Corticosteroids in the management of early and established rheumatoid disease.
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Antirheumatic Agents↗
Biomedical subjects
E Morrison
Publications and source records attributed to E Morrison.
Immunosuppressive effects of radiation on human dendritic cells: reduced IL-12 production on activation and impairment of naive T-cell priming.
Dendritic cells (DC) are professional antigen-presenting cells (APC) of the immune system, uniquely able to prime naive T-cell responses. They are the focus of a range of novel strategies for the immunotherapy of cancer, a proportion of which include treating DC with ionising radiation to high dose. The effects of radiation on DC have not, however, been fully characterised. We therefore cultured human myeloid DC from CD14+ precursors, and studied the effects of ionising radiation on their phenotype and function. Dendritic cells were remarkably resistant against radiation-induced apoptosis, showed limited changes in surface phenotype, and mostly maintained their endocytic, phagocytic and migratory capacity. However, irradiated DC were less effective in a mixed lymphocyte reaction, and on maturation produced significantly less IL-12 than unirradiated controls, while IL-10 secretion was maintained. Furthermore, peptide-pulsed irradiated mature DC were less effective at naive T-cell priming, stimulating fewer effector cells with lower cytotoxicity against antigen-specific targets. Hence irradiation of DC in vitro, and potentially in vivo, has a significant impact on their function, and may shift the balance between T-cell activation and tolerization in DC-mediated immune responses.
Apoptosis↗
Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial.
BACKGROUND: Evidence for disease modifying activity of low dose corticosteroid treatment in rheumatoid arthritis is contradictory. Studies showing radiological benefit suggest that continued treatment is required to sustain the effect. OBJECTIVE: To evaluate the effect of low dose oral prednisolone in early rheumatoid arthritis on disease activity over two years. DESIGN: Double blind placebo controlled trial. METHODS: Patients with rheumatoid arthritis, duration <3 years (n = 167), were started on a disease modifying antirheumatic drug (DMARD; sulphasalazine) and allocated by stratified randomisation to prednisolone 7 mg/day or placebo. Primary outcome measure was radiological damage, assessed by the modified Sharp method. Clinical benefit was a secondary outcome. A proactive approach to identifying and treating corticosteroid adverse events was adopted. Patients who discontinued sulphasalazine were offered an alternative DMARD. RESULTS: 90 of 257 patients eligible for the study refused to participate (more women than men). Of those enrolled, 84% were seropositive for rheumatoid factor, median age 56 years, median disease duration 12 months, female to male ratio 1.8:1. Prednisolone was given to 84 patients; of these 73% continued prednisolone and 70% sulphasalazine at 2 years. Of the 83 patients on placebo, 80% continued placebo and 64% sulphasalazine at 2 years. There were no significant differences in radiological score or clinical and laboratory measures at 0 and 2 years. CONCLUSIONS: Low dose prednisolone conferred no radiological or clinical benefit on patients maintained on a DMARD over two years. Low dose corticosteroids have no role in the routine management of rheumatoid arthritis treated with conventional disease modifying drugs.
Adult↗
Attitude of rheumatoid arthritis patients to treatment with oral corticosteroids.
OBJECTIVE: To assess the attitudes of rheumatoid arthritis (RA) patients to oral corticosteroid treatment, factors influencing these views and their likely clinical impact. METHODS: A cross-sectional survey of 158 consecutive RA out-patients was carried out at two centres over 2 weeks. Demography, disease duration, function [Health Assessment Questionnaire (HAQ)], erythrocyte sedimentation rate (ESR), years of formal education and social deprivation index were noted. Prospective recruitment into the multicentre West of Scotland Early Rheumatoid Arthritis Corticosteroid Trial (WOSERACT) was monitored and reasons for refusal to participate (when available) were noted at three of the centres. RESULTS: Forty-eight (32%) patients were willing to be treated with oral corticosteroid and 100 (68%) were not. The former were older (P = 0.002), had a higher ESR (P = 0.007), poorer function (P = 0.001) and greater previous exposure to disease-modifying anti-rheumatic drugs (P = 0.013). Ninety patients refused to participate in WOSERACT, in 46 cases (40 female, 6 male) the reason being concerns about corticosteroids. CONCLUSIONS: This study shows a high level of concern about and refusal of corticosteroid treatment in RA, due mainly to patient concerns about adverse effects. Rheumatologists need to be aware of these attitudes as they are likely to affect prescribing.
Administration, Oral↗
Mechanisms involved in the induction of apoptosis by T-2 and HT-2 toxins in HL-60 human promyelocytic leukemia cells.
T-2 and HT-2 toxins belong to a group of mycotoxins that are widely encountered as natural contaminants known to elicit toxic responses in hematopoietic cells. In the present study, HL-60 cells were used to characterize the apoptotic effects of T-2 and a major metabolite, HT-2, and to examine the mechanisms involved. Apoptotic cells were identified microscopically by chromatin condensation and nuclear fragmentation, by flow cytometric analysis, and by DNA gel electrophoresis. T-2 and HT-2 induced concentration-dependent apoptosis after 24 h in HL-60 cells, starting at concentrations of 3.1 and 6.25 ng/ml respectively. An increased number of apoptotic cells could be observed 4-6 h after exposure to 12.5 ng/ml of toxin. Little cytotoxicity (plasma membrane damage) was observed even after exposure to concentrations of toxins (25-50 ng/ml) inducing apoptosis in 60-100% of the cells. The apoptotic process was almost completely blocked in the presence of the general caspase inhibitor zVAD.fmk. In contrast, no or only minor effects were observed with the more specific caspase inhibitors DEVD.CHO, IETD.fmk, and DEVD.fmk. As judged by Western blotting, the levels of several procaspases (-3, -7, -8, -9, but not -12) were reduced 3-6 h after exposure to toxin. Substantial increases in the presumed active form(s) of caspase-8 and -9 were observed. Furthermore, poly(ADP-ribose) polymerase (PARP) was already markedly cleaved 3 h after toxin treatment, indicative of active caspase-3 and -7. No or only minor changes in Bcl-2, Bcl-XL and Bax levels were observed. BAPTA-AM and ZnCl2 blocked the degradation of procaspases, the fragmentation of PARP, and the induction of apoptosis. In summary, both T-2 and HT-2 induced apoptosis, with T-2 being somewhat more potent than HT-2. The divalent calcium concentration, [Ca2+], appears to be involved in the activation of several caspases, resulting in DNA fragmentation, chromosomal condensation, and nuclear fragmentation.
Apoptosis↗
HLA-DQ and DRB1 polymorphism and susceptibility to type 1 diabetes in Jamaica.
Genetic susceptibility to type 1 diabetes is determined by a combination of HLA-DQ and DRB1 alleles. In the present study, HLA associations with type 1 diabetes were investigated in the Jamaican population. DRB1 and DQ genotyping was performed on 45 type 1 diabetic patients and 132 control subjects born and resident in Jamaica. The small number of patients available for study reflected the low prevalence of type 1 diabetes in Jamaica. The results were compared with those from other African heritage populations and white Caucasians. The highest relative risk was associated with the DRB1*03-DQ2/DRB1*04-DQ8 genotype. Both DRB1*0401-DQ8 and DRB1*0408-DQ8 were positively associated with disease. DRB1*0408-DQ8 is uncommon amongst white Caucasians, where DRB1*0401-DQ8 is the major predisposing haplotype. The DRB1*1503-DQ6 haplotype was associated with protection from diabetes in the Jamaican population. This haplotype is rare amongst white Caucasians, where DRB1*1501-DQ6 is the protective haplotype. Data from African heritage populations suggest that DRB1*1503-DQ6 might be less protective than DRB1*1501-DQ6. DRB1*03-DQA1*0401-DQB1*0402 was associated with protection from diabetes in the Jamaican population, whereas in white Caucasians DRB1*08-DQA1*0401-DQB1*0402 is predisposing. These data demonstrate that comparison of genetic associations with type 1 diabetes in races with population-specific DRB1-DQ haplotypes provides new information as to the exact determinants of disease susceptibility. Further support is provided for roles of the DQ genes and the DRB1 gene (or a gene in linkage disequilibrium with it) in determining susceptibility to type 1 diabetes.
Adult↗
Restraint reduction in acute care: an interdisciplinary approach.
The authors discuss an interdisciplinary project to reduce the use of restraints in an acute care setting. They describe the process, beginning with initial planning and then working and evaluation phases. Common patient problems often requiring restraint are identified, with suggested solutions. Outcomes of the project were that fall rates did not increase and the use of restraints decreased by 83%.
Aged↗
A longitudinal study comparing scaling, osseous surgery, and modified Widman procedures: results after 5 years.
BACKGROUND: Scaling and root planing, osseous surgery, and modified Widman procedures are effective methods for treating periodontal diseases. Studies have been carried out to determine if these procedures are more effective than others in reducing clinical probing depths, while maintaining clinical attachment levels. The purpose of this report is to present 5-year results from a longitudinal study comparing scaling and root planing (SRP), osseous surgery (OS), and modified Widman (MW) therapies. The study has been completed for 12 years. METHODS: Sixteen adult patients with moderate to advanced periodontal disease were treated with initial scaling and oral hygiene procedures in a private practice. Posthygiene data were used to compare changes in plaque and gingival indices, probing depth (PD), clinical attachment levels (CAL), and recession. Frequency distributions were used to compare changes at individual sites. The first published report was from baseline to one year. This follow-up report is from baseline through 5 years. RESULTS: At 5 years, there were significant decreases in gingival and plaque scores. For the 3 procedures, there were significant decreases in baseline 4 to 6 mm PD (P<0.0001); however, there were no differences between the methods. Similar findings were noted for PD initially greater than 7 mm. At 5 years, OS had the greatest number of 1 to 3 mm sites (332 sites, 73.2%), while MW had the fewest number of 4 to 6 mm PD (98 sites, 21.8%). SRP had the fewest 7 mm and greater sites (15 sites, 3.4%). At 5 years, CAL loss for 1 to 3 mm PD was statistically significant for the 3 procedures. There were slight gains in CAL for 4 to 6 mm probing depths. These gains were not significant. Similar findings were seen for CAL for probing depths greater than 7 mm. OS had the greatest number of sites losing more than 2 mm of CAL (64 sites), followed by SRP (21 sites) and MW (34 sites), respectively. CONCLUSIONS: This 5-year clinical trial demonstrates that with good patient maintenance excellent clinical results can be achieved with various methods of treatment. Within the limits of this study, SRP, OS, and MW were effective at reducing probing depths with slight changes in clinical attachment levels.
Adult↗
Patients' perceptions of medical students in a longitudinal family medicine clerkship.
BACKGROUND: Although educational characteristics of ambulatory clinical environments are becoming clearer, less is known concerning patient opinions about participating in medical student instruction in ambulatory settings. Such perceptions may have an important influence on recruitment and retention of community faculty. METHODS: Surveys were administered to 121 patients seen by medical students during a longitudinal family medicine clerkship. The survey explored patients' opinions regarding the extent of direct student involvement in their care, students'competence, and patient feelings about participating in medical student instruction. RESULTS: Patients felt that students were highly involved in providing care and that they performed competently and professionally. Patients found participation in medical education enjoyable, not excessively time-consuming or disruptive, and believed that students' participation improved the quality of care they received. CONCLUSIONS: Patients in our family medicine clerkship do not have negative perceptions about their participation in medical student education. In fact, this study suggests that such participation may actually enhance patient satisfaction.
California↗
A longitudinal communication skills initiative for an academic health system.
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California↗
Activated mesothelial cells produce heparin-binding growth factors: implications for tumour metastases.
Curative surgery for gastrointestinal malignancy is commonly thwarted by local tumour recurrence. The heparin-binding growth factors, basic fibroblast growth factor (bFGF), heparin-binding epidermal growth factor-like growth factor (HB-EGF) and vascular epidermal growth factor (VEGF) are all implicated in the metastatic process, but whether or not these essential growth factors are produced by the activated peritoneum is unknown. This study reveals that peritoneal mesothelial cells constitutively express mRNA for bFGF, HB-EGF and two VEGF spliced variants, VEGF121 and VEGF165. Mesothelial activation with interleukin (IL)-1b or tumour necrosis factor (TNF)-a produced an up-regulation of mRNA for HB-EGF and VEGF, but not bFGF expression. IL-6 failed to stimulate growth factor expression, whereas IL-2 produced a marked suppression in HB-EGF and bFGF, but not VEGF expression. Mesothelial cells were shown to predominantly express mRNA for the intermediate affinity (bg(c)) IL-2 receptor. Cytokine-induced growth factor up-regulation was confirmed at the protein level using Western blotting of mesothelial cell lysates for HB-EGF and culture supernatant enzyme-linked immunosorbent assay for VEGF. The production of these growth factors by human mesothelial cells may play a significant role in post-operative peritoneal tumour recurrence. Their common heparin-binding property offers a potential therapeutic target for manipulating the growth factor environment of the human peritoneum.
Biomarkers, Tumor↗
The "EBM Rx": an initial experience with an evidence-based learning prescription.
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California↗
Processing of procorticotropin-releasing hormone (pro-CRH): molecular forms of CRH in normal and preeclamptic pregnancy.
This study examined the different molecular forms of CRH in normal and preeclampsia maternal plasma and protease-blocked placental extracts using antibodies to different regions of the CRH precursor, pro-CRH. In the absence of protease inhibitors, chromatographed normal placental extracts contained four peaks of immunoreactivity corresponding to unprocessed approximately 19-kDa pro-CRH, its approximately 8-kDa intermediate metabolite, pro-CRH125-194, its approximately 2.8-kDa midportion fragment, pro-CRH125-151, and 4.75-kDa CRH1-41. However, if protease inhibitors were included in the extraction medium, only pro-CRH and pro-CRH125-194 were found. Pro-CRH processing was more extensive in protease-blocked preeclampsia placentas than in those from normal pregnancy, with three peaks corresponding to pro-CRH, proCRH125-194, and mature CRH1-41 peptide found. Using quantitative competitive PCR, the messenger ribonucleic acid levels of CRH precursor in preeclampsia placentas were 1.7-fold higher than those in normal placentas (37.83 +/- 3.48 vs. 21.83 +/- 2.59 attomoles/microg total ribonucleic acid, respectively; P < 0.005). Preeclampsia placentas contained significantly more CRH1-41 cross-reactivity (4.72 +/- 1.22 pmol/g) than normal term placentas (1.52 +/- 0.39 pmol/g; P < 0.048) extracted in medium containing protease inhibitors. The content of pro-CRH(125+/-151)-reactive species in these extracts followed the same pattern, with more immunoreactivity detected in preeclampsia placentas (4.23 +/- 1.39 pmol/g) than in those from normal term pregnancies (1.44 +/- 0.32 pmol/g; P < 0.01). Sequential plasma samples from 10 women with normal pregnancy and 5 women with preeclampsia were assayed for pro-CRH(125-151)- and CRH(1-41)-immunoreactive species In normal pregnancy, maternal plasma CRH(1-41) immunoreactivity rose with increasing gestational age, reaching 460 +/- 48 pmol/L at term. In women with preeclampsia, CRH(1-41) levels at each gestational age point were higher than those at the equivalent stage of normal pregnancy. In contrast, the levels of pro-CRH(125-151)-immunoreactive species remained barely detectable throughout normal and preeclamptic pregnancy. Both pro-CRH and CRH(1-41), but not pro-CRH(125-151), were shown to bind to the plasma CRH-binding protein. Our findings highlight the importance of protection of placental tissue from degrading enzymes during extraction and show that most of the CRH in the human placenta exists as unprocessed pro-CRH, with very little in the form of CRH(1-41) except in preeclampsia. Our studies using maternal plasma indicate that CRH(1-41) is the only one of the pro-CRH fragments studied to be maintained in significant amounts in the maternal circulation and also the only fragment studied for which a specific plasma binding protein exists.
Animals↗
Mass rearing the weevil Hylobius transversovittatus (Coleoptera: Curculionidae), biological control agent of Lythrum salicaria, on semiartificial diet.
Lythrum salicaria L., purple loosestrife, an invasive Eurasian perennial, is degrading wetlands across temperate North America. Chemical, physical, and mechanical methods failed to provide long-term control. Therefore, four host-specific insect species (two leaf feeders, a root feeder, and a flower feeder) were introduced as biological control agents. To increase the availability of adults of the root feeding weevil Hylobius transversovittatus Goeze for field releases, we developed a semiartificial diet. Suitability of different diet formulations (varying vitamin mixes, salt mixes, antimicrobials, water content, root content) and temperatures for larval development were evaluated. We also monitored how rearing on artificial diet and the number of larvae per container affected larval development time, larval survival, adult weight, and incidences of deformities. Rearing larvae on artificial diet reduced development time from 1-2 yr to 2-3 mo. Larval development was fastest and survival rates highest under constant temperatures of 25 degrees C. Hatch rate and larval survival decreased if eggs were surface sterilized. Using FABCO antimicrobials could not prevent fungal contamination; use of methyl paraben and sorbic acid was successful in suppressing fungal and bacterial growth throughout larval development time to <10%. The moisture content of the diet did not significantly affect larval survival, development, or adult weight. Decreasing the proportion of purple loosestrife roots in the diet reduced adult weight and the proportion of larvae completing development, and increased development time; no larvae were able to complete development in root-free diet. With an increase in the number of larvae per cup, survival rates were reduced. The experiments revealed a female biased sex ratio: females consistently developed faster and were heavier than males. Incidence of adult deformities was consistently below 5%. Increased availability of adults for field release as a result of mass production using the semiartificial diet will accelerate the biocontrol program targeting purple loosestrife. We are able to produce several hundred weevils per week and have adapted the diet to rear other root-feeding weevils.
Animals↗
Corticosteroids in rheumatoid arthritis--the case against.
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Adrenal Cortex Hormones↗
Analyzing amenorrhea.
When menarche has failed to occur or menstrual cycles have stopped, the problem can be traced back to a functional or structural defect in the hypothalamus, pituitary, ovaries, or uterus. In most cases, the history is the principal source of diagnostic information. Necessary laboratory studies include one for the most common cause of amenorrhea: pregnancy.
Adult↗
Intracellular retention of the corticotrophin-releasing hormone (CRH) precursor within COS-7 cells.
We investigated the intracellular localization of CRH in transiently transfected COS-7 cells expressing the full-length rat corticotropin-releasing hormone (CRH) precursor cDNA. CRH synthesized by transfected COS-7 cells is mainly stored intracellularly. In contrast, CHO-K1 cells expressing the same CRH precursor stored and released equal amounts of immunoreactive (IR)-CRH. Ultrastructural analysis revealed that CRH is stored in electron-dense aggregates in the RER of transiently transfected COS-7 cells and does not migrate into the Golgi apparatus. On the basis of the different intracellular localization, storage, and release of CRH in COS-7 and CHO-K1 cells, we hypothesize that the intracellular trafficking of CRH within the constitutive secretory pathway for protein secretion not only depends on its primary amino acid sequence but might also be influenced by intracellular conditions or factors.
Animals↗
The effects of guided bone regeneration and grafting on implants placed into immediate extraction sockets. An experimental study in dogs.
Guided bone regeneration (gbr) for the treatment of insufficient bone volume around implants can be performed using membranes with or without grafting materials (i.e., autogenous, allogenous, xenogenous, or alloplastic grafts). A possible way to evaluate the quality of implant osseointegration is the torque necessary to remove implants from their bony housing. The aim of this study was to compare the torques necessary to remove dental implants from implant beds reconstructed with different bone substitutes and GBR or GBR alone in 6 adult mongrel dogs. All mandibular premolars were extracted and 3 extraction sockets on each side were enlarged using a trephine bur. A 13 mm titanium screw-type dental implant (3.75 mm diameter) was placed in each enlarged extraction socket so that only the apical 3 to 4 mm were engaged in bone. The 3 defects were then randomly treated with either 1) canine demineralized freeze-dried bone allograft (DFDBA) plus GBR using an expanded polytetrafluoroethylene membrane (DFDBA+GTAM); 2) bioabsorbable hydroxyapatite and GBR (HA+GTAM); or 3) GBR (GTAM alone). After 6 months, the torque to remove the implants was measured in 4 animals and analyzed using ANOVA. There were no statistically significant differences between the 3 groups (GTAM alone: 46.37+/-16.41 Ncm; HA+GTAM: 46.00+/-16.59 Ncm; DFDBA+ GTAM: 52.15+/-29.24 Ncm). In addition, the influence of early removal of barriers on the torque values was evaluated with the t-test. Comparing exposed versus retained membranes by treatment modality, the only statistically significant difference was found in the DFDBA+GTAM group. When the torque values of all implants with exposed and retrieved membranes were compared to all those with retained membranes a significant difference could be detected. Histologic sections were prepared from the 2 dogs not included in the removal torque testing. In the histometric analysis the GTAM alone group showed a mean mineralized bone-to-implant-contact of 27.1%, the DFDBA+GTAM group of 34.6%, and the HA+GTAM of 39.3%. The mineralized bone-to-implant-contact of the HA+GTAM group was significantly higher than that of the GTAM alone group. In addition, the mineralized bone-to-implant-contact was divided into an apical and coronal part using the apical seventh thread as the dividing landmark. In the apical region, there was no significant difference between the groups regarding mineralized bone-to-implant-contact. In the coronal part the mineralized bone-to-implant-contact of the GTAM alone group was significantly lower compared to the other 2 groups. Within the limits of this investigation, it can be concluded that the type of grafting material will not influence torque removal values, but that early membrane exposure and removal will negatively influence the torque measurements. The combination of GBR with a bone substitute increased the mineralized bone-to-implant contact.
Absorbable Implants↗