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Biomedical subjects

R Aston

Publications and source records attributed to R Aston.

At least 19 recordsLinked to original sources
PubMed1995

Assessing the completeness of tuberculosis notification in a health district.

We have estimated the completeness of tuberculosis notification in Bolton health district by combining notification data with information from prescriptions issued by general practitioners and hospital admission data. From 1 January 1991 to 31 December 1993, 307 cases of tuberculosis were notified in Bolton. Thirty-four cases were identified using general practitioners' prescriptions: 27 of these had been notified between January 1991 and December 1993, and seven had not been notified during this period. Although prescriptions may be used as a marker for tuberculosis, they would not be an adequate alternative to notification of cases. One hundred and forty-eight cases of tuberculosis were identified between 1 October 1992 and 30 September 1993 by combining data from the three sources: 138 cases had been notified (93.2%), 28 identified from prescriptions (23.0%), and 54 identified from hospital data (36.5%).

Antitubercular Agents↗
PubMed1994

The modulation of tumour necrosis factor-alpha, interleukin-1 alpha and glucose levels with GMDP and other analogues of muramyl dipeptide.

Immunomodulatory agent muramyl dipeptide (MDP) and seven of its analogues were tested for ability to counteract the toxic actions of lipopolysaccharide (LPS) in experimental mouse models. Female BALB/c mice were presensitized with Corynebacterium parvum (P. acnes) and given MDP or equimolar doses of one of its analogues after 2 weeks, followed by intravenous challenge with LPS 18 h later. This treatment produced a sharp increase in blood cytokine (TNF-alpha, IL-1 alpha) levels 4 h after LPS administration followed by a decline to control values after 6 h. Four analogues, GMDP, threonylMDP, GMDPBenz and GMDPOBut, were able to reduce the level of cytokines induced with LPS. For most of the analogues, the higher doses reduced the levels of TNF-alpha but slightly increased the concomitant IL-1 alpha levels. GMDP was the most effective compound tested in terms of reduction of TNF-alpha and IL-1 alpha levels, as well as for reduction of the hypoglycaemia caused by the administration of LPS.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1993

Differential effects of small tumour necrosis factor-alpha peptides on tumour cell cytotoxicity, neutrophil activation and endothelial cell procoagulant activity.

Tumour necrosis factor-alpha (TNF-alpha) is a pluripotent cytokine with its receptors distributed throughout many different cell types. Because of the diverse effects of the cytokine, it is difficult to clearly define its role in infection and immunity, and appreciate its clinical therapeutic value. We have identified peptides derived from the primary amino acid sequence of human TNF-alpha that have neutrophil-stimulating activity, as measured by enhanced chemiluminescence and superoxide production, and peptides which are both directly cytotoxic for tumour cells (WEHI-164) in vitro and also prevent TNF binding to tumour cells. However, only one of these neutrophil-stimulating peptides was toxic for tumour cells in vitro. Our results indicate that the region of amino acids 54-94 of human TNF-alpha has previously undescribed human neutrophil-stimulatory activity, while peptides encompassing the regions 43-68 and 132-150, which are in close proximity, as indicated in the recently determined three-dimensional structure of human TNF-alpha, have in vitro anti-tumour activity. These peptides also slowed tumour growth or induced tumour regression in WEHI-164 tumour-bearing mice. The peptide 73-94, which activated neutrophils but which was not cytotoxic for tumour cells in vitro, also caused in vivo tumour regression, presumably by activating neutrophils with the consequent release of free radicals at the tumour site. Peptide 63-83, which was able to activate neutrophils in vitro, did not possess tumour regression activity in vivo. The TNF peptides described in this report did not elicit procoagulant activity in cultured bovine aortic endothelial cells and as such are devoid of at least one of the potentially lethal side-effects of elevated TNF levels in vivo.

Amino Acid Sequence↗
PubMed1992

Selective enhancement of the tumour necrotic activity of TNF alpha with monoclonal antibody.

The binding and biological activity of human TNF alpha on endothelial and tumour cells has been studied in the presence of monoclonal antibodies (MAbs). In particular, one monoclonal antibody to TNF alpha (MAb 32) has been identified which failed to inhibit binding and cytotoxicity of TNF alpha on WEHI-164 tumour cells but which was a potent inhibitor of TNF alpha-induced endothelial cell procoagulant activity on bovine aortic endothelial cells. The ability of MAb 32 to inhibit selectively the actions of TNF alpha on endothelial cells but not on tumour cells suggests a mechanism for enhancement of the anti-tumour action of TNF alpha in vivo when in complex with this antibody. Treatment of tumour bearing mice (WEHI-164 and Meth A fibrosarcoma) with TNF alpha-MAb 32 complex resulted in a 5- to 10-fold enhancement in the potency of the cytokine in comparison to free TNF alpha. Complexes between this cytokine and other MAbs generally resulted in either no effect or inhibition of TNF alpha activity in vivo and in vitro. Neither intact MAb 32 nor FAb' fragments of MAb 32 showed any tumour regressive activity in the absence of TNF alpha. The FAb' fragments were equipotent to the bivalent form of the antibody in enhancing TNF alpha activity. These data provide evidence that it is possible to segregate the individual biological activities of TNF alpha with concomitant enhancement of the tumour regressive activity of the cytokine in vivo.

Animals↗
PubMed1992

Growth hormone control of tissue protein metabolism in dwarf mice: enhancement by a monoclonal antibody.

Monoclonal antibody (MAb) to GH has been shown to increase the anabolic response induced by the hormone in individual tissues of dwarf mice. Dwarf mice were treated with GH at a low and a high dose (2.5 and 50 mU/day respectively), with and without complexing to an MAb. Treatment was for 7 and 14 days, at which times protein synthesis rates in skeletal muscle, liver and heart were determined from incorporation of labelled phenylalanine following injection of a flooding dose. The MAb potentiated the actions of GH and produced increases in the rates of protein synthesis in each of the tissues to a significantly greater extent than did GH alone. The increase in protein synthesis rate induced by MAb appears to be mechanistically distinct from that observed by increasing the dose of GH. In skeletal muscle and liver there was a dose-response to the GH alone in terms of the RNA concentration, i.e. the capacity for protein synthesis, whereas in each tissue examined the MAb caused very little further response in the RNA concentration. The MAb-induced enhancement of protein synthesis rate was almost entirely due to an increase in the RNA activity, i.e. the efficiency of the synthesizing system. Complexing GH to a particular MAb, or to antisera of restricted epitope specificity, has previously been shown to enhance the in-vivo effects of GH on whole body protein content; the mechanism for this enhancement has not been adequately determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Active immunization with a synthetic peptide region of growth hormone: increased lean tissue growth.

The effects of active immunization against a specific peptide region of GH (sequence 134-154) were examined in a species relevant for animal production in vivo. Peptide-immunized lambs exhibited significant increases in carcass protein and water contents and consequently increased carcass weight. The comparatively smaller increases in carcass water and protein contents which occurred in GH-treated lambs were offset by decreased fat accretion. Thus, even though peptide immunization improved lean tissue growth, it did not simply enhance all actions of GH or mimic exogenous hormone administration. This is the first definitive demonstration that endogenously produced antibody may enhance endogenous hormone activity and performance in animals.

Amino Acid Sequence↗
PubMed1990

Two outbreaks of Legionnaires' disease in Bolton Health District.

In 1988, there were two outbreaks of legionellosis in Bolton Health District. Altogether 37 cases of Legionnaires' disease and 23 cases of non-pneumonic legionellosis were identified. Twenty-five patients with Legionnaires' disease were associated with an engineering plant, 4 with Bolton town centre, and 8 with both the plant and town centre. Twenty-two people with non-pneumonic legionellosis were linked with the engineering plant and one with the plant and the town centre. A case-control study carried out among 37 employees with legionellosis and 109 control subjects at the plant showed that infection was associated with one of the 15 cooling towers on the site. Legionella pneumophila indistinguishable by serological and genetic typing methods was isolated from this cooling tower and from sputum samples from two patients. In the town centre, no one tower was linked with infection and L. pneumophila was not cultured from any of the nine towers identified. Control measures were implemented and to date there have been no further cases of legionellosis associated with Bolton Health District.

Adult↗
PubMed1990

The proportion of glycosylated prolactin in serum is decreased in hyperprolactinemic states.

The proportion of serum PRL that is glycosylated has been determined, and the effects of physiological and pathological hyperprolactinaemia on this proportion have been examined. Glycosylated and nonglycosylated PRL were immunoprecipitated from serum and subjected to polyacrylamide gel electrophoresis under reducing and dissociating conditions. Separated proteins were then transferred to nitrocellulose paper by electroblotting and detected immunologically with anti-PRL antiserum and 125I-labeled protein-A, followed by autoradiography. The proportion of total monomeric PRL present in the glycosylated form was then estimated by densitometric scanning of autoradiograms. In normal individuals glycosylated PRL was predominant, accounting for about 72% of the circulating monomeric PRL. This proportion was markedly decreased (ranging from undetectable to about 60%) in the serum of women who were pregnant or were lactating postpartum and also in patients with hyperprolactinemia caused by a pituitary tumor. The results suggest that under basal conditions the majority of PRL secreted from the pituitary is glycosylated, but with physiological or pathological hyperprolactinemia the capacity for glycosylation is exceeded.

Adult↗
PubMed1990

Induction of lactogenic receptors in liver of hypophysectomized rats treated with bovine growth hormone-monoclonal antibody complexes.

Male hypophysectomized rats treated with bovine (b)GH-monoclonal antibody complexes showed enhanced weight gain compared with animals treated with bGH alone over a 12-day treatment period. Liver microsomes prepared from animals showing enhanced weight gain exhibited increased specific binding of human (h)GH. Studies on the specificity of these binding sites showed that they were lactogenic, 125I-labelled hGH being displaced by ovine prolactin, but not by non-mammalian growth hormones. In this respect they were similar to lactogenic binding sites in the liver of pregnant rats. Monoclonal antibodies to hGH blocked binding to lactogenic receptors to different extents. The pattern of such inhibition was similar, but not identical, for the receptors induced in hypophysectomized rats and those from pregnant rat liver. The evidence available suggests that the lactogenic receptors induced by bGH-monoclonal antibody complexes are not directly involved in the enhancement of growth.

Animals↗
PubMed1990

Enhancement of bovine growth hormone activity by antibodies against growth hormone peptides.

The biological activity of growth hormones can be enhanced by complexing with monoclonal antibodies of appropriate specificity. In order to define the regions associated with the phenomenon, site-directed antisera to ovine GH (oGH) were prepared by vaccination of sheep with synthetic peptides. Peptides from six distinct regions of the oGH molecule raised antibodies which recognized the hormone in solid-phase radioimmunoassay; however, only one peptide elicited high-affinity antibody as determined by liquid-phase assay. This peptide, corresponding to amino acid sequence 35-53, resulted in circulating hormone antibody in the majority of vaccinated sheep. Immunoglobulin prepared from the serum of immunized animals produced an enhancement of the somatotrophic activity of exogenously administered GH in dwarf mice as determined by the incorporation of [35S]sulphate into costal cartilage. The identification of an antigenic peptide sequence from oGH/bovine GH which elicits enhancing antisera, raises the possibility of a growth-promotion vaccine.

Animals↗
PubMed1989

Antibody-mediated enhancement of hormone activity.

The enhancement of hormone activity by antibodies has been known for many years; however, investigation into the molecular basis of the phenomenon has only recently begun. A number of mechanisms for this enhancement, including "buffering" or slow release, bivalency and Fc region, and conformational and receptor "restriction" effects, have been documented or proposed. The availability of panels of monoclonal antibodies of distinct combining site specificity have aided in these studies and contributed substantially to our understanding of hormone-receptor interactions.

Animals↗
PubMed1989

Potentiation of growth hormone activity in sheep using monoclonal antibodies.

Monoclonal antibody OA11 was raised against ovine GH; its effects on GH activity were examined in a target species relevant for animal production in vivo. The monoclonal antibody was found to enhance the galactopoietic response to exogenous GH in adult lactating ewes and also to potentiate the diabetogenic activity of both exogenous and endogenous GH in ewe lambs. Thus it was shown that GH activity may be manipulated above its usual dose-response range in normal, intact animals of commercial importance via immunological means.

Animals↗
PubMed1988

Bioactivity and immunoactivity of growth hormone during dynamic testing of patients with acromegaly.

We have used the Nb2 cell proliferation bioassay for lactogenic hormones to investigate the biological activity of hGH in sera of patients with acromegaly. The specificity of the assay has been improved by the use of monoclonal antibodies to block the activity of individual lactogenic hormones. Disease activity in patients was assessed by scoring signs and symptoms, and by measuring IGF-I concentrations in some patients. Patients with a wide spectrum of disease activity were studied using a TRH test. hGH concentrations were measured by bioassay, RIA and immunoradiometric assay (IRMA) at 0, 20 and 60 min after injection of TRH. There was a high degree of correlation between log10 of all hGH concentrations measured by bioassay and RIA (r = 0.995, P less than 0.0001), between bioassay and IRMA (r = 0.990, P less than 0.0001), and between RIA and IRMA (r = 0.995, P less than 0.0001). In contrast to previous reports, we found no evidence for changes in the bioactivity of hGH secreted after pituitary stimulation.

Acromegaly↗
PubMed1988

Monoclonal antibody enhancement of the effects of human growth hormone on growth and body composition in mice.

Dwarf mice were treated for 10 days with phosphate-buffered saline (PBS), human growth hormone (hGH) or hGH with monoclonal antibody EB1 (hGH/MAB-EB1); for each treatment there were three groups which received 50, 75 or 100% of the amount of food eaten when available ad libitum. The PBS control groups lost more or gained less weight than equivalent groups receiving hGH alone, and mice given hGH/MAB-EB1 showed a greater weight gain than those in comparable groups receiving hGH alone. When weight gain or loss was expressed as g/g food eaten, groups treated with hGH gained more or lost less than the PBS groups. Similarly, weight gain/g food was significantly greater in hGH/MAB-EB1 animals than in the comparable groups given hGH alone. A similar pattern of response was observed for increases in tail length and uptake of 35SO42- into costal cartilage in vivo. For mice given hGH alone, fat content was decreased compared with that in the equivalent group given PBS, and mice treated with hGH/MAB-EB1 had less fat than the equivalent group given hGH alone. Administration of hGH alone caused a concomitant increase in protein content and body weight such that, compared with mice given PBS, there was no significant increase in protein as a proportion of body weight. However, hGH/MAB-EB1 caused an increase in whole body protein which was significantly greater than that for the equivalent group given hGH alone, when expressed as per cent body weight. Monoclonal antibody EB1 has been shown to enhance the actions of hGH on growth and body composition in Snell dwarf mice and to increase food conversion efficiency.

Animals↗
PubMed1987

Monoclonal antibodies to bovine growth hormone potentiate effects of the hormone on somatomedin C levels and growth of hypophysectomized rats.

Bovine growth hormone (50 micrograms/day) elevated somatomedin C levels in plasma of hypophysectomized rats: the effect was seen 12 h after the first injection and was sustained throughout a 7-day treatment period. When monoclonal antibodies to bovine growth hormone were administered with the hormone the stimulation of somatomedin C levels was markedly enhanced, as were effects on body weight. Each one of a panel of 7 monoclonal antibodies potentiated the actions of the hormone on growth and somatomedin C levels, though the extent and pattern of potentiation varied considerably from one antibody to another. Effects on growth and somatomedin C levels correlated fairly well, though there were some discrepancies.

Animals↗
PubMed1987

Heterogeneity of growth-hormone receptors detected with monoclonal antibodies to human growth hormone.

The specificity of hormone-receptor interactions has been examined with the aid of monoclonal antibodies (MABs) (EB1, EB2, QA68 and NA71) defining four non-overlapping antigenic determinants on human growth hormone (hGH). The results indicate that growth-hormone receptors in liver obtained from different sources differ with regard to their affinities and relative numbers; they may also differ with respect to the region of the growth-hormone molecule to which they bind. Antibody NA71 effectively inhibited hormone binding to all receptor preparations tested, although with various degrees of potency. Monoclonal antibody EB1 demonstrated a graded inhibition with respect to its ability to block 125I-hGH binding to receptors from various sources, the maximum inhibition being seen in receptor preparations from mouse and ovine liver and the minimum in rat liver. MABs EB2 and QA68 also showed various abilities to inhibit hormone-receptor interaction, depending on the origin of the receptor preparation. Furthermore, the receptor-binding characteristics of hormone-antibody complexes were dependent on whether the binding-site preparation was derived from pregnant, lactating or 'normal' animals. A particularly striking difference between the ability of hormone-MAB complexes to bind to receptors from different sources was seen for microsomes (microsomal fractions) derived from livers of animals of the 'Little' mouse strain. These animals become progressively obese, and it was shown that MABs were considerably more effective in inhibiting 125I-labelled hGH binding to microsomes from phenotypically obese mice than to those derived from their non-obese littermates. The results can be explained by the presence of multiple receptor types for GH, the relative proportions of which vary according to the physiological state of the animal, and possibly between species.

Animals↗
PubMed1987

Is there an interleukin 2 inhibitor in human serum?

Normal mouse serum has been shown to contain an inhibitor of interleukin 2 (IL-2). Here we report that a molecule with similar activity cannot be found in normal human serum (NHS). Although NHS inhibited the IL-2-dependent proliferation of mouse CTLL cells, as expected of an IL-2 inhibitor, it also had inhibitory activity on IL-3-dependent cells and was cytolytic to IL-2-independent mouse cells as measured by a 51Cr release assay, indicating a nonspecific effect. In addition, NHS had no effect on the IL-2-dependent proliferation of human peripheral blood T-cell blasts. Fractionation of NHS by size exclusion HPLC failed to separate cytolytic activity from any putative true IL-2 inhibitor activity. The cytolytic component was not related to immunoglobulin since it had a molecular weight of 50,000 to 60,000 and was not bound by protein-A-Sepharose. However, its molecular weight, heat lability, and trypsin sensitivity suggest it to be a protein.

Blood Proteins↗