Biomedical subjects

A C Papageorgiou

Publications and source records attributed to A C Papageorgiou.

At least 19 recordsLinked to original sources

PubMed2001

Structural features of a zinc binding site in the superantigen strepococcal pyrogenic exotoxin A (SpeA1): implications for MHC class II recognition.

Streptococcal pyrogenic exotoxin A (SpeA) is produced by Streptococcus pyogenes, and has been associated with severe infections such as scarlet fever and Streptococcal Toxic Shock Syndrome (STSS). In this study, the crystal structure of SpeA1 (the product of speA allele 1) in the presence of 2.5 mM zinc was determined at 2.8 A resolution. The protein crystallizes in the orthorhombic space group P2(1)2(1)2, with four molecules in the crystallographic asymmetric unit. The final structure has a crystallographic R-factor of 21.4% for 7,031 protein atoms, 143 water molecules, and 4 zinc atoms (one zinc atom per molecule). Four protein ligands-Glu 33, Asp 77, His 106, and His 110-form a zinc binding site that is similar to the one observed in a related superantigen, staphylococcoal enterotoxin C2. Mutant toxin forms substituting Ala for each of the zinc binding residues were generated. The affinity of these mutants for zinc ion confirms the composition of this metal binding site. The implications of zinc binding to SpeA1 for MHC class II recognition are explored using a molecular modeling approach. The results indicate that, despite their common overall architecture, superantigens appear to have multiple ways of complex formation with MHC class II molecules.

Alleles↗

PubMed2000

Development and validation of a questionnaire to assess disabling foot pain.

This study outlines the design and validation of a new self-administered instrument for assessing foot pain and disability. The 19-item questionnaire was tested on 45 rheumatology patients, 33 patients who had attended their general practitioner with a foot-related problem and 1000 responders to a population survey of foot disorders. Levels of reported disability were found to be greatest for rheumatology patients and least for community subjects. In addition, the instrument was able to detect differences in disability levels reported by community subjects who did and did not consult with a health care professional and those who did and did not have a history of past and current foot pain. A good level of agreement was found when items on the questionnaire were compared with similar items on the ambulation sub-scale of the Functional Limitation Profile questionnaire. A Cronbach's alpha value of 0.99 and item-total correlation values between 0.25 and 0.62 confirmed the internal consistency of the instrument. Finally the results of a principal components analysis identified three constructs that reflected disabilities that are associated with foot pain: functional limitation, pain intensity and personal appearance. The design of the foot disability questionnaire makes it a suitable instrument for assessing the impact of painful foot conditions in both community and clinical populations.

Adult↗

PubMed2000

Microbial superantigens: from structure to function.

Superantigens are highly potent immune stimulators with a unique ability to interact simultaneously with MHC class II molecules and T cell receptors, forming a trimolecular complex that induces profound T-cell proliferation and massive cytokine production. Recent structural studies have provided a wealth of information regarding these complex interactions, and it is now emerging that, despite their common 3-D architecture, superantigens are able to crosslink MHC class II molecules and T cell receptors in a variety of ways.

Amino Acid Motifs↗

PubMed2000

Structural similarities and differences in Staphylococcus aureus exfoliative toxins A and B as revealed by their crystal structures.

Staphylococcal aureus epidermolytic toxins (ETs) A and B are responsible for the induction of staphylococcal scalded skin syndrome, a disease of neonates and young children. The clinical features of this syndrome vary from localized blisters to severe exfoliation affecting most of the body surface. Comparison of the crystal structures of two subtypes of ETs-rETA (at 2.0 A resolution), rETB (at 2.8 A resolution), and an active site variant of rETA, Ser195Ala at 2.0 A resolution has demonstrated that their overall topology resembles that of a "trypsin-like" serine protease, but with significant differences at the N- and C-termini and loop regions. The details of the catalytic site in both ET structures are very similar to those in glutamate-specific serine proteases, suggesting a common catalytic mechanism. However, the "oxyanion hole," which is part of the catalytic sites of glutamate specific serine proteases, is in the closed or inactive conformation for rETA, yet in the open or active conformation for rETB. The ETs contain a unique amphipathic helix at the N-terminus, and it appears to be involved in optimizing the conformation of the catalytic site residues. Determination of the structure of the rETA catalytic site variant, Ser195Ala, showed no significant perturbation at the active site, establishing that the loss of biological and esterolytic activity can be attributed solely to disruption of the catalytic serine residue. Finally, the crystal structure of ETs, together with biochemical data and mutagenesis studies, strongly confirms the classification of these molecules as "serine proteases" rather than "superantigens."

Amino Acid Sequence↗

PubMed2000

Hospital referrals for low back pain: more coherence needed.

Low back pain is a common reason for hospital referral but little is known of the resulting workload in different specialties. All new outpatient attendances for conditions with low back pain were recorded over one month in a teaching hospital and a district general hospital. The patients were seen in at least ten specialties and two-fifths of them had been seen previously with the same symptom in another department. In the two hospitals, low back pain accounted for 15% and 12% of all new outpatient attendances. A more coherent referral policy is needed.

Hospital Records↗

PubMed1999

Short-term physical risk factors for new episodes of low back pain. Prospective evidence from the South Manchester Back Pain Study.

STUDY DESIGN: A prospective population-based cohort study performed in South Manchester, United Kingdom. OBJECTIVES: To determine whether nonoccupational physical activity and indicators of physical stress on the spine predict low back pain in the short term. SUMMARY OF BACKGROUND DATA: There is evidence that physical activity outside the workplace helps to protect against low back pain in the long term. However, such activity may injure or stress the spine in the short term. METHODS: A baseline survey questionnaire identified 2715 adults, aged 18-75 years, with no low back pain at the time of the survey. Information on potential predictors of low back pain also was obtained. New episodes of back pain were identified during the subsequent year. RESULTS: A new low back pain episode occurred in 34% of men and 37% of women. Poor general health at baseline was the strongest predictor of a new episode of pain (men: relative risk (RR) 1.5, 95% confidence intervals (CI) 0.8, 2.7; women: RR 2.2, 95% CI 1.2, 4.0). High weight was associated with subsequent low back pain in women (RR 1.4; 95% CI 1.0, 2.0), but neither height nor weight predicted low back pain in men. A self-rated low level of physical activity was not consistently linked with subsequent low back pain, nor were specific nonoccupational physical activities, apart from home-improvement work in men and regular sports in women. CONCLUSION: Although some specific activities may be hazardous to the back, physical activity outside the workplace does not increase the short-term risk of low back pain overall. Leisure-time physical activity is not a hazard to the back, whereas poor physical health in both genders and heavier weight in women do increase the risk of new low back pain episodes in the short term.

Adult↗

PubMed1999

Predicting who develops chronic low back pain in primary care: a prospective study.

OBJECTIVES: To quantify the relative contribution of premorbid and episode specific factors in determining the long term persistence of disabling symptoms of low back pain. DESIGN: Prospective cohort study. SETTING: Two general practices in the south Manchester area. PARTICIPANTS: 180 patients, who previously participated in a cross sectional population survey, who consulted because of low back pain during the study period. They were followed at 1 week and 3 and 12 months after consultation. MAIN OUTCOME MEASURE: Persistent disabling low back pain in the 12 months after the consultation. RESULTS: Disabling low back pain persisted in one third of participants after consultation and was more common with increasing age, among those with a history of low back pain, and in women. Persistence of symptoms was associated with "premorbid" factors (high levels of psychological distress (odds ratio 3.3; 95% confidence interval 1.5 to 7.2), poor self rated health (3.6; 1.9 to 6.8), low levels of physical activity (2.8; 1.4 to 5.6), smoking (2. 1; 1.0 to 4.3), dissatisfaction with employment (2.4; 1.3 to 4.5)) and factors related to the episode of low back pain (duration of symptoms, pain radiating to the leg (2.6; 1.3 to 5.1), widespread pain (6.4; 2.7 to 15), and restriction in spinal mobility). A multivariate model based on six factors identified groups whose likelihood of persistent symptoms ranged from 6% to 70%. CONCLUSIONS: The presence of persistent low back pain is determined not only by clinical factors associated with pain but also by the premorbid state.

Adolescent↗

PubMed1999

Structural basis for the recognition of superantigen streptococcal pyrogenic exotoxin A (SpeA1) by MHC class II molecules and T-cell receptors.

Streptococcal pyrogenic exotoxin A (SpeA) is a superantigen produced by Streptococcus pyogenes and is associated with severe infections characterized by rash, hypotension, multiorgan failure and a high mortality rate. In this study, an allelic form of this toxin, SpeA1, was crystallized with four molecules in the crystallographic asymmetric unit and its crystal structure was determined at 2.6 A resolution. The crystallographic R-factor was 19.4% (33 497 reflections) for 7031 protein atoms and 88 water molecules. The overall structure of SpeA1 is considerably similar to that of other prototype microbial superantigens, either of staphylococcal or streptococcal origin, but has greatest similarity to staphylococcal enterotoxin C (SEC). Based on structural and mutagenesis data, we have mapped several important residues on the toxin molecule, which are involved in the recognition of major histocompatibility complex (MHC) class II molecules and T-cell receptors. Also, the toxin appears to possess a potential zinc-binding site which may have implications in binding to particular MHC class II molecules. Finally, we propose models for SpeA1-MHC class II and SpeA1-T-cell receptor association and the relevance of this phenomenon to the superantigenic action of this toxin is considered.

Amino Acid Sequence↗

PubMed1999

Predictors of early improvement in low back pain amongst consulters to general practice: the influence of pre-morbid and episode-related factors.

Low back pain symptoms are extremely common. affecting as many as 80% of the population at some time in their lives. However, the majority of the medical costs arise from the minority of patients whose symptoms become chronic. The authors propose a model in which chronicity is determined not only by factors related to the episode of low back pain, but also factors prior to the onset of symptoms (pre-morbid factors). No previous study has collected information on predictors of low back pain chronicity prior to the onset of symptoms. Participants in the South Manchester Low Back Pain Study, recruited by means of a cross-sectional population survey were followed prospectively over 18 months to identify those who consulted their general practitioner with a new episode of low back pain. At interview, 1-2 weeks post-consultation, it was determined whether or not subjects' symptoms had improved. In males, low levels of psychological distress, a higher than average reported level of physical activity, being in employment, and being satisfied with current work status were associated with a quick improvement in symptoms. In addition factors related to the episode, namely a short duration before consultation and symptoms with a sudden onset and confined to the lower back area, also strongly predicted a good early outcome. Using information on both pre-morbid and episode related factors, groups of male patients were identified whose probability of an early resolution of symptoms ranged between 0.25 and 1. Few factors, either pre-morbid or episode-related, were strongly associated with outcome amongst females. This large population-based study has shown, despite the known heterogeneity in the origin of low back pain and the pathologies associated with symptoms, an early improvement in symptoms amongst male attenders at general practice can be predicted on the basis of a small number of variables.

Adolescent↗

PubMed1999

Chronic widespread pain in the community: the influence of psychological symptoms and mental disorder on healthcare seeking behavior.

OBJECTIVE: To determine whether psychological symptoms and mental disorder are an intrinsic part of the chronic widespread pain syndrome or whether they have been observed in clinic attenders primarily because of their influence on the decision to seek a medical consultation. METHODS: A population survey of 1953 subjects was conducted in the Greater Manchester area of the United Kingdom. The survey included a postal questionnaire, and in a subgroup of respondents with high levels of distress, the presence of mental disorder was assessed by a semistructured standardized interview. Subjects with chronic widespread pain were classified according to whether they had sought a medical consultation for the reported pain ("consulters") or not ("nonconsulters"). RESULTS: In all, 252 subjects (13%) satisfied American College of Rheumatology criteria for chronic widespread pain, and of these 72% reported having consulted a general practitioner about this pain. There was a clear difference in levels of psychological distress, measured by the General Health Questionnaire (GHQ), between consulters, nonconsulters, and those with no pain. Consulters did not differ from nonconsulters in terms of levels of fatigue, social dysfunction, or number of somatic symptoms reported. Although consulters (among whom one in 4 had a mental disorder) were more likely to have a mental disorder than subjects without pain [OR = 4.9, 95% CI (2.6, 9.5)] the increase in risk comparing consulters to nonconsulters [OR = 2.1, 95% CI (0.7, 5.9)] and nonconsulters to subjects without pain [OR = 1.4, 95% CI (0.7, 2.6)] was not significant. CONCLUSION: The results suggest that psychological distress is associated with chronic widespread pain in addition to any effect on whether consultation is sought for symptoms. The finding that one-quarter of consulters to primary care with chronic widespread pain have a mental disorder should alert primary care physicians and rheumatologists to screen for mental disorder in this group.

Adolescent↗

PubMed1998

Outcome of low back pain in general practice: a prospective study.

OBJECTIVES: To investigate the claim that 90% of episodes of low back pain that present to general practice have resolved within one month. DESIGN: Prospective study of all adults consulting in general practice because of low back pain over 12 months with follow up at 1 week, 3 months, and 12 months after consultation. SETTING: Two general practices in south Manchester. 490 subjects (203 men, 287 women) aged 18-75 years. MAIN OUTCOME MEASURES: Proportion of patients who have ceased to consult with low back pain after 3 months; proportion of patients who are free of pain and back related disability at 3 and 12 months. RESULTS: Annual cumulative consultation rate among adults in the practices was 6.4%. Of the 463 patients who consulted with a new episode of low back pain, 275 (59%) had only a single consultation, and 150 (32%) had repeat consultations confined to the 3 months after initial consultation. However, of those interviewed at 3 and 12 months follow up, only 39/188 (21%) and 42/170 (25%) respectively had completely recovered in terms of pain and disability. CONCLUSIONS: The results are consistent with the interpretation that 90% of patients with low back pain in primary care will have stopped consulting with symptoms within three months. However most will still be experiencing low back pain and related disability one year after consultation.

Adolescent↗

PubMed1998

Crystal structure of microbial superantigen staphylococcal enterotoxin B at 1.5 A resolution: implications for superantigen recognition by MHC class II molecules and T-cell receptors.

Staphylococcal enterotoxin B is a member of a family of toxins known as superantigens that activate a large number of T-cells (up to 20%) by cross-linking MHC class II molecules with T-cell receptors in a Vbeta-restricted fashion. The crystal structure of staphylococcal enterotoxin B presented here has been determined at 1.5 A resolution, the highest resolution so far for a superantigen. The final model contains 1948 protein atoms and 177 water molecules and has excellent geometry with root-mean-square (rms) deviation of 0.007 A and 1.73 degrees in bond lengths and bond angles, respectively. The overall fold is similar to that of other microbial superantigens, but as it lacks the zinc-binding site found in other members of this family, such as staphylococcal enterotoxin A, C2 and D, this enterotoxin possesses only one MHC class II binding site. Comparison of the crystal structure of free SEB and in complex with an MHC class II molecule revealed no major changes in the MHC-binding site upon complex formation. However, a number of water molecules found in the free SEB may be displaced in the complex or contribute further to its stability. Detailed analysis of the TcR-binding site of SEB, SEA and SEC2 shows significant differences which may account for the ability of each superantigen to bind specific Vbeta sequences.

Amino Acid Sequence↗

PubMed1998

Association between measures of spinal mobility and low back pain. An analysis of new attenders in primary care.

STUDY DESIGN: Comparison of spinal movements in new attenders to primary care with an episode of low back pain with a sample with no recalled history of ever having had low back pain. OBJECTIVES: To examine the association between restriction of spinal movement and the presence of low back pain in primary care. SUMMARY OF BACKGROUND DATA: The presence of restriction in spinal mobility has frequently been investigated by specialists in the clinical setting. What is not known, however, is whether an association exists between pain and restriction in those newly presenting to primary care and whether these measurements can be used to discriminate between those with and without back pain. METHODS: The study participants consisted of 344 consulters to two general practices, prospectively ascertained in the South Manchester Back Pain Study, who were compared with 118 individuals from the same practices who denied ever having back pain. The two groups were compared for right and left lateral flexion, standing extension, modified Schober's test, finger-to-floor distance, and right and left knee extension. RESULTS: There was a statistically significant reduction in all planes in those with low back pain. Modified Schober's, standing extension, and left knee extension were the most discriminatory, with likelihood ratios of approximately 5 for the optimal cutoff. Restriction of three or more of these seven movements was observed in 50% of the low back pain cases and in less than 5% of the pain-free participants. Stratification by presence or absence of radiation of pain to the legs did not alter these findings. CONCLUSIONS: Measures of spinal mobility are restricted to varying extents in a community-based sample of subjects with low back pain. Maximal discrimination was observed when restriction was present in three or more planes. The utility of these measures in predicting outcome remains to be assessed.

Adult↗

PubMed1998

Psychosocial risks for low back pain: are these related to work?

OBJECTIVES: To examine whether psychosocial risks for low back pain, reported in previous studies, are specific to the working population or are more widely relevant. METHODS: A large population-based survey identified subjects free of low back pain, and obtained information on the degree of satisfaction with work (or not working) and the adequacy of income for their family's needs. New episodes of consulting and non-consulting low back pain were identified prospectively over 12 months. The psychosocial risks for developing a new low back pain episode are examined in employed and non-employed groups separately. RESULTS: Dissatisfaction with work status doubled the risk of reporting a new low back pain episode in both the employed (odds ratio 2.0, 95% confidence intervals 1.2, 3.3) and non-employed (OR 2.0, 1.2, 3.1). Those perceiving their income as inadequate were at a threefold risk of consulting for this symptom regardless of their employment status (employed: OR 3.6, 1.8, 7.2; non-employed: OR 3.6, 1.4, 9.0). CONCLUSION: Psychosocial factors pose similar risks for a new low back pain episode in workers and the non-employed. This suggests that such influences may not be related solely to work but be a function of general aspects of life. The economic and individual impact of psychosocial interventions in the workplace, therefore, are likely to be limited unless account is taken of the influence of broader non-work related aspects.

Adult↗

PubMed1997

Molecular recognition of human angiogenin by placental ribonuclease inhibitor--an X-ray crystallographic study at 2.0 A resolution.

Human placental RNase inhibitor (hRI), a leucine-rich repeat protein, binds the blood vessel-inducing protein human angiogenin (Ang) with extraordinary affinity (Ki <1 fM). Here we report a 2.0 A resolution crystal structure for the hRI-Ang complex that, together with extensive mutagenesis data from earlier studies, reveals the molecular features of this tight interaction. The hRI-Ang binding interface is large and encompasses 26 residues from hRI and 24 from Ang, recruited from multiple domains of both proteins. However, a substantial fraction of the energetically important contacts involve only a single region of each: the C-terminal segment 434-460 of hRI and the ribonucleolytic active centre of Ang, most notably the catalytic residue Lys40. Although the overall docking of Ang resembles that observed for RNase A in the crystal structure of its complex with the porcine RNase inhibitor, the vast majority of the interactions in the two complexes are distinctive, indicating that the broad specificity of the inhibitor for pancreatic RNase superfamily proteins is based largely on its capacity to recognize features unique to each of them. The implications of these findings for the development of small, hRI-based inhibitors of Ang for therapeutic use are discussed.

Amino Acid Sequence↗

PubMed1997

Superantigens as immunomodulators: recent structural insights.

Superantigens interact with major histocompatibility complex (MHC) class II molecules and T-cell receptors (TcRs) forming a trimolecular complex which is able to induce proliferation and cytokine production in T cells. Although superantigens appear to act through a common mechanism, they very in many of their specific interactions and biological properties. X-ray crystallographic studies and biochemical experiments have now established that cross-linking of MHC class II molecules and the TcR by superantigens can occur in a number of different modes.

Adjuvants, Immunologic↗

PubMed1997

A structural and functional comparison of staphylococcal enterotoxins A and C2 reveals remarkable similarity and dissimilarity.

Staphylococcal enterotoxins and toxic shock syndrome toxin-1 are known as superantigens due to their ability to activate a large number of T-cells by crosslinking the major histocompatibility complex class II molecules with the T-cell receptor. Although superantigens seem to act by a common mechanism, they vary in many of their specific interactions and biological properties. A structural comparison of staphylococcal enterotoxins A and C2, members of the staphylococcal superantigens, has shown large conformational differences at the putative TcR interaction site (loops between alphaN-alpha2, alpha4-beta9 and beta10-alpha5 in staphylococcal enterotoxin A) that could explain the variability in their T-cell receptor specificity. A common Zn2(+)-binding site was identified in both staphylococcal enterotoxin A and C2 that is superimposable but differs somewhat in its coordination geometry between the two molecules.

Amino Acid Sequence↗

PubMed1997

Psychosocial factors in the workplace--do they predict new episodes of low back pain? Evidence from the South Manchester Back Pain Study.

STUDY DESIGN: A prospective, population-based cohort study of working adults. OBJECTIVES: To determine whether work-related psychosocial factors and social status predict the occurrence of new episodes of low back pain and influence consultation behavior. SUMMARY AND BACKGROUND DATA: Dissatisfaction with work and social status has been associated with low back pain in several studies; few of these studies have been prospective or population based. METHODS: An initial postal survey was returned by 4,501 (59%) adults (18-75 years old) registered with two primary care practices. From this, a cohort of 1,412 people currently in employment and free of low back pain was identified, and baseline information on work-related psychosocial factors and psychologic distress was obtained. Social class was derived from current occupation using a standardized classification. New episodes of low back pain occurring in the next 12 months were identified by continuous monitoring of primary care consulters and by mailing a second questionnaire a year later to identify occurrences of low back pain for which no consultation was sought. RESULTS: The baseline cross-sectional survey showed modest but significant associations between low back pain and perceived inadequacy of income (risk ratio 1.3), dissatisfaction with work (risk ratio 1.4) and social class IV/V (risk ratio 1.2). In the follow-up year, the risk of reporting low back pain for which no consultation was sought doubled in those dissatisfied with their work. Both perceived inadequacy of income (odds ratio 3.6) and social class IV/V (odds ratio 4.8) were strongly associated with consulting with a new episode of low back pain during the follow-up year, an association more marked in women. The associations with work dissatisfaction and perceived adequacy of income were not explained by general psychologic distress or social status. CONCLUSION: People dissatisfied with work are more likely to report low back pain for which they do not consult a physician, whereas lower social status and perceived inadequacy of income are independent risks for working people to seek consultation because of low back pain.

Adult↗