Biomedical subjects
J Cooper
Publications and source records attributed to J Cooper.
X-ray crystallographic analysis of inhibition of endothiapepsin by cyclohexyl renin inhibitors.
The crystal structures of endothiapepsin, a fungal aspartic proteinase (EC 3.4.23.6), cocrystallized with two oligopeptide renin inhibitors, PD125967 and PD125754, have been determined at 2.0-A resolution and refined to R-factors of 0.143 and 0.153, respectively. These inhibitors, which are of the hydroxyethylene and statine types, respectively, possess a cyclohexylalanine side chain at P1 and have interesting functionalities at the P3 position which, until now, have not been subjected to crystallographic analysis. PD125967 has a bis(1-naphthylmethyl)acetyl residue at P3, and PD125754 possesses a hydroxyethylene analogue of the P3-P2 peptide bond for proteolytic stability. The structures reveal that the S3 pocket accommodates one naphthyl ring with conformational changes of the Asp 77 and Asp 114 side chains, the other naphthyl group residing in the S4 region. The P3-P2 hydroxyethylene analogue of PD125754 forms a hydrogen bond with the NH of Thr 219, thereby making the same interaction with the enzyme as the equivalent peptide groups of all inhibitors studied so far. The absence of side chains at the P2 and P1' positions of this inhibitor allows water molecules to occupy the respective pockets in the complex. The relative potencies of PD125967 and PD125754 for endothiapepsin are consistent with the changes in solvent-accessible area which take place on inhibitor binding.
Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus.
BACKGROUND: The efficacy of conventional treatment with surgery and radiation for cancer of the esophagus is limited. The median survival is less than 10 months, and less than 10 percent of patients survive for 5 years. Recent studies have suggested that combined chemotherapy and radiation therapy may result in improved survival. METHODS: This phase III prospective, randomized, and stratified trial was undertaken to evaluate the efficacy of four courses of combined fluorouracil (1000 mg per square meter of body-surface area daily for four days) and cisplatin (75 mg per square meter on the first day) plus 5000 cGy of radiation therapy, as compared with 6400 cGy of radiation therapy alone, in patients with squamous-cell carcinoma or adenocarcinoma of the thoracic esophagus. The trial was stopped after the accumulated results in 121 patients demonstrated a significant advantage for survival in the patients who received chemotherapy and radiation therapy. RESULTS: The median survival was 8.9 months in the radiation-treated patients, as compared with 12.5 months in the patients treated with chemotherapy and radiation therapy. In the former group, the survival rates at 12 and 24 months were 33 percent and 10 percent, respectively, whereas they were 50 percent and 38 percent in the patients receiving combined therapy (P less than 0.001). Seven patients in the radiotherapy group and 25 in the combined-therapy group were alive at the time of the analysis. The patients who received combined treatment had fewer local (P less than 0.02) and fewer distant (P less than 0.01) recurrences. Severe and life-threatening side effects occurred in 44 percent and 20 percent, respectively, of the patients who received combined therapy, as compared with 25 percent and 3 percent of those treated with radiation alone. CONCLUSIONS: Concurrent therapy with cisplatin and fluorouracil and radiation is superior to radiation therapy alone in patients with localized carcinoma of the esophagus, as measured by control of local tumors, distant metastases, and survival, but at the cost of increased side effects.
Antithrombin III and arterial disease.
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Cell diameter in the discrimination of verrucous carcinoma and squamous papilloma.
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Expression of human alpha 1 antitrypsin in transgenic sheep.
We have recently described the production of large amounts (< or = 65 grams per litre) of enzymatically active human alpha 1 antitrypsin in the milk of transgenic sheep (Wright et al., 1991). Here, we describe in more detail the expression of the human protein in the milk of these animals throughout the lactation period. Human alpha 1 antitrypsin is also found at much lower levels in the plasma of transgenic ewes before, during and after lactation. It is also detected in male plasma at very low levels. We have previously shown human alpha 1 antitrypsin purified from transgenic sheep milk to be indistinguishable from commercially available human plasma derived alpha 1 antitrypsin in terms of gross sugar content and in vitro activity. Here we extend this comparison to more detailed analyses of glycosylation state, amino-terminal sequence, pI value, and molecular weight determination by mass spectrometry.
Hoarseness; a unique clinical presentation for renal cell carcinoma.
The first reported case of an isolated metastasis to the larynx from a regionally localized renal cell carcinoma presenting clinically as hoarseness is discussed. Aggressive management and outcome are presented.
The 42-kilodalton rhoptry-associated protein of Plasmodium falciparum.
The gene coding for a 42-kDa rhoptry protein of Plasmodium falciparum has been cloned. On the basis of prior monkey vaccination studies, this protein is regarded as an important vaccine candidate, but its identity has been the subject of considerable uncertainty. Analysis of the cloned sequence shows that it is a basic, hydrophobic protein, without repetitive elements, unrelated to any of the previously postulated gene products and shows minimal sequence diversity. The availability of the corresponding recombinant protein will enable studies of its efficacy in human vaccine trials to be undertaken.
Clinical implications of vergence adaptation.
Placement of a prism in front of an eye results in a change in the tonic position of the eyes, a shift in the forced fixation disparity curve, and a shift in fusional amplitudes. These changes remain in effect as long as motor fusion is maintained. Elimination of fusion by occlusion or by removal of the prism results in a slow movement of the eyes back to the preprism position. This phenomenon, known as prism adaptation or slow fusional vergence, has important clinical implications in maintaining binocular vision with anisometropic prescriptions, age-related physiological changes in the positions of the eyes, blinking, high phorias, etc. Vergence adaptation is useful in explaining previous discrepancies between alternate and unilateral cover test, pre- and postorthoptic ACA ratios, stimulus and response ACA ratios, changes in phorias after orthoptics, and the observation of patients "eating up prism." Vergence adaptation anomalies have been implicated in causing asthenopia. Adaptation has been shown to change after orthoptic therapy. This paper reviews the clinical findings associated with vergence adaptation.
Vergence adaptation in esotropia.
Vergence adaptation and anomalous fusional movements have been used by strabismics to overcome prism. There has been controversy in the literature regarding the nature of the vergence responses by esotropes to prism, i.e., fusional, avoidance of fusion, and/or anomalous fusion. This paper reviews the various types of movements made by esotropes to prism and attempts to explain the mechanism. In addition, the relation of these vergence movements to prismatic, orthoptic, and surgical correction is discussed.
Asthenopia induced by computer-generated fusional vergence targets.
A questionnaire was used to evaluate asthenopia in 30 normal subjects (Ss). Then, each S experienced 3 min of continuous alternating convergent and divergent fusional vergence or a control condition which was identical to the experimental condition, but without any vergence demand, i.e., version. The stimulus was a computer-generated flat fusion red-blue anaglyph picture of a horse. The order of vergence and version conditions were randomized. Asthenopia measures and maximal fusional vergence ranges measures were repeated immediately after each condition. Results indicated a significantly higher rating of asthenopia after induced vergence than version. There were no differences in maximal fusional vergence ranges or recovery values after the two conditions. Correlations between pretreatment asthenopia scores and asthenopia scores after either induced vergence or version were also not significant. Post hoc analyses of Ss grouped as having either high or low asthenopia, according to baseline ratings, revealed no significant differences in vergence or version conditions. Alternative hypotheses for these results are presented.
Relative strength of central and peripheral fusion as a function of stimulus parameters.
We investigated the role of various stimulus parameters that influence motor fusion responses for peripheral as compared to central fusional stimuli. Results from the initial experiment indicated that a central stimulus equal in size to a peripheral fusion stimulus dominated the response independent of the amount of retinal eccentricity of the peripheral target. A second experiment indicated that the central stimulus dominated even when the peripheral stimulus was larger. However, when the peripheral stimulus was changed in shape so that it became an annulus surrounding the central stimulus, the peripheral stimulus was always stronger. In another phase of the experiment, we found that the extent to which a peripheral stimulus surrounded the central one determined which controlled the response. We concluded that the surrounding perceptual gestalt produced by the peripheral stimulus was the most significant variable determining the relative strengths of central and peripheral fusion stimuli. Clinical implications are discussed.
The pharmacogenetics of chemical carcinogenesis.
The human body is endowed with a large number of xenobiotic chemical metabolizing enzymes, a significant proportion of which are polymorphic and thus render one individual at greater or lesser risk than another of chemically-induced disease. All examples of genetic polymorphism of chemical metabolizing enzymes have been reviewed in relation to their potential to activate and detoxicate procarcinogens and promutagens. Many examples are cited whereby phenotype can act as a carcinogenic risk factor. With the availability of a large amount of DNA sequence data for chemical metabolizing enzymes there has emerged a number of polymerase chain reaction (PCR) strategies aimed at discerning one metabolic phenotype or another. This is seen as a very positive and democratic scientific development, widening the franchise for studies of disease risk. Nevertheless, it is argued that, at these early stages with many laboratory-based scientists scarcely familiar with epidemiological study design, a cautious approach should obtain when interpreting single studies.
Graves' ophthalmopathy in relation to cigarette smoking and ethnic origin.
OBJECTIVE: We aimed to study the effect of cigarette smoking on the prevalence and severity of Graves' ophthalmopathy (GO). PATIENTS: One hundred and fifty-five newly diagnosed patients with Graves' disease (GD) were diagnosed clinically and by routine biochemical methods. Twenty-five per cent (39) were of Asian origin. METHODS: Eye signs were classified according to the American Thyroid Association Classification. A detailed smoking questionnaire and data from hospital notes were used to calculate an index of cigarette consumption. RESULTS: Thirty-four per cent of all patients had Graves' ophthalmopathy, and the prevalence in males (26%) and females (36%) did not differ significantly. There was a prevalence of 42% among Europeans compared to 7.7% in Asians (P = 0.0002). The overall risk for Europeans for developing Graves' ophthalmopathy was 6.4 (1.78-22.7 confidence interval) times higher than for Asians. Corrected for the ethnic factor the increased risk from smoking for Europeans was 2.4 (1.12-5.18, 95% confidence interval) times higher. There was a significant dose effect (P = 0.008). CONCLUSIONS: The present findings confirm an effect of cigarette smoking on Graves' ophthalmopathy and in addition show that Europeans have a substantially greater risk of developing Graves' ophthalmopathy than have Asians.
An autophosphorylating but not transphosphorylating activity is associated with the unique N terminus of the herpes simplex virus type 1 ribonucleotide reductase large subunit.
We report on a protein kinase function encoded by the unique N terminus of the herpes simplex virus type 1 (HSV-1) ribonucleotide reductase large subunit (R1). R1 expressed in Escherichia coli exhibited autophosphorylation activity in a reaction which depended on the presence of the unique N terminus. When the N terminus was separately expressed in E. coli and partially purified, a similar autophosphorylation reaction was observed. Importantly, transphosphorylation of histones and of proteins in HSV-1-infected cell extracts was also observed with purified R1 and with truncated R1 mutants in which most of the N terminus was deleted. Ion-exchange chromatography was used to separate the autophosphorylating activity of the N terminus from the transphosphorylating activity of an E. coli contaminant protein kinase. We propose a putative function for this activity of the HSV-1 R1 N terminus during the immediate-early phase of virus replication.
Injury in nonischemic lung after unilateral pulmonary ischemia with reperfusion.
We developed an in vivo intact canine model to study pulmonary ischemia-reperfusion (IR) injury. The surgical approach simulates that of unilateral lung transplantation but is free of technical difficulties and other factors related to lung preservation. Serial measurements of regional pulmonary blood flow (rPBF), extravascular density (EVD), and transcapillary protein flux were made with the quantitative imaging technique of positron emission tomography. Eleven experimental and six control animals were studied. After 2 h of warm ischemia followed by reperfusion, no significant change occurred in rPBF despite significantly increased EVD, which was greater on the ischemic than on the nonischemic side. Protein flux, measured as a rate constant, was also greater on the ischemic than on the nonischemic side (median 181 x 10(-4)/min, range 104-619, vs. median 90, range 33-132) immediately after reperfusion. Both sides were also significantly different from control values (median 37, range 21-57). On both sides, protein flux decreased over time and at 5 h after reperfusion was not different from that of controls. Data from the control animals showed that these findings in the experimental animals were not due to surgical technique, deterioration in the surgical preparation, or hyperperfusion of the nonischemic lung. Thus IR injury of one lung can lead to similar, but less severe, injury in the contralateral lung. Because injury in the nonischemic lung develops only after reperfusion of the ischemic lung, injury to the nonischemic lung is probably humorally mediated. The model is a useful and relevant method for studying the physiological consequences of pulmonary IR injury.
Inflammation and oxygen free radical formation during pulmonary ischemia-reperfusion injury.
In a companion study, we showed that 2 h of warm unilateral lung ischemia followed by reperfusion resulted in bilateral tissue injury, indicated by increases in extravascular density (EVD) and permeability, measured as the pulmonary transcapillary escape rate (PTCER) for radiolabeled transferrin. EVD and PTCER measurements were obtained with the quantitative imaging technique of positron emission tomography (PET). In the current study, we evaluated this increase in EVD histologically and correlated EVD and PTCER with measurements of oxidant-reactive sulfhydryls (RSH) in plasma as a marker of oxygen free radical (OFR) formation. Histologically edema, leukocyte infiltration, and hemorrhage were all present on the ischemic side, but only after reperfusion, whereas only neutrophil infiltration was observed on the nonischemic side. Histology scores correlated with EVD (r = 0.81) and PTCER (r = 0.75), but permeability was abnormal at times even in the absence of neutrophil infiltration. Plasma RSH concentration from the ischemic lung decreased significantly (P less than 0.05) during pulmonary ischemia (i.e., before reperfusion) and returned to baseline on reperfusion. The degree of RSH oxidation did not correlate with the severity of injury as measured by PET or histology. Thus pulmonary ischemia-reperfusion injury is characterized by inflammation, hemorrhage, edema, and OFR formation. Injury occurred after reperfusion, not after ischemia alone. In addition, injury to the contralateral nonischemic lung suggests a neutrophil-independent circulating mediator of injury.
Modifying pulmonary ischemia-reperfusion injury by altering ventilatory strategies during ischemia.
We used an intact in vivo canine model of pulmonary ischemia-reperfusion (IR) injury to evaluate the differential effects of alveolar hypoxia and ventilation during 2 h of unilateral warm lung ischemia. Serial measurements of regional pulmonary blood flow, extravascular density (EVD), and transcapillary protein flux were made after reperfusion with the quantitative imaging technique of positron emission tomography. Twenty-seven animals were divided into five experimental groups: VENT O2 (n = 5) in which the left lung was ventilated with 40% O2 during ischemia, STATIC O2 (n = 4) in which the left lung was statically inflated with 40% O2 during ischemia, VENT N2 (n = 5) in which the left lung was ventilated with 100% N2 during ischemia, VENT N2/CO2 (n = 5) in which the left lung was ventilated with 95% N2-5% CO2 during ischemia, and STATIC N2 (n = 8) in which the left lung was statically inflated with 100% N2 during ischemia. These groups were compared with a control group (CONT, = 3) that was studied previously. Protein flux was significantly increased in the previous ischemic lung only for the STATIC N2 group [median 175 x 10(-4) min-1 (range 53-1,217) for the STATIC N2 group vs. 50 x 10(-4) min-1 (range 40-56) for the CONT group] 0.25 h after reperfusion and did not change over 3 h. EVD also increased but not significantly. Protein flux and EVD in the other groups were not different from CONT.(ABSTRACT TRUNCATED AT 250 WORDS)