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Biomedical subjects

J Paterson

Publications and source records attributed to J Paterson.

At least 37 records · Page 2Linked to original sources

Liposomal distribution in malignant glioma: possibilities for therapy.

We investigated the potential of 111In-labelled liposomes to specifically target recurrent high-grade glioma in eight patients, all of whom had clinical and radiological evidence of relapse following prior treatment with surgery and radiotherapy. The phospholipid liposomes were labelled with 74 MBq 111In and injected intravenously. The distribution of radioactive material in the brain was imaged using a dedicated neuro-SPET imager. Images were taken 1 h post-injection and repeated at 24, 48 and 72 h. In addition, whole-body images were performed with a gamma camera and blood taken for radioactivity determination. At 72 h post-injection, excellent tumour demarcation could be seen in seven of eight patients. The images obtained correlated well with the corresponding computed tomography images. Blood radioactivity levels gradually declined over the 72 h. Tumour uptake continued to rise throughout this time and, together with the steady fall in normal brain tissue, the tumour-to-brain contrast gradually increased (maximum 7:5). Whole-body images indicate that the liver is the major organ of uptake with up to 50% of the injected dose. No toxicity could be attributed to the injected liposomes. Although the total percentage uptake was low (1.1%), the tumour-to-brain contrast ratios, together with the SPET images, suggest the potential for tumour-specific targeting.

Brain Neoplasms↗

The role of ErbB-2 tyrosine kinase receptor in cellular intrinsic chemoresistance: mechanisms and implications.

The erbB family of tyrosine kinase receptors is involved in the regulation of a variety of vital functions including cell proliferation, cell differentiation, and stress response. Alteration in the expression of erbB receptors occurs in numerous tumor types and plays an important role in cancer development, cancer progression, and susceptibility to cell killing by anticancer agents. Of particular interest is the intrinsic drug resistance associated with overexpression of the erbB-2 receptor. In general, tumor cells overexpressing erbB-2 are intrinsically resistant to DNA-damaging agents such as cisplatin. While the molecular mechanisms by which erbB-2 induces drug resistance are not yet established, there is evidence that this may be a consequence of altered cell cycle checkpoint and DNA repair mechanisms and dysregulation of apoptotic pathway(s). The apoptotic signal induced by many anticancer drugs originates at a receptor on the cell membrane and is transduced through a signaling cascade to the nucleus. Drug-induced apoptosis is dependent on the balance between cell cycle checkpoints and DNA repair mechanisms. Blockade of erbB-2 signaling using erbB-2 antagonists, dominant negative mutants, or chemical inhibitors of erbB-2 tyrosine kinase activity induces cell cycle arrest, inhibits DNA repair, and (or) promotes apoptosis. Less understood are downstream signal transduction cascades by which erbB-2 affects these regulatory mechanisms. The diversity of erbB receptors results in an interconnected network of cell signaling pathways that determine tumor cell fate in response to chemotherapy stress. Further investigations on the role of erbB-coupled signaling in the regulation of stress responsive genes are critical to understand the mechanisms by which tumor cells escape cell death, and will contribute to the development of alternative therapeutic targets to overcome intrinsic drug resistance in clinical settings.

Animals↗

Using factor analysis to explore nurses' fear of AIDS in the United States of America.

The purpose of this study was to create a reliable research instrument to test the fear of AIDS (FOA) and to explore the dimension of FOA among nurses. We hypothesized that certain factors, such as physical closeness to AIDS patients or HIV-positive blood and nontolerance of homosexuals, increase fear of AIDS among nurses. A sample of 365 nurses in a mid-Atlantic state of the United States was surveyed with an 82-item Knowledge, Attitudes, and Practice (KAP) questionnaire to examine the fear of AIDS among nurses in the United States. Using correlation, item and factorial analysis, a 23-item FOA Scale II (alpha = 0.826) was created and seven FOA factors were identified. Factor analysis was used to help understand the dimensions of FOA as measured by FOA Scale II. Principal components analysis was used to analyse the correlation matrix because some items were on a five-point scale and some were on a three-point scale. The varimax rotation was used, because if one were to define dimensions then these dimensions should be as independent of each other as possible. The coefficient alpha of 0.826 obtained from using FOA Scale II indicated that FOA could be considered to be a general factor; but the general factor could be exhibited through several avenues. It was determined that FOA could be represented by four or by seven dimensions, and if one uses the eigenvalue of 1 for a cut-off point then one would argue that there were seven factors. If one used the screen test, then one could assume that there were four factors of interest. Our decision for the analysis of this paper was to attempt the interpretation of the seven factors. We used both the factor loadings-the correlation of the item score with the linear combination-and the factor score coefficients (the weights of the items to form the linear combinations) to interpret the factor. The factor analysis thus seems to give insight into the dimensions of FOA as measured by FOA Scale II. Fear of AIDS seems to be exhibited in the following seven ways: (a) support for policies which would protect me from AIDS, (b) fear of contact with blood and bodily fluids of AIDS patient, (c) turning against those who have AIDS, (d) only care for those who deserve to be helped, (e)concern that I would have no help if I had AIDS, (f) concern about the financial burden of AIDS, and (g) loss of self-worth for one who has AIDS.

Acquired Immunodeficiency Syndrome↗

A study of FRAXE in mentally retarded individuals referred for fragile X syndrome (FRAXA) testing in the United Kingdom.

The folate-sensitive fragile site FRAXE is located in proximal Xq28 of the human X chromosome and lies approximately 600 kb distal to the fragile X syndrome (FRAXA) fragile site at Xq27.3. The cytogenetic expression of FRAXE is thought to be associated with mental handicap, but this is usually mild compared to that of the more common fragile X syndrome that is associated with the expression of the FRAXA fragile site. The exact incidence of FRAXE mental retardation is uncertain. We describe here the results of a U.K. survey designed to assess the frequency of FRAXE in a population of individuals referred for fragile X syndrome testing and found to be negative for expansion events at the FRAXA locus. No FRAXE expansion events were found in 362 cytogenetically negative males studied, and one expansion event was identified in a sample of 534 males for whom cytogenetic analyses were either unrecorded or not performed. Further FRAXE expansion events were detected in two related females known to be cytogenetically positive for a fragile site in Xq27.3-28. To gain insight into the FRAXE phenotype, the clinical details of the identified FRAXE male plus three other FRAXE individuals identified through previous referrals for fragile X syndrome testing are presented. For the population studied, we conclude that FRAXE mental retardation is a relatively rare but significant form of mental retardation for which genetic diagnosis would be appropriate.

Base Sequence↗

Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy.

Non-small cell lung cancer (N-SCLC) is generally unresponsive to chemotherapy even without previous drug treatment, as opposed to small cell lung cancer (SCLC), which is initially responsive to chemotherapy. The mechanisms of this intrinsic resistance are unknown. This study was designed to investigate the role of DNA repair in intrinsic resistance of N-SCLC to cisplatin. A panel of primary N-SCLC cell cultures and established cell lines were examined and compared to SCLC cell lines established previously from untreated patients. The overall DNA repair capacity was estimated by the ability of cells to reactivate the pRSV-CAT plasmid damaged by cisplatin ("host cell reactivation" assay). Cytotoxicity was determined for cisplatin in vitro. N-SCLC cells were found to be significantly more resistant to cisplatin than SCLC cell lines isolated from untreated patients (P < 0.01). The capacity of N-SCLC cells to reactivate pRSV-CAT plasmid damaged with cisplatin and transfected into cells was higher in N-SCLC cells than in SCLC cells originating from patients who were untreated previously (P < 0.05). Correlation was also observed between chloramphenicol acetyltransferase activity and intrinsic resistance to cisplatin. However, no significant difference was observed between primary N-SCLC cultures and established cell lines. This study indicates that elevated DNA repair capacity is associated with drug resistance in lung cancer and suggests that modulation of DNA repair mechanism(s), such as the incorporation of specific DNA repair inhibitor(s) in therapeutic regimens, may help to improve therapeutic strategies of N-SCLC.

Aged↗

The effects of fescue toxicosis on beef cattle productivity.

Consumption of tall fescue forage infested with the endophytic fungus Acremonium coenophialum can result in a condition termed "fescue toxicosis," which is characterized by decreased weight gains, milk production, conception, and serum prolactin and an inability to dissipate body heat by beef cattle. These decreases in productivity have been estimated to cost beef producers more than $600 million annually. The unthrifty appearance of cattle consuming endophyte-infected tall fescue (E+) is most evident during periods of environmental heat or cold stress, suggesting an interaction with environmental conditions. Without temperature stress, cows consumed similar amounts of E+ and endophyte-free tall fescue (E-). But, when temperatures exceeded 32 degrees C, cows that grazed E+ consumed less forage than cows that grazed E-. After removal of E+ from the diet of steers, compensatory growth was observed, indicating no long-term negative effects of E+. A decrease in serum prolactin but apparently little change in other hormones has been measured after consumption of E+. Under periods of heat stress, animals had reduced ability to dissipate body heat, and blood flow to peripheral (rib skin), core-body (duodenum colon), and brain (cerebellum) tissues was decreased. Due to the depressive effects of E+ on prolactin and heat dissipation, dopamine antagonist therapy has been used in an attempt to rectify these changes. Dopamine antagonists have increased serum prolactin but there is limited evidence to suggest an improvement in heat dissipation. Experiments to elucidate the effects of E+ on alpha-1 and -2 adrenergic receptors may also offer insights into developing strategies to overcome the negative effects of E+ consumption. Preliminary results suggest that injections of an alpha-1 adrenergic antagonist (prazosin) in rats fed E+ under 32 degrees C conditions increased DM intake and reduced rectal temperature.

Acremonium↗

Differentiation and tumor response to retinobenzoic acid RE-80 in a malignant conversion model.

The synthetic retinobenzoic acid RE-80 was evaluated for its potential as an inductor of tumor cell differentiation and as a chemopreventive agent. A minimally toxic dose of RE-80 in vitro produced morphologic changes typical differentiation in epidermal tumor cell colonies. Indirect immunofluorescence indicated induction of a differentiation-associated keratin of internal stratified epithelia, K13, and inhibition of the differentiation-associated epidermal keratin K1. Cultured cells were skin-grafted to athymic nu/nu mice to evaluate RE-80 effects on early stage malignant progression in vivo. When tumors had grown to 3 to 4 mm in diameter, mice were treated by intraperitoneal injection with RE-80 (67 micrograms, 170 mmol, i.p., two times per week) or vehicle (100 microliters 20% ethanol). Papillomas (benign) and moderately differentiated squamous cell carcinomas were reduced in volume about 4-fold by RE-80 treatment. Larger, poorly differentiated squamous cell carcinomas were unaffected. RE-80 resulted in a lower proportion of proliferative cells (detectable by bromodeoxyuridine incorporation) and a higher proportion of moderately to well differentiated tumors after 40 days of treatment compared with control tumors, which were mainly poorly differentiated squamous cell carcinomas. K13 induction in vitro was correlated with response to retinoid in vivo. Induction of differentiation may be mechanism of the response to RE-80 in vivo since carcinoma cells expressing K13 did not incorporate bromodeoxyuridine and were on a terminal pathway.

Animals↗

New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome.

The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function.

Abnormalities, Multiple↗

X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.

X-linked hydrocephalus, spastic paraplegia type I and MASA syndrome are related disorders with loci in subchromosomal region Xq28. We have previously shown that X-linked hydrocephalus is caused by mutations in the gene for neural cell adhesion molecule L1 (L1CAM), an axonal glycoprotein involved in neuronal migration and differentiation. Here we report mutations of the L1 gene in MASA syndrome and SPG1, in addition to HSAS families. Two of the HSAS mutations would abolish cell surface expression of L1 and represent the first functional null mutations in this disorder. Our results indicate that these three syndromes from part of a clinical spectrum resulting from a heterogeneous group of mutations in the L1 gene.

Aphasia↗

A new look at national medical workforce strategy.

The efforts of governments in medical workforce policy have been unimpressive, and this has had serious consequences. Political compromise, theoretical error and administrative laxity have all contributed. It is demonstrated that market evidence, viewed through the prism of orthodox price theory, allows useful prescriptions to be made. These can be implemented through vigorous continuing maintenance and adjustment work on the Commonwealth Medical Benefits Schedule, together with periodic adjustments to rates of undergraduate and specialist medical education and training.

Australia↗

AIDS-related knowledge, fear, and behavioral change among nurses in Taiwan.

Current literature documents a phenomenon of fear that affects the willingness of health care professionals to care for persons with acquired immunodeficiency syndrome (AIDS). We attempted to identify differences between nurses who exhibit fearful attitudes toward AIDS and those who do not, based on knowledge and behavior. Taiwan, site of the study, is only beginning to identify the first of its citizens with AIDS. The subjects were a population of caregivers from a culture with little exposure, therefore, either through education or experience, to the disease and the issues it engenders. A cross-sectional, self-administered survey was conducted in 1990 of 1759 nurses in 12 institutions throughout Taiwan. Data on AIDS-related knowledge, fear, and behavior, as well as selected demographic data, were gathered. Analysis revealed significantly less fear of AIDS among nurses who reported three behavioral changes related to AIDS than among those who reported fewer changed behaviors (F = 4.43, df = 3; P < 0.004); those with higher levels of education (F = 3.54, df = 3; P < 0.014); and those who were single rather than married (t = 2.81; P < 0.005).

Acquired Immunodeficiency Syndrome↗

Refining the genetic location of the gene for X linked hydrocephalus within Xq28.

The most common inherited form of hydrocephalus, X linked hydrocephalus (HSAS), is characterised by mental retardation, adducted thumbs, and spastic paraplegia. Genetic analysis has mapped the locus for HSAS to subchromosomal band Xq28 within a region of approximately 2 megabases of DNA. In order to refine the location of the disease gene we have conducted genetic linkage analysis with Xq28 marker loci in four additional HSAS families. A lod score of 4.26 with polymorphic marker DXS52 (St14) confirms the linkage of HSAS to Xq28. Identification of a recombination event between the HSAS gene and Xq28 loci F8C and DXS605 (2-19) reduces the size of the interval likely to contain the disease locus to about 1.5 megabases, the distance between DXS605 and DXS52. The locus for neural cell adhesion molecule, L1CAM, maps within this interval and therefore represents a candidate gene for HSAS.

Adolescent↗

Structure and transcription of the singed locus of Drosophila melanogaster.

Developmental and genetic studies of the singed gene of Drosophila melanogaster indicate that the gene has a role in somatic cells during the formation of adult bristles and hairs, and in the female germline during oogenesis. During metamorphosis a single 3.6-kilobase (kb) RNA is made, and this RNA is also present in adults and early embryos. Early embryos and adult females have additional 3.3- and 3.0-kb RNAs. The RNAs differ only in the length of the 3' untranslated region and a single gene product of 57 kilodaltons is predicted. Analysis of RNA from females lacking ovaries suggests that the 3.3- and 3.0-kb RNAs are made only in ovaries. The absence of the 3.3- and 3.0-kb RNAs in pupae and the time course of their appearance in adult females after eclosion suggests that transcription of singed in the ovary is from middle to late stages of oogenesis. Analysis of RNA in embryos from the reciprocal crosses between wild type and singed-3 showed that all three RNAs are maternally inherited with very little zygotic transcription in embryos. The mutation singed-3 appears to separate the two requirements for singed function as it has an extreme effect upon bristle development, but does not obviously affect oogenesis. In singed-3, there is a deletion at the 5' end of the gene, but the coding region is intact. Transcription in singed-3 is from a cryptic promoter in the upstream flanking sequences which is sufficiently active during oogenesis for fertility, but less active than the wild-type promoter during metamorphosis. The role of the single singed gene product may be in the asymmetric organization and/or movement of cytoplasmic components.

Amino Acid Sequence↗

Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration.

There is growing evidence that renally-impaired patients receiving morphine therapy are at greater risk of developing opiate toxicity, due to the accumulation of an active metabolite, morphine-6-glucuronide (M6G), which is usually excreted by the kidneys. This study examined the relationships between morphine dosage, renal function, and trough plasma concentrations of morphine and its glucuronide metabolites in 21 patients (aged mean: 68.5 years: 11 males) receiving either oral or subcutaneous morphine for terminal cancer pain. The median daily morphine dosages (mg.kg-1) were: orally 1.87 (range 0.37-6.82) and subcutaneously 1.64 (range 0.22-3.60). The median plasma concentrations of morphine, morphine-3-glucuronide (M3G), and M6G (ng.ml-1) were: 36.0, 1035.2, and 142.3, respectively. The plasma concentrations of morphine, M3G and M6G were each significantly related to the daily morphine dosage (n = 21, Spearman r = 0.79, 0.91, and 0.88 respectively). Accumulation of the morphine glucuronides was dependent on renal function. The plasma concentrations of M3G and M6G, when divided by the morphine concentration, were significantly related to the calculated creatinine clearance of the patient. Patients receiving oral morphine had higher plasma concentration ratios of glucuronide/morphine than those receiving subcutaneous therapy, presumably due to first-pass glucuronidation. The results of this study confirm that accumulation of the pharmacologically active M6G is related to renal function, which probably explains the observation that morphine dosage requirements are generally reduced in patients with renal impairment.

Aged↗

Dosage prescribing and plasma oxipurinol levels in patients receiving allopurinol therapy.

This study examined dosage prescribing patterns and steady-state oxipurinol plasma concentrations in 66 patients receiving chronic allopurinol therapy. Most patients (65%) were taking 300 mg allopurinol daily, although renal impairment was common. Using published guidelines, it was estimated that 35% of patients were receiving excessive dosages of allopurinol. Consequently, the plasma oxipurinol concentrations were often very high (mean (SD) was 156 (109) mumol.l-1). Accumulation of oxipurinol was inversely related to renal function. Plasma concentrations of oxipurinol and urate were not significantly related. However, most patients with oxipurinol concentrations of up to 100 mumol.l-1 had urate concentrations within the normal reference range.

Aged↗

Palliative care.

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Aged↗