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Biomedical subjects

A Wells

Publications and source records attributed to A Wells.

At least 19 recordsLinked to original sources
PubMed1992

Comparison of nedocromil sodium at two dosage frequencies with placebo in the management of chronic asthma.

Nedocromil sodium (4 mg b.d. or q.i.d.) was added to the therapy of 76 chronic asthmatic patients in a four-centre, double-blind cross-over, placebo-controlled trial. Patients had troublesome symptoms uncontrolled by high doses of inhaled corticosteroids (mean 1450 micrograms). In 54 patients who completed the study, nedocromil sodium was significantly more efficacious than placebo (P < 0.01) in relieving morning chest-tightness and cough, in reducing total diary card score and nocturnal bronchodilator usage, and in increasing morning and evening peak flow. Asthma severity at clinic visits decreased significantly (P = 0.001) following treatment with nedocromil sodium, which was globally rated more effective than placebo (P < 0.01). Treatment differences favored q.i.d. over b.d. dosage but without statistical significance. There were no serious adverse effects. Although the pulmonary function changes were small, these findings suggest that the addition of nedocromil sodium may benefit asthmatic patients who are inadequately controlled by high doses of inhaled corticosteroids.

Adolescent↗
PubMed1992

"Subclinical" pacemaker syndrome: a randomised study of symptom free patients with ventricular demand (VVI) pacemakers upgraded to dual chamber devices.

OBJECTIVE: To determine whether symptom free patients with single chamber pacemakers benefit from dual chamber pacing. DESIGN: A randomised double blind crossover comparison of ventricular demand (VVI), dual chamber demand (DDI), and dual chamber universal (DDD) modes after upgrading from a VVI device. SETTING: Cardiology outpatient department. PATIENTS: Sixteen patients aged 41-84 years who were symptom free during VVI mode pacing for three or more years. INTERVENTION: Pacemaker upgrade during routine generator change. MAIN OUTCOME MEASURES: Change in subjective (general health perception, symptoms) and objective (clinical assessment, treadmill exercise, and radiological and echocardiographic indices) results between pacing modes before and after upgrading. RESULTS: 75% preferred DDD, 68% found VVI least acceptable with 12% expressing no preference. Perceived general well-being and exercise capacity (p less than 0.01) and treadmill times (p less than 0.05) were improved in DDD mode but VVI and DDI modes were similar. Clinical, echocardiographic, radiological, and electrophysiological indices confirmed the absence of overt pacemaker syndrome, although mitral and tricuspid regurgitation was greatest in VVI mode (p less than 0.01). CONCLUSIONS: Most patients who were satisfied with long term pacing in VVI mode benefited from upgrading to DDD mode pacing suggesting the existence of "subclinical" pacemaker syndrome in up to 75% of such patients. The DDI mode offered little subjective or objective benefit over VVI mode in this population and should be reserved for patients with paroxysmal atrial arrhythmias. VVI mode pacing should be used only for patients with very intermittent symptomatic bradycardia or atrial fibrillation with a good chronotropic response during exercise.

Adult↗
PubMed1991

Ligand-induced internalization and increased cell calcium are mediated via distinct structural elements in the carboxyl terminus of the epidermal growth factor receptor.

Signals that can mediate ligand-induced receptor internalization and calcium regulation are present in a 48-amino acid "calcium-internalization" domain in the C' terminus of the epidermal growth factor (EGF) receptor. The basis of calcium and internalization regulation signalled by this 48-amino acid sequence was analyzed using deletion and substitution mutant receptors. Cells expressing truncated receptors containing either the NH2- or COOH-terminal portion of the 48-residue domain displayed high affinity EGF-dependent endocytosis and receptor down-regulation. These endocytosis-competent EGF receptor mutants that lacked any autophosphorylation site were unable to increase the concentration of intracellular calcium. To investigate the role of self-phosphorylation in EGF-induced calcium mobilization, phenylalanine was substituted for the single autophosphorylated tyrosine residue in this region of an internalization-competent truncated receptor. The receptor-mediated calcium response was abolished, while ligand-dependent receptor internalization was unimpaired. These results demonstrate that EGF-dependent receptor endocytosis and calcium mobilization are separate events. Tyrosine self-phosphorylation is required for increased [Ca2+]i, while structural features distinct from autophosphorylation are required for receptor internalization.

Animals↗
PubMed1991

Enhanced tumorigenesis of NR6 cells which express non-down-regulating epidermal growth factor receptors.

Sequences in the regulatory carboxyl terminus of the epidermal growth factor (EGF) receptor are required for ligand-induced internalization via a high-affinity saturable endocytic pathway and for receptor down-regulation. To investigate the role of down-regulation in attenuating mitogenic signals, we compared the ability of NR6 cells expressing holo and mutant down-regulation defective EGF receptors to form tumors in athymic mice. NR6 cells expressing mutant EGF receptors reproducibly formed rapidly growing tumors, whereas cells expressing holo EGF receptors had a low tumorigenic potential. Serial passage of tumors of NR6 cells expressing mutant EGF receptors resulted in an enhanced rate of tumor formation that directly correlated with increased expression of mutant receptors. Tumor growth was inhibited by a competitive antagonist anti-EGF receptor monoclonal antibody. Excessive signaling from the cell surface can result from lack of sequences required for endocytosis and from saturation of endocytic mechanisms. Non-down-regulating kinase-active EGF receptors provide an especially strong growth signal, manifested as rapid tumor growth in athymic mice.

Animals↗
PubMed1991

A negative feedback loop attenuates EGF-induced morphological changes.

Activation of the EGF receptor tyrosine kinase by ligand indirectly activates a series of other cellular enzymes, including protein kinase C. To test the hypothesis that phosphorylation of the EGF receptor by protein kinase C provides an intracellular negative feedback loop to attenuate EGF receptor signaling, we used scanning EM to follow the characteristic EGF-induced retraction of lamellipodia and concomitant cell shape changes. Wild type and mutant EGF receptors were expressed in receptor-deficient NR6 cells. The mutant receptors were prepared by truncation at C' terminal residue 973 (c'973) to provide resistance to ligand-induced down regulation that strongly attenuates receptor signaling and by replacement of threonine 654 (T654) with alanine (A654) to remove the site of phosphorylation by protein kinase C. Cells expressing WT and c'973 EGF receptors demonstrated characteristic lamellipodial retraction after exposure to EGF, with the non-down regulating c'973 EGF receptors responding more rapidly. Exposure of cells to TPA blocked this response. Replacement of T654 by alanine resulted in EGF receptors that were resistant to TPA. Cells expressing the A654 mutation underwent more rapid and more extensive morphologic changes than cells with the corresponding T654 EGF receptor. In cells expressing T654 EGF receptors, down regulation of protein kinase C resulted in more rapid and extensive EGF-induced changes similar to those seen in cells expressing A654 EGF receptors. These data indicate that activation of protein kinase C and subsequent phosphorylation of the EGF receptor at T654 lead to rapid physiological attenuation of EGF receptor signaling.

Alanine↗
PubMed1991

Reactions of police officers to body-handling after a major disaster. A before-and-after comparison.

This study reports the results of an unusual opportunity to follow up a group of police officers who were involved in body-handling duties following the Piper Alpha disaster, and for whom there were available data from pre-disaster assessments. In addition, after these duties, the officers were compared with a matched control group of officers who had not been involved in such work. The comparisons failed to demonstrate high levels of post-traumatic distress or psychiatric morbidity. The results are interpreted in terms of issues such as the officers' own coping strategies, and major organisational and managerial factors.

Absenteeism↗
PubMed1991

Localization of epidermal growth factor receptor in hepatocyte nuclei.

Experiments undertaken to investigate the binding of epidermal growth factor by hepatocyte nuclei showed that: (a) isolated nuclei from both normal and regenerating rat liver are capable of binding 125I-epidermal growth factor, (b) the nuclear epidermal growth factor-binding protein is similar in molecular weight to the plasma membrane epidermal growth factor receptor, (c) monoclonal antibodies produced against the plasma membrane epidermal growth factor receptor recognize the nuclear epidermal growth factor receptor and (d) the nuclear receptor has an affinity for epidermal growth factor comparable to that of the plasma membrane receptor, but fewer (approximately 10%) nuclear receptors are available per protein unit compared with the plasma membrane.

Animals↗
PubMed1990

Ligand-induced transformation by a noninternalizing epidermal growth factor receptor.

Identification of a mutant epidermal growth factor (EGF) receptor that does not undergo downregulation has provided a genetic probe to investigate the role of internalization in ligand-induced mitogenesis. Contact-inhibited cells expressing this internalization-defective receptor exhibited a normal mitogenic response at significantly lower ligand concentrations than did cells expressing wild-type receptors. A transformed phenotype and anchorage-independent growth were observed at ligand concentrations that failed to elicit these responses in cells expressing wild-type receptors. These findings imply that activation of the protein tyrosine kinase activity at the cell membrane is sufficient for the growth-enhancing effects of EGF. Thus, downregulation can serve as an attenuation mechanism, without which transformation ensues.

Cell Division↗
PubMed1990

Prevalence of tendinitis and related disorders of the upper extremity in a manufacturing workforce.

A cross sectional survey of a randomly selected population of 2,261 textile workers form an overall population of 8,539 eligible workers was performed to evaluate the prevalence of tendinitis in related upper extremity disorders. Of the sample, 2,047 respondents (91.3%) participated in a nurse screening history and examination: 1,091 (53%) had no upper extremity symptoms or abnormalities on examination; 959 (47%) with positive findings were examined by trained physicians. Of these, 347 (36.5%) were found to have no abnormality, whereas, 548 (57.3%) workers were assigned a diagnosis. Of these 227 were considered to fall into the categories of tendinitis (n = 69) or related disorders (n = 158). The projected prevalence of tendinitis and related disorders for the overall group was 11.6% (carpal tunnel syndrome 1.1%, epicondylitis 2.0%, tendinitis 3.5%, shoulder condition 2.3%, ganglion 2.3%, neck conditions 4.0%). Tendinitis was less frequent in the older age group and those employed for a longer time. The prevalence of tendinitis was found to be statistically higher in physically demanding job categories. Ninety-four percent of ailments were of mild or moderate severity. Although our study provides prevalence data for these conditions in a large manufacturing workforce across several job categories.

Adult↗
PubMed1989

Keratoconjunctivitis sicca with associated secondary uveitis elicited in rats after systemic xylazine/ketamine anesthesia.

The systemic administration of an anesthetic dosage of a combination of xylazine and ketamine hydrochloride produced an acute exposure keratopathy which progressed into a syndrome resembling keratoconjunctivitis sicca. Within a few minutes corneal changes occurred that were characterized by viscous mucus, loss of corneal luster and dryness. Other acute but transient changes included development of cataracts, mydriasis and proptosis. Progressive changes were observed in the cornea within 4 days which lasted at least 8 weeks in some cases, and included punctate epithelial keratopathy progressing to devitalized or keratinized epithelial plaques. Polymorphonuclear cell infiltration of the corneal stroma associated with plaques occurred. Epithelial denudation and neovascularization of the cornea, dilation and engorgement of iridial blood vessels, as well as flare in the anterior chamber were also seen. The ocular lesions induced by xylazine/ketamine should be considered carefully when designing or interpreting research on the anterior segment. Ketamine hydrochloride with sodium pentobarbital produced excellent anesthesia without any significant ocular side-effects and may be preferred in many instances.

Animals↗
PubMed1988

Genetic determinants of neoplastic transformation by the retroviral oncogene v-erbB.

The retroviral oncogene v-erbB is a mutant version of the gene (c-erbB or ERBB1) that encodes the cell-surface epidermal growth factor receptor (EGFR). The mutations take three forms: (i) a large deletion that removes the entire ligand-binding domain of EGFR, (ii) smaller deletions that affect the carboxyl-terminal domain of EGFR, and (iii) point mutations that cause conservative substitutions of amino acids. Previous work has shown that, in the absence of the large deletion, ERBB1 cannot transform cells autonomously. Here we report that when the large deletion is present, no other mutation is required for ERBB1 to transform established rodent fibroblasts to a tumorigenic phenotype. In particular, there is no need for deletions affecting the carboxyl terminus of the gene product. It appears, therefore, that removal of the ligand-binding domain from the EGFR suffices to create a transforming protein. Deletions at the carboxyl terminus of the EGFR apparently play only a secondary role in transformation by affecting the host range and perhaps the potency of transformation; and there is as yet no evidence to implicate point mutations in the activation of ERBB1 to an oncogene. Our findings support the view that augmented activity of the EGFR can contribute to tumorigenesis.

Alleles↗
PubMed1988

Amplified gene for the epidermal growth factor receptor in a human glioblastoma cell line encodes an enzymatically inactive protein.

The gene encoding the receptor for epidermal growth factor was amplified two- to fivefold in the human glioblastoma cell line SF268. The amplified gene gave rise to abundant quantities of receptor that bound EGF with a high affinity (Kd, 0.35 nM). The binding of ligand failed to elicit cellular DNA synthesis, however, and the receptor was enzymatically inactive. We presume that the amplified receptor gene carries a mutation(s) that affects several aspects of the receptor's function. Characterization of the mutation(s) may illuminate how structure dictates function in the receptor protein.

Cell Cycle↗
PubMed1987

Insulin-like and insulin-inhibitory effects of monoclonal antibodies for different epitopes on the human insulin receptor.

Monoclonal antibodies previously shown to react with five distinct epitopes on the human insulin receptor were tested for their metabolic effects on isolated human adipocytes. Two antibodies which reacted with receptor alpha-subunit and completely inhibited 125I-insulin binding mimicked the actions of insulin to stimulate lipogenesis from [14C]glucose and to inhibit catecholamine-induced lipolysis. On a molar basis, these antibodies were comparable in potency with insulin itself. Two other antibodies which decreased insulin binding only slightly or not at all also mimicked these metabolic effects of insulin. One of these antibodies reacted with receptor beta-subunit. In contrast, a further antibody which reacted with alpha-subunit and inhibited insulin binding did not affect basal lipogenesis or catecholamine-induced lipolysis, but was able to antagonize the effects of insulin on these processes. The same antibody antagonized the insulin-like effect of another antibody with which it competed in binding to insulin receptor, but not the effect of an antibody which bound independently to the receptor. It is concluded that binding of ligand at or close to the insulin-binding site is neither necessary nor sufficient to trigger insulin-like metabolic effects, which may rather depend on some general property of antibodies, such as their ability to cross-link and aggregate receptor molecules.

Adipose Tissue↗
PubMed1986

Uveitis and arthritis induced by systemic injection of streptococcal cell walls.

A single injection of an aqueous suspension of group A streptococcal peptidoglycan-polysaccharide complexes (PG-PS) when injected intraperitoneally into Lewis rats induced a self-limiting bilateral uveitis with associated perpetuating polyarthritis. The uveitis was characterized clinically during the first 72 h by iritis and fibrin deposition. Acutely, there was infiltration of polymorphonuclear cells. The symptoms gradually subsided, and at the close of the experiment eyes were normally clinically and histologically. In contrast, perpetuating inflammation and severe tissue injury developed in the limb. Using an enzyme immunoassay with specificity for the group A streptococcal polysaccharide, the levels of PG-PS in tissues of animals that were killed 1 to 7 days post-injection were measured. The relative amounts of antigen in eye:limb:liver of PG-PS injected animals were 1:9:170. The differences in the amounts of antigen detected in the eye and limb may help explain the development of the acute uveitis in contrast to the perpetuating polyarthritis observed on PG-PS administration. The authors suggest that bacterial debris may act similarly in causing ocular inflammation in man.

Animals↗