Mesalazine preparations.
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
C Chadwick
Publications and source records attributed to C Chadwick.
Vancomycin-resistant enterococci: implications for infection control.
The incidence of vancomycin-resistant enterococci (VRE) infection is increasing. Immunosuppressed individuals are particularly vulnerable to infection with VRE. Strict attention to infection control measures is important in preventing the spread of multiresistant organisms.
Anti-Bacterial Agents↗
Cleaning as a cost-effective method of infection control.
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Cost-Benefit Analysis↗
Enzyme therapy of xeroderma pigmentosum: safety and efficacy testing of T4N5 liposome lotion containing a prokaryotic DNA repair enzyme.
Xeroderma pigmentosum (XP) is a rare genetic disease in which patients are defective in DNA repair and are extremely sensitive to solar UV radiation exposure. A new treatment approach was tested in these patients, in which a prokaryotic DNA repair enzyme specific for UV-induced DNA damage was delivered into the skin by means of topically applied liposomes to supplement the deficient activity. Acute and chronic safety testing in both mice and humans showed neither adverse reactions nor significant changes in serum chemistry or in skin histology. The skin of XP patients treated with the DNA repair liposomes had fewer cyclobutylpyrimidine dimers in DNA and showed less erythema than did control sites. The results encourage further clinical testing of this new enzyme therapy approach.
Adolescent↗
A comparison of proliferation markers (BrdUrd, Ki-67, PCNA) determined at each cell position in the crypts of normal human colonic mucosa.
Samples of microscopically normal human sigmoid colon fixed in 70% ethanol from 15 patients who had received bromodeoxyuridine (BrdUrd) prior to surgery have been reanalyzed using a combination of proliferation markers. The specimens have been immunostained for proliferating cell nuclear antigen (PCNA) and after microwave treatment, they have been stained for BrdUrd and Ki-67. The 15 patients selected comprised 5 patients whose mucosa previously gave high BrdUrd labelling indices in the crypt, 5 that gave median values for BrdUrd labelling and 5 that gave low values for bromodeoxyuridine labelling on a previous analysis using tissue fixed in 70% ethanol and formal saline and using a different antibody (Potten et al., 1992). The relative levels of labelling at each cell position in the crypts has been compared using the 3 proliferation markers with the data being compared with the BrdUrd labelling as a standard labelling for S phase cells. One objective was to see whether all three proliferation markers discriminated equally well between the three groups of patient samples. The data show that the distinction between high, medium and low values seen with BrdUrd labelling was retained when Ki-67 immunostaining was analysed. PCNA immunostaining resulted in high levels of labelling and the different levels of labelling seen with BrdUrd and Ki-67 were largely lost.
Aged↗
Apoptosis, intrinsic radiosensitivity and prediction of radiotherapy response in cervical carcinoma.
Apoptosis is an important mechanism of cell death in tumours and it is seen both prior to and following radiotherapy. In this study patients with proven carcinoma of the cervix had measurement made of the percentage of apoptotic cells (apoptotic index or AI) in pre-therapy biopsies. Measurements of intrinsic radiosensitivity (SF2), already shown to be a predictor of outcome, had previously been made on the same pre-therapy biopsies. Mitotic index (MI) and Ki-67 antigen staining were also recorded as markers for proliferation. Patients were divided into those with an AI above or below the median and in general increasing apoptosis was associated with poor prognosis. The 5-year survival rate for tumours with an AI below the median was 79% and was significantly greater than the rate of 47% for those with an AI above the median (p = 0.003). There was also a significantly increased 5-year local recurrence-free rate for patients with an AI below the median compared with those with an AI above the median (79 versus 61%, p = 0.012). In addition, AI and SF2 acted as independent prognostic indicators. Patients with both an SF2 and AI value above the median did badly (25% 5-year survival, 46% local control) compared with those with an SF2 and AI below the median (80% 5-year survival, 100% local control). Apoptosis showed correlation with MI (n = 66, r = 0.34, p = 0.002) and cell staining for the Ki-67 antigen (n = 57, r = 0.25, p = 0.03), but neither MI nor Ki-67 were related to patient outcome. This suggests that while apoptosis may be a reflection of tumour proliferation this cannot in itself explain the ability of apoptosis to predict clinical outcome for this series of patients. The study raises the possibility of AI and SF2 being used together as predictors of tumour response to radiotherapy.
Adult↗
Cryo-EM of the native structure of the calcium release channel/ryanodine receptor from sarcoplasmic reticulum.
The native structure of the calcium release channel (ryanodine receptor) from rabbit skeletal muscle has been analyzed in two dimensions from electron micrographs of frozen hydrated specimens. Within a resolution of 3.0 nm there is excellent agreement between the structure as seen in vitreous water and in negative stained specimens. Features seen in the three-dimensional reconstruction of the negatively stained channel can be identified in the projection of the unstained receptor.
Animals↗
The MRC Multicentre Study of Cognitive Function and Ageing: a EURODEM incidence study in progress.
The purpose of this paper is to describe the design and methodology of this multicentre study of cognitive function and ageing, which is currently funded by the Medical Research Council (MRC) and the Department of Health for a period of 5 years. The study is designed to estimate and compare the prevalence and incidence of dementia in five centres in the United Kingdom, to examine the natural history of cognitive decline and dementia in the population and to evaluate the degree of disability associated with any decline. This will be achieved by the examination, twice, of the cognitive function of individuals aged 65 and over, with an interval of 2 years between the examinations. A 20% subsample, taken across the full range of cognitive function will be reviewed annually in more detail to chart the level of cognitive function and to ascertain a diagnosis of dementia. This represents the first systematic examination of different populations using a common methodology in the United Kingdom.
Aged↗
Molecular cloning and characterization of the ryanodine receptor/junctional channel complex cDNA from skeletal muscle sarcoplasmic reticulum.
Major progress has been made in elucidating the calcium release mechanism involved in excitation-contraction coupling. The ryanodine receptor of sarcoplasmic reticulum has been isolated and found to be morphologically identical to the foot structure, which is involved in the junctional association of terminal cisternae with the transverse tubule. The foot structure also contains the calcium release channel itself. For this reason, we refer to the foot structure as the junctional channel complex (JCC). The JCC consists of an oligomer of a single high molecular weight protein. Although progress has been made in characterizing important aspects of the structure and function of the JCC, further understanding of the JCC protein subunit awaits the molecular cloning of the JCC. We report on the isolation of cDNA clones encoding portions of the JCC from rabbit fast-twitch skeletal muscle and its tissue distribution and expression. The large size and lack of solubility of the JCC protein posed particular challenges to cloning this molecule. Among these was the necessity to develop techniques for partially digesting the JCC protein subunit with endoproteases in the presence of detergent. With this approach we obtained partial amino acid sequences from regions of the JCC and designed oligonucleotide primers and probes to synthesize and screen cDNA libraries. The rabbit skeletal muscle JCC mRNA encodes an approximately 16-kilobase mRNA present in skeletal, heart, and aortic smooth muscle, as determined by RNA blot analysis with a 700-base-pair cDNA probe. Whereas the JCC mRNA appears to be relatively abundant in adult rabbit fast-twitch skeletal muscle, it is much less abundant in heart and smooth muscle. The JCC mRNA in BC3H1 (a myoblast cell line) is reversibly regulated by growth factors in a manner similar to muscle-specific contractile protein genes.
Amino Acid Sequence↗
Availability of treatment and diagnostic labelling.
A sample of pre-1967 case records with a hospital diagnosis of schizoaffective disorder were presented for rediagnosis to members of the present staff of the Institute of Psychiatry/Maudsley Hospital. The raters were asked to make a diagnostic choice of either schizophrenia or schizoaffective disorder or affective disorder and indicate how useful they would consider certain treatments for the present episode and for the long term. There was a significant trend in diagnosis to affective disorder but this trend was not correlated with the usefulness of certain treatments, e.g. lithium, a drug which had not been in use before 1967.
Affective Disorders, Psychotic↗
Isolation of the junctional face membrane of sarcoplasmic reticulum.
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Animals↗
Monomers of the Neurospora plasma membrane H+-ATPase catalyze efficient proton translocation.
Liposomes prepared by sonication of asolectin were fractionated by glycerol density gradient centrifugation, and the small liposomes contained in the upper region of the gradients were used for reconstitution of purified, radiolabeled Neurospora plasma membrane H+-ATPase molecules by our previously published procedures. The reconstituted liposomes were then subjected to two additional rounds of glycerol density gradient centrifugation, which separate the H+-ATPase-bearing proteoliposomes from ATPase-free liposomes by virtue of their greater density. The isolated H+-ATPase-bearing proteoliposomes in two such preparations exhibited a specific H+-ATPase activity of about 11 mumol of Pi liberated/mg of protein/min, which was approximately doubled in the presence of nigericin plus K+, indicating that a large percentage of the H+-ATPase molecules in both preparations were capable of generating a transmembrane protonic potential difference sufficient to impede further proton translocation. Importantly, quantitation of the number of 105,000-dalton ATPase monomers and liposomes in the same preparations by radioactivity determination and counting of negatively stained images in the electron microscope indicated ATPase monomer to liposome ratios of 0.97 and 1.06. Because every liposome in the preparations must have had at least one ATPase monomer, these ratios indicate that very few of the liposomes had more than one, and simple calculations show that the great majority of active ATPase molecules in the preparations must have been present as proton-translocating monomers. The results thus clearly demonstrate that 105,000-dalton monomers of the Neurospora plasma membrane H+-ATPase can catalyze efficient ATP hydrolysis-driven proton translocation.
Adenosine Triphosphate↗
Characterization of the junctional face membrane from terminal cisternae of sarcoplasmic reticulum.
We have recently described a preparation of junctional terminal cisternae (JTC) from fast skeletal muscle of rabbit hind leg. The fraction differs from other heavy sarcoplasmic reticulum (SR) fractions in that it contains a substantial amount of junctional face membrane (JFM) (15-20% of the membrane) with morphologically well-defined junctional feet structures. In common with other heavy SR preparations, it contains predominantly the calcium pump membrane (80-85% of the membrane) and compartmental contents (CC), consisting mainly of calcium-binding protein (calsequestrin). In this study, a modified procedure for the preparation of JTC from frozen rabbit back muscle is described. The yield is substantially greater (threefold per weight of muscle), yet retaining characteristics similar to JTC from fresh hind leg muscles. Methodology has been developed for the disassembly of the JTC. This is achieved by selectively extracting the calcium pump membrane with 0.5% Triton X-100 in the presence of 1 mM CaCl2 to yield a complex of JFM with CC. The CC are then solubilized in the presence of EDTA to yield JFM. This fraction contains unidirectionally aligned junctional feet structures protruding from the cytoplasmic face of the membrane with repeat spacings comparable to that observed in JTC. The JFM contains 0.16 mumol phosphorus (lipid) per milligram protein. Characteristic proteins include 340 and 79-kD bands, a doublet at 28 kD, and a component that migrates somewhat slower than or equivalent to the calcium pump protein. Approximately 10% of the calcium-binding protein remains bound to the JFM after EDTA extraction, indicating the presence of a specific binding component in the JFM. The JFM, which is involved in junctional association with transverse tubule and likely in the Ca2+ release process in excitation-contraction coupling, is now available in the test tube.
Animals↗
The recruitability and cell-cycle state of intestinal stem cells.
Evidence is presented which suggests that the crypts of the small intestine contain at least two discrete but interdependent classes of stem cells, some with discrete cell kinetic properties and some with discrete radiation responses or radiosensitivities. Very low doses of X rays or gamma rays, or neutrons, kill a few cells in the stem cell regions of the crypt in a sensitive dose-dependent manner. Similar doses generate several different cell kinetic responses within either the clonogenic fraction or the cells at the stem cell position within the crypt. The cell kinetic responses range from apparent recruitment of G0 clonogenic cells into cycle, to a marked shortening of the average cell cycle of the cells at the stem cell position. It is suggested that the cell kinetic changes may be the consequence of the cell destruction.
Animals↗
Cell death (apoptosis) in the mouse small intestine after low doses: effects of dose-rate, 14.7 MeV neutrons, and 600 MeV (maximum energy) neutrons.
The production of dead (apoptotic) cells by low doses of gamma-rays was independent of dose-rate between 0.27 and 450 cGy per min. The r.b.e. for doses of 14.7 MeV neutrons between 1 and 15 cGy was about 4, and for neutrons generated by bombarding a beryllium target with 600 MeV protons the r.b.e. was about 2.7. The dose-incidence curves for all three radiation types reached a plateau at about 3-4 dead cells per crypt section, and this occurred at about 20-40 cGy of gamma-rays. These curves are compatible with exponential survival of the cell population at risk (D0 of 24 cGy for gamma-rays, 6 cGy for 14.7 MeV neutrons and 9 cGy for 600 MeV neutrons). Since the dose-response is exponential there is no indication of much higher r.b.e. values at very low doses, a point of concern in radiation protection. The spatial distribution of dead cells in the crypt was similar after doses of gamma-rays or neutrons, indicating that the same population of target cells was affected in both cases.
Animals↗
Potential methodological errors in the application of equilibrium dialysis to the determination of "free" and "bound" plasma tryptophan.
The application of equilibrium dialysis to the determination of the "free", i.e. non-albumin bound fraction of human plasma or serum tryptophan has been re-examined. A potentially serious error in the application of this method is outlined and the necessary correction and some precautionary measures are discussed.
Dialysis↗