PubMed Health⌕ Search

Biomedical subjects

P Emery

Publications and source records attributed to P Emery.

At least 19 recordsLinked to original sources
PubMed1998

CRY, a Drosophila clock and light-regulated cryptochrome, is a major contributor to circadian rhythm resetting and photosensitivity.

Light is a major environmental signal for circadian rhythms. We have identified and analyzed cry, a novel Drosophila cryptochrome gene. All characterized family members are directly photosensitive and include plant blue light photoreceptors. We show that cry transcription is under circadian regulation, influenced by the Drosophila clock genes period, timeless, Clock, and cycle. We also show that cry protein levels are dramatically affected by light exposure. Importantly, circadian photosensitivity is increased in a cry-overexpressing strain. These physiological and genetic data therefore link a specific photoreceptor molecule to circadian rhythmicity. Taken together with the data in the accompanying paper, we propose that CRY is a major Drosophila photoreceptor dedicated to the resetting of circadian rhythms.

ARNTL Transcription Factors↗
PubMed1998

The cryb mutation identifies cryptochrome as a circadian photoreceptor in Drosophila.

A new rhythm mutation was isolated based on its elimination of per-controlled luciferase cycling. Levels of period or timeless clock gene products in the mutant are flat in daily light-dark cycles or constant darkness (although PER and TIM oscillate normally in temperature cycles). Consistent with the fact that light normally suppresses TIM, cryb is an apparent null mutation in a gene encoding Drosophila's version of the blue light receptor cryptochrome. Behaviorally, cryb exhibits poor synchronization to light-dark cycles in genetic backgrounds that cause external blindness or demand several hours of daily rhythm resets, and it shows no response to brief light pulses. cryb flies are rhythmic in constant darkness, correlating with robust PER and TIM cycling in certain pacemaker neurons.

Animals↗
PubMed1998

Classification of inflammatory arthritis by enthesitis.

Imaging studies of early synovitis suggest that the first abnormality to appear in swollen joints associated with spondyloarthropathy is an enthesitis (inflammation at sites where ligaments, tendons, or joint capsules are attached to bone). We propose that the synovitis of spondyloarthropathy is secondary to liberation of proinflammatory mediators from the enthesis, whereas the synovitis of rheumatoid arthritis is primary. This suggestion allows a classification of arthritis as either primary synovial (rheumatoid-like) or entheseal (spondyloarthropathy-like) and allows differentiation of presentation of a polyarthritis with a good prognosis (spondyloarthropathy-like), from that with a bad prognosis (rheumatoid arthritis). Pathogenesis of spondyloarthropathy, in particular the part played by HLA-B27 and micro-organisms, should be assessed at the enthesis rather than in the synovium.

Arthritis↗
PubMed1998

DNA binding properties of a chemically synthesized DNA binding domain of hRFX1.

The RFX DNA binding domain (DBD) is a novel highly conserved motif belonging to a large number of dimeric DNA binding proteins which have diverse regulatory functions in eukaryotic organisms, ranging from yeasts to human. To characterize this novel motif, solid phase synthesis of a 76mer polypeptide corresponding to the DBD of human hRFX1 (hRFX1/DBD), a prototypical member of the RFX family, has been optimized to yield large quantities (approximately 90 mg) of pure compound. Preliminary two-dimensional1H NMR experiments suggested the presence of helical regions in this sequence in agreement with previously reported secondary structure predictions. In gel mobility shift assays, this synthetic peptide was shown to bind in a cooperative manner the 23mer duplex oligodeoxynucleotide corresponding to the binding site of hRFX1, with a 2:1 stoichoimetry due to an inverse repeat present in the 23mer. The stoichiometry of this complex was reduced to 1:1 by decreasing the length of the DNA sequence to a 13mer oligonucleotide containing a single half-site. Surface plasmon resonance measurements were achieved using this 5'-biotylinated 13mer oligonucleotide immobilized on an avidin-coated sensor chip. Using this method an association constant (K a = 4 x 10(5)/M/s), a dissociation constant (K d = 6 x 10(-2)/s) and an equilibrium dissociation constant (K D = 153 nM) were determined for binding of hRFX1/DBD to the double-stranded 13mer oligonucleotide. In the presence of hRFX1/DBD the melting temperature of the 13mer DNA was increased by 16 degreesC, illustrating stabilization of the double-stranded conformation induced by the peptide.

Amino Acid Sequence↗
PubMed1998

Quantitative microscopic analysis of inflammation in rheumatoid arthritis synovial membrane samples selected at arthroscopy compared with samples obtained blindly by needle biopsy.

OBJECTIVE: To evaluate microscopic measures of inflammation in rheumatoid arthritis synovial tissue samples selected at arthroscopy compared with those obtained blindly by needle biopsy from the suprapatellar pouch (SPP) of the same joint. METHODS: Samples were selected at knee arthroscopy from the SPP and the lateral and medial gutters. Immediately following arthroscopy, a biopsy needle was inserted through the same portal into the SPP by a second investigator, and 3 further samples were obtained blindly. Using standard immunohistologic methods, all samples were analyzed by a single investigator without knowledge of the original tissue location and biopsy technique. Following staining with anti-CD3 and anti-CD68 monoclonal antibodies, T lymphocyte and macrophage infiltration were measured by quantitative analysis. RESULTS: Synovial tissues from 14 patients were analyzed. In comparing microscopic measures of inflammation using the 2 procedures, mean scores of lining cell depth and the percentage of CD68+ cells in the lining layer correlated positively (tau = 0.59, P = 0.003 and tau = 0.73, P = 0.0003, respectively). In the sublining layer, CD3+ cell counts also correlated significantly (tau = 0.71, P = 0.0004). Sublining CD68+ cell counts did not correlate. This was explained by the observation that CD68+ cell infiltration in areas adjacent to articular cartilage was significantly greater than in the SPP (P = 0.01), suggesting preferential trafficking to this site by macrophages, but not by T lymphocytes. Macroscopic appearance at arthroscopy did not predict microscopic features. CONCLUSION: Most microscopic measures of inflammation in synovial tissue samples obtained blindly from the SPP were similar to those determined in samples selected at arthroscopy. However, measurements in samples from the SPP may underestimate the intensity of macrophage infiltration in areas more adjacent to cartilage. These observations have important implications for future study of macrophage function in synovial tissue.

Arthritis, Rheumatoid↗
PubMed1998

Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy.

OBJECTIVE: To use magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA) to determine if the primary site of abnormality differs. METHODS: Twenty patients with recent-onset knee effusion (10 with SpA and 10 with RA) were evaluated using fat-suppressed MRI. Knee joint effusion and synovitis were confirmed using ultrasonography. MRI scans were independently scored by 2 observers who were blinded to the patient's diagnosis. RESULTS: All 10 of the SpA patients, but only 4 of the 10 RA patients, had focal peri-entheseal high signal (compatible with fluid or edema) outside the joint (P = 0.01). Six of the SpA patients had bone marrow edema that was maximal at entheseal insertions; in 4 cases this was multifocal. No RA patients showed such an abnormality (P = 0.01). CONCLUSION: Prominent entheseal abnormalities on MRI are a consistent feature of new-onset synovitis in SpA, but are a minor feature of RA. This finding has important implications for the diagnosis, classification, and mechanisms of synovitis in patients with SpA.

Adult↗
PubMed1998

Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist.

OBJECTIVE: To evaluate the efficacy and safety of interleukin-1 receptor antagonist (IL-1Ra) in patients with rheumatoid arthritis (RA). METHODS: Patients with active and severe RA (disease duration <8 years) were recruited into a 24-week, double-blind, randomized, placebo-controlled, multicenter study. Doses of nonsteroidal antiinflammatory drugs and/or oral corticosteroids (< or =10 mg prednisolone daily) remained constant throughout the study. Any disease-modifying antirheumatic drugs that were being administered were discontinued at least 6 weeks prior to enrollment. Patients were randomized to 1 of 4 treatment groups: placebo or a single, self-administered subcutaneous injection of IL-1Ra at a daily dose of 30 mg, 75 mg, or 150 mg. RESULTS: A total of 472 patients were recruited. At enrollment, the mean age, sex ratio, disease duration, and percentage of patients with rheumatoid factor and erosions were similar in the 4 treatment groups. The clinical parameters of disease activity were similar in each treatment group and were consistent with active and severe RA. At 24 weeks, of the patients who received 150 mg/day IL-1Ra, 43% met the American College of Rheumatology criteria for response (the primary efficacy measure), 44% met the Paulus criteria, and statistically significant improvements were seen in the number of swollen joints, number of tender joints, investigator's assessment of disease activity, patient's assessment of disease activity, pain score on a visual analog scale, duration of morning stiffness, Health Assessment Questionnaire score, C-reactive protein level, and erythrocyte sedimentation rate. In addition, the rate of radiologic progression in the patients receiving IL-1Ra was significantly less than in the placebo group at 24 weeks, as evidenced by the Larsen score and the erosive joint count. IL-1Ra was well tolerated and no serious adverse events were observed. An injection-site reaction was the most frequently observed adverse event, and this resulted in a 5% rate of withdrawal from the study among those receiving IL-1Ra at 150 mg/day. CONCLUSION: This study confirmed both the efficacy and the safety of IL-1Ra in a large cohort of patients with active and severe RA. IL-1Ra is the first biologic agent to demonstrate a beneficial effect on the rate of joint erosion.

Adolescent↗
PubMed1998

The assessment of knowledge in ankylosing spondylitis patients by a self-administered questionnaire.

The aim of the present study was to assess ankylosing spondylitis (AS) patients' level of knowledge, using a self-administered multiple-choice questionnaire. The questionnaire, based on the Arthritis and Rheumatism Council (ARC) leaflet on AS, examined four areas: (A) general knowledge; (B) immunogenetic tests and inheritance; (C) general management; (D) joint protection, pacing and priorities. Statistical analysis was used to validate the questionnaire and to examine correlations with gender, age, disease duration and level of general education. The questionnaire was consistent, reliable and easy to read. The results showed AS patients to have a high level of knowledge (mean = 19.4, maximum possible = 25), although some wrong beliefs about the role of blood tests, the HLA-B27 antigen and inheritance were discovered. No statistical correlation was found between gender, age, duration of the disease, level of general education and the level of knowledge. These data suggest that this questionnaire is a simple way to detect the level of knowledge of patients with AS. The average score achieved by AS patients was outstanding, possibly reflecting the good quality of previous educational programmes. Patients' confusion regarding blood tests, genetics and inheritance was highlighted and should be addressed.

Activities of Daily Living↗
PubMed1998

Effect of vitamin D receptor gene alleles on bone loss in early rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a polygenic disease characterized by localized joint destruction and generalized osteoporosis resulting in increased fracture risk. The pathogenetic mechanisms that determine the severity of generalized bone loss in RA are poorly understood. Polymorphisms in the vitamin D receptor (VDR) gene have been described as a significant determinant of bone turnover and mass. In this prospective study we describe VDR gene allele effects on bone loss in patients with early RA. METHODS: We recruited 232 patients with early RA. Bone mineral density measurements were repeated in 167 patients. Serial clinical and laboratory measures were recorded during the period of followup. DNA extraction, polymerase chain reaction amplification, and restriction fragment length polymorphism analysis of VDR alleles were performed using standard techniques. Presence of the Taq restriction site for both alleles was denoted "tt", and absence "TT". RESULTS: In women with RA the tt genotype group lost bone more rapidly than subjects with TT genotype at both the lumbar spine (-0.1 vs -4.9% p.a, respectively; p < 0.05) and femoral neck (-3.9 vs -9.6%, respectively; p < 0.01). The effect was independent of other disease characteristics. CONCLUSION: The presence of the VDR gene "t" allele in female patients with RA was associated with accelerated bone loss.

Alleles↗
PubMed1998

Safety and tolerability of conversion from stable Sandimmun maintenance treatment to Sandimmun Neoral in patients with rheumatoid arthritis.

OBJECTIVE: To assess the safety and tolerability of converting patients with rheumatoid arthritis (RA) taking a stable dose of cyclosporin A (CyA) maintenance treatment (Sandimmun, SIM) to a new microemulsion capsule formulation, Sandimmun Neoral (Neoral), at an initial dose of 2.5 mg/kg/day. METHODS: In this single arm, open multicenter study, 28 patients were recruited to enter a 6 week pre-conversion period; of these, 22 patients completed 12 weeks' treatment with Neoral. RESULTS: During the 12 week post-conversion period, 11 patients experienced adverse events considered to be drug related; most were mild to moderate in severity and reflected the known safety profile for CyA. Only slight differences in efficacy variables were observed after conversion. The mean Neoral dose at Week 12 (2.84 mg/kg/day) was lower than the mean SIM pre-conversion dose (3.38 mg/kg/day). The study showed that, in patients with RA undergoing stable SIM maintenance treatment, conversion to an initial Neoral dose of 2.5 mg/kg/day did not give rise to any clinically relevant safety and tolerability concerns, and efficacy of the treatment was maintained compared with SIM. CONCLUSION: This conversion strategy constitutes a clinically acceptable alternative to a 1:1 dose conversion.

Adult↗
PubMed1998

Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis.

OBJECTIVE: To use clinical measures and biochemical markers of bone turnover to investigate mechanisms of generalized bone loss in early rheumatoid arthritis (RA). METHODS: We studied 232 patients with RA of less than 2 years' duration and 72 healthy controls using serial dual x-ray absorptiometry scanning of lumbar spine and hips. Patients attended the clinic for clinical and laboratory assessment with storage of serum, urine, and plasma at each visit. Change in bone mineral density (BMD) was calculated for patients and controls and compared with baseline and mean serial values of bone markers over the same intervals. Serum was assayed for procollagen I carboxyterminal propeptide (PICP) and skeletal alkaline phosphatase (sALP); urine for pyridinoline and deoxypyridinoline corrected for creatinine; and plasma for interleukin 1 (IL-1) and IL-6. RESULTS: Patients lost bone significantly faster than controls at all sites (p < 0.01 for all). At first visit patients had significantly lower PICP levels than controls (p < 0.05) and sALP correlated with initial BMD in both patients (p < 0.01, r > 0.35, all sites) and controls (p < 0.0001, r > 0.50, all sites). We rescanned 167 patients at one year and 121 patients at 2 years. Mean urinary pyridinoline and deoxypyridinoline levels correlated strongly with BMD change at all sites, were increased in patients with active disease (p < 0.005), and correlated closely with mean C-reactive protein (CRP) (p < 0.005, r > 0.41 for both). CONCLUSION: This study suggests that osteoclastic activation, rather than suppression of bone formation, is the dominant process leading to bone loss in early RA. Although urinary pyridinoline and deoxypyridinoline were excellent markers of BMD change, CRP was found to be best overall. This provides a rational approach for selecting and treating patients with RA to reduce their established longterm risk of osteoporotic fracture.

Absorptiometry, Photon↗
PubMed1998

Patient education in psoriatic arthritis: a cross sectional study on knowledge by a validated self-administered questionnaire.

OBJECTIVE: To assess the level of knowledge in a group of patients with psoriatic arthritis (PsA) following one reading of an information leaflet [UK Arthritis Rheumatism Council (ARC) booklet] using a validated self-administered questionnaire. Comparisons with subsets of the disease and level of general education were also made. METHODS: A multiple choice self-administered questionnaire was carried out in a group of 59 patients (32 male, 27 female, mean age 47.53 +/- 12.71 yrs) with established disease (mean duration 9.6 +/- 8.5 yrs). The questionnaire covered 4 broad areas of the disease (general knowledge of skin and joint disease, etiology, symptoms, blood test; general management and drug therapy; physiotherapy treatments; joint protection and priorities) and it was written collecting the majority of the information from an ARC booklet on PsA and from advice from the rheumatology team. Detailed statistical analysis was performed to validate the questionnaire and to measure any associations with demographic data. RESULTS: The questionnaire was consistent, reliable, and easy to read. Patients showed a lack of knowledge with some erroneous beliefs about their disease (i.e., causes, blood tests, longterm drugs). No statistical associations were found between the level of knowledge achieved and demographic data and patterns of disease. A significant association was found between the median score and level of general education (Kruskal-Wallis analysis of variance 7.97, p = 0.02). CONCLUSION: The questionnaire is a good instrument to assess knowledge in PsA. The ARC booklet alone seems inadequate to provide sufficient knowledge of disease. Patients' erroneous beliefs were highlighted and these should be addressed.

Analysis of Variance↗
PubMed1997

RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency.

Major Histocompatibility Complex class II (MHC-II) deficiency is a disease of gene regulation that provides a unique opportunity for the genetic dissection of the molecular mechanisms controlling transcription of MHC-II genes. Cell lines from MHC-II deficiency patients have been assigned to three complementation groups (A, B and C) believed to reflect the existence of distinct essential MHC-II regulatory genes. Groups B and C, as well as an in vitro generated regulatory mutant representing a fourth group (D), are characterized by a specific defect in the binding activity of RFX, a multimeric DNA binding complex that is essential for activation of MHC-II promoters. RFX5, a subunit of RFX, was recently shown to be mutated in group C. We have now isolated a novel gene, RFXAP (RFX Associated Protein), that encodes a second subunit of the RFX complex. RFXAP is mutated in the 6.1.6 cell line (group D), as well as in an MHC-II deficiency patient (DA). This establishes that group D is indeed a fourth MHC-II deficiency complementation group. Complementation of the 6.1.6 and DA cell lines by transfection with RFXAP fully restores expression of all endogenous MHC-II genes in vivo, demonstrating that RFXAP is a novel essential MHC-II regulatory gene.

Amino Acid Sequence↗
PubMed1997

Inhibition of T cell apoptosis in the rheumatoid synovium.

Synovial T cells in rheumatoid arthritis are highly differentiated and express a phenotype suggesting susceptibility to apoptosis (CD45RB dull, CD45RO bright, Bcl-2 low, Bax high, Fas high). However, no evidence of T cell apoptosis was found in synovial fluid from any of 28 patients studied. In contrast, synovial fluid from 10 patients with crystal arthritis showed substantial levels of T cell apoptosis. The failre of apoptosis was not an intrinsic property of rheumatoid synovial T cells, as they showed rapid spontaneous apoptosis on removal from the joint. Synovial T cells from rheumatoid arthritis and gout patients could be rescued from spontaneous apoptosis in vitro either by IL-2R gamma chain signaling cytokines (which upregulate Bcl-2 and Bcl-XL) or by interaction with synovial fibroblasts (which upregulates Bcl-xL but not Bcl-2). The phenotype of rheumatoid synovial T cells ex vivo (Bcl-2 low, Bcl-xL high) suggested a fibroblast-mediated mechanism in vivo. This was confirmed by in vitro culture of synovial T cells with fibroblasts which maintained the Bcl-xL high Bcl-2 low phenotype. Synovial T cells from gout patients were Bcl-2 low Bcl-xL low and showed clear evidence of apoptosis in vivo. Inhibition experiments suggested that an integrin-ligand interaction incorporating the Arg-Gly-Asp motif is involved in fibroblast-mediated synovial T cell survival. We propose that environmental blockade of cell death resulting from interaction with stromal cells is a major factor in the persistent T cell infiltration of chronically inflamed rheumatoid synovium.

Apoptosis↗