Subversion of the innate immune response by micro-organisms.
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Bacterial Proteins↗
Biomedical subjects
A Davies
Publications and source records attributed to A Davies.
Three-dimensional structure of an invertebrate rhodopsin and basis for ordered alignment in the photoreceptor membrane.
Invertebrate rhodopsins activate a G-protein signalling pathway in microvillar photoreceptors. In contrast to the transducin-cyclic GMP phosphodiesterase pathway found in vertebrate rods and cones, visual transduction in cephalopod (squid, octopus, cuttlefish) invertebrates is signalled via Gq and phospholipase C. Squid rhodopsin contains the conserved residues of the G-protein coupled receptor (GPCR) family, but has only 35% identity with mammalian rhodopsins. Unlike vertebrate rhodopsins, cephalopod rhodopsin is arranged in an ordered lattice in the photoreceptor membranes. This organization confers sensitivity to the plane of polarized light and also provides the optimal orientation of the linear retinal chromophores in the cylindrical microvillar membranes for light capture. Two-dimensional crystals of squid rhodopsin show a rectilinear arrangement that is likely to be related to the alignment of rhodopsins in vivo.Here, we present a three-dimensional structure of squid rhodopsin determined by cryo-electron microscopy of two-dimensional crystals. Docking the atomic structure of bovine rhodopsin into the squid density map shows that the helix packing and extracellular plug structure are conserved. In addition, there are two novel structural features revealed by our map. The linear lattice contact appears to be made by the transverse C-terminal helix lying on the cytoplasmic surface of the membrane. Also at the cytoplasmic surface, additional density may correspond to a helix 5-6 loop insertion found in most GPCRs relative to vertebrate rhodopsins. The similarity supports the conservation in structure of rhodopsins (and other G-protein-coupled receptors) from phylogenetically distant organisms. The map provides the first indication of the structural basis for rhodopsin alignment in the microvillar membrane.
Animals↗
Dominant-negative synthesis suppression of voltage-gated calcium channel Cav2.2 induced by truncated constructs.
Voltage-gated calcium channel alpha1 subunits consist of four domains (I-IV), each with six transmembrane segments. A number of truncated isoforms have been identified to occur as a result of alternative splicing or mutation. We have examined the functional consequences for expression of full-length Ca(v)2.2 (alpha1B) of its coexpression with truncated constructs of Ca(v)2.2. Domains I-II or domains III-IV, when expressed individually, together with the accessory subunits beta1b and alpha2delta-1, did not form functional channels. When they were coexpressed, low-density whole-cell currents and functional channels with properties similar to wild-type channels were observed. However, when domain I-II, domain III-IV, or domain I alone were coexpressed with full-length Ca(v)2.2, they markedly suppressed its functional expression, although at the single channel level, when channels were recorded, there were no differences in their biophysical properties. Furthermore, when it was coexpressed with either domain I-II or domain I, the fluorescence of green fluorescent protein (GFP)-Ca(v)2.2 and expression of Ca(v)2.2 protein was almost abolished. Suppression does not involve sequestration of the Ca(v)beta subunit, because loss of GFP-Ca(v)2.2 expression also occurred in the absence of beta subunit, and the effect of domain I-II or domain I could not be mimicked by the cytoplasmic I-II loop of Ca(v)2.2. It requires transmembrane segments, because the isolated Ca(v)2.2 N terminus did not have any effect. Our results indicate that the mechanism of suppression of Ca(v)2.2 by truncated constructs containing domain I involves inhibition of channel synthesis, which may represent a role of endogenously expressed truncated Ca(v) isoforms.
Animals↗
Evidence for two concentration-dependent processes for beta-subunit effects on alpha1B calcium channels.
beta-Subunits of voltage-dependent Ca(2+) channels regulate both their expression and biophysical properties. We have injected a range of concentrations of beta3-cDNA into Xenopus oocytes, with a fixed concentration of alpha1B (Ca(V)2.2) cDNA, and have quantified the corresponding linear increase of beta3 protein. The concentration dependence of a number of beta3-dependent processes has been studied. First, the dependence of the a1B maximum conductance on beta3-protein occurs with a midpoint around the endogenous concentration of beta3 (approximately 17 nM). This may represent the interaction of the beta-subunit, responsible for trafficking, with the I-II linker of the nascent channel. Second, the effect of beta3-subunits on the voltage dependence of steady-state inactivation provides evidence for two channel populations, interpreted as representing alpha1B without or with a beta3-subunit, bound with a lower affinity of 120 nM. Third, the effect of beta3 on the facilitation rate of G-protein-modulated alpha1B currents during a depolarizing prepulse to +100 mV provides evidence for the same two populations, with the rapid facilitation rate being attributed to Gbetagamma dissociation from the beta-subunit-bound alpha1B channels. The data are discussed in terms of two hypotheses, either binding of two beta-subunits to the alpha1B channel or a state-dependent alteration in affinity of the channel for the beta-subunit.
Animals↗
Myositis, polyserositis with a large pericardial effusion and constrictive pericarditis as manifestations of chronic graft-versus-host disease after non-myeloablative peripheral stem cell transplantation and subsequent donor lymphocyte infusion.
The clinical features of chronic graft-versus-host disease (cGVHD) following a non-myeloablative peripheral blood stem cell (PBSC) transplant may differ from those that occur after a conventional allograft. We describe a man with Hodgkin's disease refractory to chemotherapy and radiotherapy who was transplanted from an HLA-identical brother, who developed cGVHD characterised, in particular, by polymyositis, polyserositis with a large pericardial effusion and constrictive pericarditis, 1 month after donor lymphocyte infusion for relapsed disease. Constrictive pericarditis has not been previously reported after a conventional allograft, and none of these features have been reported after a non-myeloablative transplant. The course of cGVHD necessitated potent immunosuppression leading to the presumed loss of graft-versus-lymphoma (GVL) effect.
Adult↗
Streptococcal inhibitor of complement (SIC) inhibits the membrane attack complex by preventing uptake of C567 onto cell membranes.
Streptococcal inhibitor of complement (SIC) was first described in 1996 as a putative inhibitor of the membrane attack complex of complement (MAC). SIC is a 31 000 MW protein secreted in large quantities by the virulent Streptococcus pyogenes strains M1 and M57, and is encoded by a gene which is extremely variable. In order to study further the interactions of SIC with the MAC, we have made a recombinant form of SIC (rSIC) in Escherichia coli and purified native M1 SIC which was used to raise a polyclonal antibody. SIC prevented reactive lysis of guinea pig erythrocytes by the MAC at a stage prior to C5b67 complexes binding to cell membranes, presumably by blocking the transiently expressed membrane insertion site on C7. The ability of SIC and clusterin (another putative fluid phase complement inhibitor) to inhibit complement lysis was compared, and found to be equally efficient. In parallel, by enzyme-linked immunosorbent assay both SIC and rSIC bound strongly to C5b67 and C5b678 complexes and to a lesser extent C5b-9, but only weakly to individual complement components. The implications of these data for virulence of SIC-positive streptococci are discussed, in light of the fact that Gram-positive organisms are already protected against complement lysis by the presence of their peptidoglycan cell walls. We speculate that MAC inhibition may not be the sole function of SIC.
Bacterial Proteins↗
Fibroblast growth factor receptors and their ligands in the adult rat kidney.
BACKGROUND: Fibroblast growth factors (FGFs) are a family of at least 21 heparin-binding proteins involved in many biological processes, both during development and in the adult, including cell proliferation, differentiation, and angiogenesis. FGFs mediate their effects through high-affinity tyrosine kinase receptors (FGFRs), which are encoded by four genes. The aims of the present study were to localize FGFR-1 through FGFR-3 in the normal adult rat kidney and to determine which functional FGFR variants and FGFs were expressed. METHODS: Avidin-biotin-enhanced horseradish peroxidase immunohistochemistry was used on paraffin sections of rat kidney to localize FGFR-1 through FGFR-3, whereas reverse transcriptase-polymerase chain reaction was used to examine expression of the receptor variants and also of FGF-1 through FGF-10 in cortex, outer medulla, and inner medulla. RESULTS: By immunohistochemistry, each receptor was localized to distinct and overlapping nephron segments, such that one or more FGFRs were localized to all nephron and collecting duct epithelia. FGFR-1 and FGFR-3 were localized to glomeruli, FGFR-3 to proximal tubules and FGFR-1 to thin limbs. FGFR-1 through FGFR-3 were localized to distal straight tubules, with FGFR-1 and FGFR-3 localized to distal convoluted tubules. FGFR-1 and FGFR-3 were localized to medullary collecting ducts. In addition, FGFR-1 was localized to the smooth muscle of renal arteries. All seven FGFR variants were expressed in the cortex and outer medulla, with fewer FGFRs in the inner medulla. FGF-1, FGF-2, FGF-7, FGF-8, and FGF-9 were expressed in the kidney, with FGF-10 expression found only in the cortex. CONCLUSIONS: Mapping of these receptors is critical to the determination of the effects of FGF ligands in discrete regions of the kidney. The distributions of the FGFRs in the normal adult kidney and the restricted expression of FGF ligands suggest that specific FGFs have distinct and important roles in the maintenance of normal kidney structure and function.
Animals↗
Early and late reactions after the use of iopamidol 340, ioxaglate 320, and iodixanol 320 in cardiac catheterization.
BACKGROUND: Although modern contrast agents have tolerability superior to older agents, significant differences remain between the agents currently in use. METHODS: To investigate the incidence of early (<24 hours) and late (>24 hours to 7 days) reactions to 3 contrast agents commonly used in cardiac catheterization, we performed a randomized, prospective, double-blind trial in which 2001 patients received one of the following agents: iopamidol 340, a nonionic monomer; ioxaglate 320, an ionic dimer; and iodixanol 320, a nonionic dimer. Possible reactions to contrast were recorded during the hospital admission and after discharge by means of a questionnaire, telephone follow-up, or both. RESULTS: Early reactions occurred in 22.2% of those receiving ioxaglate, 7.6% of those receiving iodixanol, and 8.8% of those receiving iopamidol (P <.0001). Late skin reactions occurred in 12.2% of those receiving iodixanol, 4.3% of those receiving ioxaglate, and 4.2% of those receiving iopamidol (P <.0001). CONCLUSIONS: The early side effect profile of certain ionic contrast agents suggests that these agents should no longer be used routinely in cardiac catheterization. The use of nonionic agents, however, is associated with late skin reactions, but there are notable differences between the monomeric and dimeric compounds. Although the skin reactions are generally benign, this is not always the case. Patients should be advised accordingly.
Adult↗
The hysterectomy lottery.
We report a postal survey of consultant gynaecologists carried out to determine the pattern of current hysterectomy practice, to obtain views on indications and contraindications to vaginal hysterectomy, and to predict future practice. There was a 75% response rate. Approximately two-thirds of hysterectomies were performed abdominally, one-third vaginally and 3% laparoscopically by each gynaecologist, although there was significant variation between them. The most common factors limiting the use of vaginal hysterectomy were a lack of uterine prolapse, the presence of fibroids and the need for prophylactic oophorectomy. It was predicted that there would be a significant change in hysterectomy practice with the majority being performed vaginally but still with a large variation. Gynaecologists who currently perform laparoscopic hysterectomy have the highest vaginal hysterectomy rates and predict the greatest role for it in the future. The large variations in practice indicate that the route of surgery is more dependent on the clinical preference of the gynaecologist than the medical condition.
Journal Article↗
The effects of domestic cooking on the levels of 3-monochloropropanediol in foods.
The results are reported of a study to determine the effect of domestic cooking procedures on the level of 3-monochloropropane-1,2-diol (3-MCPD) in selected foods. Samples of 23 foods comprising stock cubes, gravies, a cake mix, batters, breads, cheese and meats were subjected to a range of cooking procedures including grilling, toasting and microwaving. The resulting levels of 3-MCPD were compared with those present in the foods before cooking. Grilling and toasting produced substantial increases in the 3-MCPD content of bread, forming up to 0.3 mg/kg, and of most cheeses, resulting in levels of up to about 0.1 mg/kg. Microwave cooking produced elevated 3-MCPD levels in some cheeses. Frying laboratory-produced batters increased 3-MCPD levels to about 0.1 mg/kg whereas a retail batter contained no detectable 3-MCPD when fried. The remaining foods showed little or no discernible increase on cooking.
Bread↗
Selective use of abciximab in coronary stenting: overall outcomes can still be equivalent to those in the EPISTENT treatment group.
BACKGROUND: The EPISTENT trial reported improved early outcomes with routine use of abciximab after coronary stenting. Increasing use of stents means that routine abciximab adds significantly to costs of percutaneous coronary intervention (PCI). This paper reports the results of a protocol encouraging restriction of abciximab therapy to high-risk patients only. METHODS: Data were collected prospectively over a 34-month period for patients undergoing PCI with stenting. In addition to those who fulfilled criteria for inclusion in the EPISTENT trial, patients treated in the setting of acute myocardial infarction (AMI) were studied. Demographic data, procedural details and early clinical outcomes were recorded. RESULTS: Of 808 patients studied, 601 fulfilled EPISTENT inclusion criteria and comprised 367 patients (45%) treated for stable angina and 234 (30%) treated for unstable or post-infarct angina. The additional 207 patients (25%) were treated during AMI. The 808 patients received a total of 981 stents. Abciximab was given in only 88 cases (10.9%). Major adverse clinical events occurred in 39 patients (4.8%). CONCLUSION: Selective use of abciximab for patients undergoing coronary stenting can be associated with outcomes equivalent to those reported for routine use, but with significant cost savings.
Journal Article↗
Iomeprol: current and future profile of a radiocontrast agent.
RATIONALE AND OBJECTIVES: To review the safety and efficacy profiles of iomeprol by examining the most indicative comparative clinical studies of iomeprol with widely used low-osmolar ionic or nonionic contrast agents, and to illustrate the recent development in iomeprol liposomal formulations for liver imaging and intravascular enhancement. METHODS: Randomized, double-blind, comparative studies were performed of iomeprol versus iopamidol, iopromide, ioxaglate, iopentol, iodixanol, ioversol, and iohexol. In all studies, safety controls included pre- and postadministration physical examinations, monitoring of vital signs, electrocardiography, clinical laboratory investigations, and 24- or 72-hour postadministration monitoring of patients for adverse events. Technically adequate images were rated for diagnostic efficacy by masked assessors. RESULTS: Iomeprol showed similar safety and diagnostic efficacy compared with the nonionic monomers iopamidol, iohexol, and ioversol, and no statistically significant differences were observed. No differences in diagnostic efficacy between iomeprol and iopromide were observed, but in one study on 1,200 patients, the incidence of adverse events and adverse reactions was significantly higher with iopromide than with iomeprol. Iomeprol caused significantly less heat/pain than iopentol in one study; it showed similar safety and tolerability to the nonionic dimer iodixanol, the two agents causing no or modest, superimposable pain and heat sensation at injection and showing similar renal tolerability after intra-arterial injection. A comparison of iomeprol versus ionic dimer ioxaglate in 2,000 patients undergoing percutaneous coronary interventions showed that the incidence of thrombus-related events was similar with the two agents, but ioxaglate caused a significantly higher incidence of allergy-like reactions. First results with iomeprol-containing liposomal formulations show that these agents may facilitate the CT assessment of intrahepatic malignancies and CT angiography procedures. CONCLUSIONS: The overall results of numerous randomized, double-blind, comparative clinical studies in a variety of indications show that the diagnostic efficacy of iomeprol solutions does not differ significantly from that of the low-osmolar contrast media available on the marketplace when similar iodine strengths are used, although iomeprol may have better tolerability and safety than the ionic dimer and some of the nonionic monomers in selective applications. First results obtained with iomeprol-containing liposomal formulations are promising and may foster additional clinical testing.
Animals↗
Interaction between host complement and mosquito-midgut-stage Plasmodium berghei.
After ingestion by mosquitoes, gametocytes of malaria parasites become activated and form extracellular gametes that are no longer protected by the red blood cell membrane against immune effectors of host blood. We have studied the action of complement on Plasmodium developmental stages in the mosquito blood meal using the rodent malaria parasite Plasmodium berghei and rat complement as a model. We have shown that in the mosquito midgut, rat complement components necessary to initiate the alternative pathway (factor B, factor D, and C3) as well as C5 are present for several hours following ingestion of P. berghei-infected rat blood. In culture, 30 to 50% of mosquito midgut stages of P. berghei survived complement exposure during the first 3 h of development. Subsequently, parasites became increasingly sensitive to complement lysis. To investigate the mechanisms involved in their protection, we tested for C3 deposition on parasite surfaces and whether host CD59 (a potent inhibitor of the complement membrane attack complex present on red blood cells) was taken up by gametes while emerging from the host cell. Between 0.5 and 22 h, 90% of Pbs21-positive parasites were positive for C3. While rat red and white blood cells stained positive for CD59, Pbs21-positive parasites were negative for CD59. In addition, exposure of parasites to rat complement in the presence of anti-rat CD59 antibodies did not increase lysis. These data suggest that parasite or host molecules other than CD59 are responsible for the protection of malaria parasites against complement-mediated lysis. Ongoing research aims to identify these molecules.
Animals↗
Silent myocardial ischaemia in patients with proved coronary artery disease: a comparison of diabetic and non-diabetic patients.
OBJECTIVE: To determine whether diabetic patients with coronary artery disease are more likely to experience silent myocardial ischaemia than subjects without diabetes. SUBJECTS: Patients undergoing coronary angiography at a regional cardiothoracic unit, identified as having diabetes from the local district diabetic register/database. DESIGN: The coronary angiograms and exercise treadmill tests of 100 diabetic and 100 non-diabetic patients who all had significant coronary artery disease and maximal effort exercise tests were reviewed. Patients were individually matched for age group, gender, severity of coronary artery disease, and indication for treadmill test. OUTCOME MEASURES: Significant coronary artery disease was defined as a stenosis of greater than 50% diameter in at least one of the major coronary artery segments. Exercise tests were graded as positive if the electrocardiographic (ECG) recording showed planar or downsloping ST segment depression of > or = 1 mm in more than two leads at 80 ms post J-point or if there was a blood pressure fall > or = 10 mm Hg after an initial rise. A negative exercise test was defined as one in which the subject experienced no pain, had no ECG changes after maximal effort and had a normal blood pressure response. Subjects who did not experience any form of typical angina-type pain during a positive exercise test were defined as having an episode of silent ischaemia. Patients with symptomatic ischaemia were those who experienced typical angina-type pain with accompanying ST segment changes. Patients with a negative exercise test were defined as having "undetermined ischaemia". This category included all those without ECG evidence of myocardial ischaemia during the exercise test (with or without accompanying chest pain). RESULTS: In the diabetic patients, 34% had ECG evidence of silent ischaemia on treadmill testing compared with only 19% of the non-diabetic controls (p < 0.02). CONCLUSIONS: This study shows that diabetic patients with proved coronary artery disease have a higher risk of developing silent myocardial ischaemia during exercise than non-diabetic patients.
Adult↗
An aberrant form of CD59 derived from HeLa cells.
We isolated a CD59 cDNA from a HeLa cell library which encoded a mutated form of CD59, having a single base substitution (G to T) that changed Arg55 to Met. Since this mutation occurred in the vicinity of the putative active site of CD59, we expressed the aberrant form of the protein in Chinese hamster ovary cells in order to test for effects upon function. We found that the mutation did not influence complement inhibitory activity of CD59. However, the epitopes recognised by the function-blocking CD59 monoclonal antibodies BRIC229 and YTH 53.1 were significantly affected. The G to T substitution caused loss of an Mnl I restriction site which permitted PCR-RFLP analysis. All of 52 human subjects studied, and our in-house HeLa cells, were homozygous for the normal CD59 sequence, indicating that the altered sequence was not due to normal variation in the general population. Therefore this mutation probably arose spontaneously in the HeLa cell line used to generate the commercially obtained cDNA library.
Amino Acid Sequence↗
A new approach to improving facilities for resident hospital doctors.
The British Medical Association and the Department of Health recently agreed tougher systems to force NHS trusts to improve living conditions for resident doctors. Central to the proposals is the system of monitoring pioneered in the West Midlands, described below, which has resulted in significant improvements in the facilities provided by the region's trusts in the last 3 years.
Accreditation↗
Educating children's nurses in Wales.
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Child Health Services↗
Ten steps to successful chargemaster reviews.
Is your chargemaster current, compliant, and comprehensive? In the age of APCs, healthcare facilities would do well to answer these questions regularly. Here's how an HIM professional can help.
Ambulatory Care↗