies outside the thoracic cavity, thereby minimizing the risk of pneumothorax. This approach to the subclavian vein is an easy technique to learn, with few immediate complications and there may be less chance of lead fracture due to subclavian crush in the longer term.

Adult↗
PubMed1997

Catering services. Measuring the wasteline.

The study found that overall almost half (46 per cent) of the food served in the hospitals surveyed was wasted. Waste was higher where meals were put onto plates in wards (57 per cent) than where meals were plated in the hospital kitchen (35 per cent). The researchers observed that meals often arrived late and were not well presented.

Age Factors↗
PubMed1997

Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300.

We report here the identification of a novel cofactor, ACTR, that directly binds nuclear receptors and stimulates their transcriptional activities in a hormone-dependent fashion. ACTR also recruits two other nuclear factors, CBP and P/CAF, and thus plays a central role in creating a multisubunit coactivator complex. In addition, and unexpectedly, we show that purified ACTR is a potent histone acetyltransferase and appears to define a distinct evolutionary branch to this recently described family. Thus, hormonal activation by nuclear receptors involves the mutual recruitment of at least three classes of histone acetyltransferases that may act cooperatively as an enzymatic unit to reverse the effects of histone deacetylase shown to be part of the nuclear receptor corepressor complex.

Acetyltransferases↗
PubMed1997

Right hemidiaphragmatic twitching: a complication of bipolar atrial pacing.

A patient with an atrioventricular sequential pacemaker developed rhythmic contractions of the right hemidiaphragm. This was found to be the result of right phrenic nerve stimulation, which was directly related to the wide distance between the poles of an ELA atrial lead when pacing in bipolar mode. Pole separation in current atrial leads is discussed.

Aged↗
PubMed1997

Pectoral muscle stimulation after falling off a ladder.

A-pacemaker that had been implanted correctly was found at follow-up to have "flipped over" as a result of a fall from a ladder. Symptomatic pectoral muscle stimulation ceased immediately when the generator was manually flipped back into the correct position.

Accidental Falls↗