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1.
Adv Protein Chem Struct Biol ; 105: 127-71, 2016.
Article in English | MEDLINE | ID: mdl-27567487

ABSTRACT

The dual-specificity tyrosine (Y) phosphorylation-regulated kinase DYRK1A, also known as Down syndrome (DS) kinase, is a dosage-dependent signaling kinase that was originally shown to be highly expressed in DS patients as a consequence of trisomy 21. Although this was evident some time ago, it is only in recent investigations that the molecular roles of DYRK1A in a wide range of cellular processes are becoming increasingly apparent. Since initial knowledge on DYRK1A became evident through minibrain mnb, the Drosophila homolog of DYRK1A, this review will first summarize the scientific reports on minibrain and further expand on the well-established neuronal functions of mammalian and human DYRK1A. Recent investigations across the current decade have provided rather interesting and compelling evidence in establishing nonneuronal functions for DYRK1A, including its role in infection, immunity, cardiomyocyte biology, cancer, and cell cycle control. The latter part of this review will therefore focus in detail on the emerging nonneuronal functions of DYRK1A and summarize the regulatory role of DYRK1A in controlling Tau and α-synuclein. Finally, the emerging role of DYRK1A in Parkinson's disease will be outlined.


Subject(s)
Down Syndrome/metabolism , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Amino Acid Sequence , Animals , Drosophila , Humans , Neoplasms/metabolism , Neurons/metabolism , Protein Serine-Threonine Kinases/chemistry , Protein-Tyrosine Kinases/chemistry , Sequence Homology, Amino Acid , Dyrk Kinases
2.
Mol Psychiatry ; 19(10): 1106-14, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24166413

ABSTRACT

Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling.


Subject(s)
Antidepressive Agents/pharmacology , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Animals , Brain-Derived Neurotrophic Factor/metabolism , Chronic Disease , Citalopram/pharmacology , Cyclic AMP Response Element-Binding Protein/metabolism , Depressive Disorder/drug therapy , Depressive Disorder/pathology , Depressive Disorder/physiopathology , Disease Models, Animal , Elongation Factor 2 Kinase/metabolism , Female , Mice, Inbred BALB C , Olfactory Bulb/physiopathology , Prefrontal Cortex/drug effects , Prefrontal Cortex/pathology , Prefrontal Cortex/physiopathology , Pyramidal Cells/drug effects , Pyramidal Cells/pathology , Pyramidal Cells/physiopathology , Receptor, Serotonin, 5-HT2C/metabolism , Receptors, Dopamine D1/antagonists & inhibitors , Receptors, Dopamine D1/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Stress, Psychological , TOR Serine-Threonine Kinases/metabolism , Time Factors
3.
Clin Exp Allergy ; 43(7): 741-51, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23786281

ABSTRACT

BACKGROUND: Prostaglandin E2 (PGE2 ) has been shown to inhibit IgE-dependent histamine release from human lung mast cells. This effect of PGE2 is believed to be mediated by EP2 receptors. However, definitive evidence that this is the case has been lacking in the absence of EP2 -selective antagonists. Moreover, recent evidence has suggested that PGE2 activates EP4 receptors to inhibit respiratory cell function. OBJECTIVE: The aim of this study was to determine the receptor by which PGE2 inhibits human lung mast cell responses by using recently developed potent and selective EP2 and EP4 receptor antagonists alongside other established EP receptor ligands. METHODS: The effects of non-selective (PGE2 , misoprostol), EP2 -selective (ONO-AE1-259, AH13205, butaprost-free acid) and EP4 -selective (L-902,688, TCS251) agonists on IgE-dependent histamine release and cyclic-AMP generation in mast cells were determined. The effects of EP2 -selective (PF-04418948, PF-04852946) and EP4 -selective (CJ-042794, L-161,982) antagonists on PGE2 responses of mast cells were studied. The expression of EP receptor subtypes was determined by RT-PCR. RESULTS: Prostaglandin E2 , EP2 agonists and EP4 agonists inhibited IgE-dependent histamine release from mast cells. PGE2 and EP2 agonists, but not EP4 agonists, increased cyclic-AMP levels in mast cells. EP4 -selective antagonists did not affect the PGE2 inhibition of histamine release, whereas EP2 -selective antagonists caused rightward shifts in the PGE2 concentration-response curves. RT-PCR studies indicated that mast cells expressed EP2 and EP4 receptors. CONCLUSIONS AND CLINICAL RELEVANCE: Although human lung mast cells may express both EP2 and EP4 receptors, the principal mechanism by which PGE2 inhibits mediator release in mast cells is by activating EP2 receptors.


Subject(s)
Dinoprostone/metabolism , Histamine Release/physiology , Histamine/metabolism , Immunoglobulin E/metabolism , Mast Cells/metabolism , Receptors, Prostaglandin E, EP2 Subtype/metabolism , Dinoprostone/agonists , Dinoprostone/antagonists & inhibitors , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Histamine Release/drug effects , Humans , Lung , Mast Cells/cytology , Receptors, Prostaglandin E, EP2 Subtype/agonists , Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors , Receptors, Prostaglandin E, EP4 Subtype/agonists , Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors
4.
Clin Exp Allergy ; 41(3): 378-88, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21255137

ABSTRACT

BACKGROUND: Previous studies indicate that the protein tyrosine kinase, syk, is critical in transducing FcɛRI-mediated signals. In human basophils, 'releasability' has been linked to the extent of syk expression. Human lung mast cells, like basophils, are also found to be variably responsive to IgE-dependent activation. OBJECTIVE: The aim of the present study was to determine whether the wide variability in human lung mast cell responses, following IgE-dependent activation, has a relationship with syk expression. METHODS: Mast cells were isolated from human lung tissue and 'releasability' was determined by activating the cells with a maximal releasing concentration of anti-IgE. Syk levels in mast cells were determined by immunoblotting and flow cytometry. RESULTS: Histamine release from mast cells, challenged with a maximal releasing concentration of anti-IgE, ranged from 0% to 69% (mean±SEM, 24±2%, n=53). A proportion of these preparations (nine out of 53) released very low levels of histamine (5%) in response to anti-IgE. Flow cytometry of a subset of preparations indicated that a weak response to anti-IgE was not related to a lack of surface IgE. Immunoblotting and flow cytometry studies demonstrated that, compared with mononuclear cells, human lung mast cells express low and variable levels of syk. However, there was no correlation between syk expression and mast cell releasability. Nonetheless, a number of putative inhibitors of syk including NVP-QAB205 (EC50, 0.2 µm) effectively attenuated the IgE-dependent release of histamine from mast cells. CONCLUSION AND CLINICAL RELEVANCE: These studies indicate that although syk may play an important role in mediating degranulation, the relative level of syk expression does not govern human lung mast cell releasability. Identification of the mechanisms that govern IgE-dependent activation of human lung mast cells is likely to be of wider clinical significance, given the central role that mast cells play in the development of allergic asthma.


Subject(s)
Lung/immunology , Mast Cells/metabolism , Protein-Tyrosine Kinases/biosynthesis , Signal Transduction/immunology , Cell Degranulation/immunology , Cell Separation , Flow Cytometry , Histamine Release/immunology , Humans , Immunoblotting , Immunoglobulin E/immunology , Intracellular Signaling Peptides and Proteins , Lung/cytology , Mast Cells/immunology , Syk Kinase
5.
Arthritis Rheum ; 57(6): 921-7, 2007 Aug 15.
Article in English | MEDLINE | ID: mdl-17665486

ABSTRACT

OBJECTIVE: To document pathways of care, management, and interval from onset of symptoms to first pediatric rheumatology multidisciplinary team (PRhMDT) assessment for children with incident juvenile idiopathic arthritis (JIA). METHODS: We conducted a retrospective observational study of children with incident JIA over a 3-year period. RESULTS: The study included 152 patients with JIA (87 females). The median interval from symptom onset to first PRhMDT assessment was 20 weeks (range 0-416), with significant variation between JIA subtypes (P = 0.0097); children with extended oligoarticular JIA had the longest interval (median 60 weeks, range 12-320). Prior to pediatric rheumatology assessment, many children had referrals to multiple secondary care specialties and had been subjected to multiple and often invasive procedures including arthroscopy/synovial biopsy (18 [11.8%] of 152), but none were referred for ophthalmologic screening, physical therapy, or nursing input and a diagnosis of JIA was rarely made (98%). At first PRhMDT assessment, most patients had untreated active disease with active joint count >or=1 (135 [89%] of 152), restricted joint count >or=1 (135 [89%] of 152), and functional disability by Child Health Assessment Questionnaire score >0 (53 [68%] of 118); 1 child had undetected uveitis. Following PRhMDT assessment, interventions were invariably indicated, including joint injections (69 [45%] of 152), methotrexate (49 [32%] of 152), and physical therapy programs (all patients). CONCLUSION: Delay in access to pediatric rheumatology assessment is common with complex pathways of referral. Many children were subjected to inappropriate invasive investigations and many had prolonged untreated active disease at the initial PRhMDT assessment. This delay is likely to affect long-term outcome and warrants further exploration.


Subject(s)
Arthritis, Juvenile/diagnosis , Arthritis, Juvenile/therapy , Health Services Accessibility/statistics & numerical data , Referral and Consultation/statistics & numerical data , Adolescent , Arthritis, Juvenile/physiopathology , Child , Child, Preschool , Disease Progression , Early Diagnosis , Female , Health Surveys , Humans , Infant , Male , Musculoskeletal System/physiopathology , Patient Care Team , Retrospective Studies , Rheumatology , Time Factors
6.
Br J Pharmacol ; 152(3): 323-31, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17643132

ABSTRACT

BACKGROUND AND PURPOSE: Previous studies have shown that beta(2)-adrenoceptor-mediated responses in human lung mast cells are highly variable. The aims of the present study were to establish whether polymorphisms of the beta (2)-adrenoceptor gene (ADRB2) influence this variability in (a) beta(2)-adrenoceptor-mediated inhibition and (b) desensitization of beta(2)-adrenoceptor-mediated responses in human lung mast cells. EXPERIMENTAL APPROACH: Mast cells were isolated from human lung tissue. The inhibitory effects of the beta-adrenoceptor agonist, isoprenaline (10(-10)-10(-5) M), on IgE-mediated histamine release from mast cells were determined (n=92). Moreover, the inhibitory effects of isoprenaline were evaluated following a desensitizing treatment involving long-term (24 h) incubation of mast cells with isoprenaline (10(-6) M) (n=65). A potential influence of polymorphisms on these functional responses was determined by genotyping 11 positions, in the promoter and coding regions, of ADRB2 previously reported as polymorphic. KEY RESULTS: There was no influence of any of the polymorphic positions of ADRB2 on the potency of isoprenaline to inhibit histamine release from mast cells with the exception of position 491C>T (Thr164Ile). There was no influence of any of the polymorphic positions of ADRB2 on the extent of desensitization of the isoprenaline-mediated response following a desensitizing treatment except for position 46G>A (Gly16Arg). Analyses at the haplotype level indicated that there was no influence of haplotype on beta (2)-adrenoceptor-mediated responses in mast cells. CONCLUSIONS AND IMPLICATIONS: These data indicate that certain polymorphisms in ADRB2 influence beta(2)-adrenoceptor-mediated responses in human lung mast cells.


Subject(s)
Lung/drug effects , Mast Cells/metabolism , Polymorphism, Genetic , Receptors, Adrenergic, beta-2/genetics , Adrenergic beta-Agonists/pharmacology , Desensitization, Immunologic , Female , Genotype , Haplotypes , Histamine/metabolism , Humans , Immunoglobulin E/drug effects , Immunoglobulin E/metabolism , Isoproterenol/pharmacology , Lung/cytology , Male , Mast Cells/drug effects , Open Reading Frames , Promoter Regions, Genetic , Time Factors
7.
Arthritis Rheum ; 55(5): 709-16, 2006 Oct 15.
Article in English | MEDLINE | ID: mdl-17013854

ABSTRACT

OBJECTIVE: To develop and validate a musculoskeletal screening examination applicable to school-age children based on the adult Gait, Arms, Legs, Spine (GALS) screen. METHODS: Adult GALS was tested in consecutive school-age children attending pediatric rheumatology clinics and was compared with an examination conducted, on the same day, by a pediatric rheumatologist who classified children as having abnormal or normal joints. Adult GALS was tested for validity compared with the pediatric rheumatologist's assessment and deficiencies in adult GALS were identified. Experts proposed amendments to adult GALS, achieving consensus by modified Delphi techniques. The resultant pediatric screening tool (pGALS) was tested (methodology identical to the testing of adult GALS) in an additional group of children. RESULTS: Adult GALS was tested in 50 children (median age 11 years, range 4-16), of whom 37 (74%) had juvenile idiopathic arthritis. Adult GALS missed important abnormalities in 18% of children, mostly at the ankle, foot, and temporomandibular joints. The pGALS was tested in 65 children (median age 13 years, range 5-17 years) and demonstrated excellent sensitivity (97-100%) and specificity (98-100%) at all joints, with high acceptability scored by child and parent/guardian. The median time to perform pGALS was 2 minutes (range 1.5-3 minutes). CONCLUSION: The pGALS musculoskeletal screening tool has excellent validity, is quick to perform, and is acceptable to school-age children and parents/guardians. We propose that pGALS be incorporated into undergraduate and postgraduate medical training to improve pediatric musculoskeletal clinical skills and facilitate diagnosis and referral to specialists.


Subject(s)
Joint Diseases/diagnosis , Mass Screening/methods , Musculoskeletal Diseases/diagnosis , Musculoskeletal System/physiopathology , Adolescent , Age Factors , Arthritis, Juvenile/diagnosis , Arthritis, Juvenile/physiopathology , Child , Child, Preschool , Education, Medical/trends , Female , Humans , Male , Musculoskeletal Diseases/physiopathology , Physical Examination/methods , Reproducibility of Results , Rheumatic Diseases/diagnosis , Rheumatic Diseases/physiopathology , Sensitivity and Specificity , Severity of Illness Index
8.
Rheumatology (Oxford) ; 45(11): 1376-9, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17040892

ABSTRACT

OBJECTIVES: The British Society for Rheumatology Biologics Register (BSRBR) is a prospective cohort study to determine the efficacy and toxicity of biological agents in rheumatoid arthritis (RA) patients compared with RA controls. Entry of patients to the register is a condition of use of anti-tumour necrosis factor (anti-TNF) therapy in the UK, but little is known of clinicians' views of its usefulness. Data from the register suggest uneven provision of anti-TNF-alpha therapy. METHODS: A questionnaire was sent on behalf of the BSRBR to all UK consultant rheumatologists concerning provision and use of anti-TNF-alpha therapy and their experience of working with the BSRBR. RESULTS: Response rate was 49.5% representing 252 consultants. Fourty-six per cent had some limitation of access to anti-TNF-alpha drugs, usually a financial cap (70%), even for RA patients meeting National Institute for Health and Clinical Excellence (NICE) criteria. Sixty-seven per cent could prescribe for ankylosing spondylitis (AS) or psoriatic arthritis (PsA) in some circumstances but only 25 and 35%, respectively, could prescribe according to BSR guidance. More than 50% found the workload involved in submitting data to the registry at least difficult, but most had favourable impressions of the BSRBR and thought similar registries desirable or essential for PsA, AS and rituximab. CONCLUSIONS: Access to anti-TNF therapy for patients with inflammatory arthritis is variable in the UK, even for RA where it is NICE-approved. Access is more limited for conditions where NICE has not yet issued guidance. The BSRBR generates a significant workload for rheumatology staff but is generally well-regarded.


Subject(s)
Antirheumatic Agents/pharmacology , Arthritis, Rheumatoid/drug therapy , Attitude of Health Personnel , Immunologic Factors/pharmacology , Registries , Rheumatology , Antirheumatic Agents/supply & distribution , Antirheumatic Agents/therapeutic use , Arthritis, Psoriatic/drug therapy , Consultants/psychology , Drug Prescriptions/standards , Drug Utilization/statistics & numerical data , Guideline Adherence/statistics & numerical data , Health Care Rationing/statistics & numerical data , Humans , Immunologic Factors/supply & distribution , Immunologic Factors/therapeutic use , Practice Guidelines as Topic , Spondylitis, Ankylosing/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , United Kingdom
9.
Rheumatology (Oxford) ; 44(6): 773-6, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15757963

ABSTRACT

OBJECTIVE: To quantify the frequency of siblings of patients with psoriatic arthritis (PsA) having psoriasis and/or inflammatory arthritis. To describe the similarity or otherwise of patterns of arthritis in siblings. METHODS: Available and consenting index cases with PsA and one or more siblings living locally were assessed. Mean sibling concordance rates and Weinberg's segregation analysis were calculated. Heritability was also estimated. To assess whether the same type of arthritis occurred within the same sibship, the dually affected sibships were then classified for type of arthritis according to methods suggested by Moll, Helliwell, Veale and McGonagle. RESULTS: Eighty index cases and 112 siblings were assessed. The median age of index cases was 49 yr (range 24-80 yr) and for siblings 46 yr (range 18-79 yr). The concordance rate for all types of PsA was 14% (9% if enthesitis is excluded) and for psoriasis 21%. There was no difference in the two methods used to calculate concordance rates. Sixteen dually affected sib pairs were found. Four of the 16 sibships (25%) had the same pattern of joint involvement (Moll and Wright classification). The most frequent pattern seen was joint involvement identical to rheumatoid arthritis (3/5). The most common symptom in affected siblings was enthesitis (approximately 5%). When the dually affected sibships were analysed using the other classifications, the simpler the classification the greater the concordance for joint pattern. CONCLUSION: The concordance for psoriasis is greater than for PsA, but the concordance rate for PsA was similar to that in HLA identical siblings with rheumatoid arthritis. There was discordance in pattern of arthritis for most sib pairs. There is no support for the use of more complex classifications of PsA.


Subject(s)
Psoriasis/etiology , Siblings , Adolescent , Adult , Age of Onset , Aged , Aged, 80 and over , Arthritis, Psoriatic/etiology , Arthritis, Psoriatic/genetics , Family Health , Female , Humans , Male , Middle Aged , Psoriasis/genetics , Recurrence , Rheumatoid Factor/analysis , Risk Factors
10.
Ann Rheum Dis ; 63(12): 1690-2, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15547098

ABSTRACT

OBJECTIVE: To review cases of stress fracture in patients with rheumatoid arthritis (RA) presenting to our service over a 10 year period; to identify possible risk factors and test these in a case-control study. METHODS: A retrospective case note review of all patients with a final diagnosis of stress fracture, presenting between 1990 and 1999 was performed. A case-control study of consecutive patients with RA, matched for age, sex and duration of disease, attending the same clinics. CASE SERIES: 24 stress fractures were identified in 18 patients, representing 0.8% of the RA clinic population; all were women, median age 69.5 years (range 47-79). Bone mineral densitometry showed median T scores of -3.06 and -2.27 SD at the hip and lumbar spine, respectively. Case-control study: In the stress fractures group, past steroid doses were higher (p = 0.003). No significant differences in the bone mineral density (BMD) T score at the hip or lumbar spine were found (p = 0.59, p = 0.77). CONCLUSIONS: Stress fractures are a significant cause of morbidity in RA. Diagnosis is often delayed and presentation can be misleading. Past steroid use, particularly at higher doses, confers an increased risk of stress fracture, but the increased risk is not attributable to osteoporosis as assessed by BMD.


Subject(s)
Arthritis, Rheumatoid/complications , Fractures, Stress/etiology , Adrenal Cortex Hormones/adverse effects , Aged , Antirheumatic Agents/adverse effects , Bone Density , Case-Control Studies , Female , Fractures, Stress/physiopathology , Humans , Middle Aged , Osteoporosis, Postmenopausal/etiology , Retrospective Studies , Risk Factors
11.
Rheumatology (Oxford) ; 43(8): 1045-9, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15187245

ABSTRACT

OBJECTIVES: The aim of this study was to describe the assessment of the musculoskeletal (MSK) system in comparison with other systems in routine paediatric medical clerking. Furthermore, to survey trainee paediatricians (SPRs, specialist registrars) about their self-rated confidence in assessing the MSK system. METHODS: Case notes of consecutive general paediatric medical patients admitted to three UK hospitals over a 4-week period were assessed using a standard pro forma. All patients had been assessed by a consultant paediatrician during their admission. A postal questionnaire was sent to all SPRs in training in each of the hospitals, regarding their confidence in assessing the MSK system compared with other systems and their exposure to MSK teaching. RESULTS: Case notes of 257 patients [117 females, median age 3 yr (range 1-18 yr)] were reviewed. The most common reason for admission was acute infection, although the spectrum of other recorded diagnoses varied between hospitals. Thirteen children (5%) had an acute problem (e.g. infection) against a background of chronic disease. The case note documentation showed that cardiovascular (CVS), respiratory (RS) and gastrointestinal (GI) systems were assessed in the vast majority (>90%) of patients, irrespective of the underlying diagnosis. However, other systems were less well recorded; the trend being the same in each hospital and in descending order, the neurological system (38%), skin (32%), eyes (10%) and musculoskeletal system (4%). Only 2.7% (7/257) patients were documented to have been asked about MSK symptoms, and only 1.6% (4/257) had any documentation of joint examination--in all cases this was limited (e.g. range of movement of the knee only), and no patients had documentation of gait being examined, even in those children presenting with 'limp'. The response rate to the postal questionnaire was 60% (67/112). The self-rated confidence in MSK assessment was markedly low in comparison with other systems, even though 61/67 recalled some teaching of the MSK system as an undergraduate (61/67) or postgraduate (50/67). Of note none could recall teaching as an undergraduate in paediatric MSK assessment and where there had been postgraduate rheumatology MSK teaching this had been delivered by paediatric rheumatologists in many cases (34/50), reflecting the centres participating in the study. CONCLUSIONS: In routine general paediatric medical in-patient clerking and throughout the admission, MSK assessment was rarely documented, and even where present was limited. This contrasts markedly with other systems which were examined in most children irrespective of the presenting complaint. Self-rated confidence in MSK assessment is low amongst SPRs compared with other systems, despite most recalling some teaching. This discrepancy between teaching and clinical practice needs to be addressed in undergraduate and postgraduate training.


Subject(s)
Musculoskeletal System/physiopathology , Adolescent , Attitude of Health Personnel , Child , Child, Preschool , Clinical Competence , Documentation/standards , Female , Hospitalization , Humans , Infant , Joints/physiopathology , Male , Medical History Taking/standards , Pediatrics/education , Physical Examination/standards , Retrospective Studies
12.
Rheumatology (Oxford) ; 43(8): 1034-8, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15150436

ABSTRACT

OBJECTIVES: Anti-tumour necrosis factor (anti-TNF) therapy is a highly effective treatment for rheumatoid arthritis (RA), as documented using standard outcome measures in clinical trials. Anecdotal experience suggests health benefits for patients other than those measured in this way. We wished to explore Patients' experience of and views about this treatment and the British Society for Rheumatology Biologics Registry (BSR BR) process. METHODS: Separate focus groups for patients treated with infliximab (n = 7) and etanercept (n = 12) were undertaken. They were taped and transcribed verbatim, analysed and subjected to peer review and themes were identified. RESULTS: Five main themes were identified: expectations of treatment, experience of treatment and its effects, concerns about taking a new class of drug, views about the BSR Biologics Registry process and costs. CONCLUSIONS: Patients' experience of anti-TNF therapy was good, particularly in terms of physical function and well-being, although it did not live up to the very high expectations of some patients. The BSR BR process caused initial apprehension but patients had personal and altruistic reasons for being happy to comply with monitoring requirements. Qualitative methods add to our understanding of the effects of anti-TNF therapy for people with RA.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Immunoglobulin G/therapeutic use , Patient Satisfaction , Receptors, Tumor Necrosis Factor/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/economics , Antirheumatic Agents/adverse effects , Antirheumatic Agents/economics , Attitude to Health , Costs and Cost Analysis , Etanercept , Female , Humans , Immunoglobulin G/adverse effects , Immunoglobulin G/economics , Infliximab , Male , Middle Aged , Practice Guidelines as Topic , Quality of Life , Registries , Societies, Medical , United Kingdom
13.
Scand J Rheumatol ; 33(1): 47-51, 2004.
Article in English | MEDLINE | ID: mdl-15124943

ABSTRACT

OBJECTIVES: To elicit the barriers to the effective teaching of musculoskeletal examination skills amongst medical students. METHODS: This was a qualitative study including six focus groups with specialities most often involved in delivering musculoskeletal clinical teaching: rheumatology, orthopaedics, general practice, and geriatrics. RESULTS: The main barriers to the delivery of effective clinical teaching included the lack of agreement on what to teach, lack of confidence in teaching amongst non-musculoskeletal specialities, and poor communication between specialities. CONCLUSIONS: There is a need to overcome the identified barriers if musculoskeletal clinical teaching to medical students is to be improved. In particular, there is a need to agree which examination skills medical students should learn.


Subject(s)
Clinical Competence , Education, Medical, Undergraduate/methods , Musculoskeletal Diseases/diagnosis , Physical Examination/methods , Teaching/methods , Adult , Educational Measurement , Family Practice/education , Female , Focus Groups , Geriatrics/education , Humans , Male , Musculoskeletal System/physiopathology , Orthopedics/education , Rheumatology/education , Students, Medical , United Kingdom
15.
Rheumatology (Oxford) ; 43(3): 272-6, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14523226

ABSTRACT

OBJECTIVE: To determine matrix metalloproteinase-1 (MMP-1) and tissue-inhibitor metalloproteinase-1 (TIMP-1) serum levels in patients with psoriatic arthritis (PsA) and to compare this with their siblings and local blood donor controls. PsA is an interesting condition in which to study metalloproteinases because there are variations in the level of destructiveness, including a significant proportion of cases without destructive change. This is unlike rheumatoid arthritis (RA) which is more uniformly destructive and where MMP-1/TIMP-1 levels are known to be elevated. METHODS: MMP-1 and TIMP-1 serum levels were determined by enzyme-linked immunosorbent assay (ELISA) in (a) index cases with PsA (subtype: RA n = 43, distal interphalangeal disease n = 2, oligoarticular n = 15, spondyloarthropathy n = 9, enthesitis n = 1), (b) siblings with PsA, (c) siblings with psoriasis (Ps), (d) unaffected siblings and (e) local controls. Patients with Ps were divided according to the onset of disease: type I disease, onset before age 40 yr and type II, onset after age 40 yr. RESULTS: MMP-1 and TIMP-1 levels were significantly increased in both the index cases and the group including all siblings compared with the controls (P < 0.0001). There was no statistical difference in MMP-1 or TIMP-1 levels between index cases and their siblings. There was no difference in serum MMP-1 level between the different subtypes (Moll and Wright) of PsA, but there was an increased level of serum TIMP-1 in patients with rheumatoid pattern (P = 0.05). In the index cases there were increased levels of TIMP-1 in type II onset psoriasis (P = 0.03) but no difference in MMP-1 levels. CONCLUSION: MMP-1 and TIMP-1 serum levels are elevated in PsA. This is greatest in RA pattern PsA. These levels were also elevated in unaffected siblings suggesting that genetic factors may be important. TIMP-1 levels were elevated in psoriasis alone, more so in late onset psoriasis, suggesting that the pathological processes of early and late onset psoriasis may be different.


Subject(s)
Arthritis, Psoriatic/enzymology , Matrix Metalloproteinase 1/blood , Tissue Inhibitor of Metalloproteinase-1/blood , Adult , Age of Onset , Case-Control Studies , Female , Humans , Male , Middle Aged , Psoriasis/enzymology , Siblings
17.
Rheumatology (Oxford) ; 42(12): 1518-22, 2003 Dec.
Article in English | MEDLINE | ID: mdl-12832716

ABSTRACT

OBJECTIVES: To investigate the ability of consultant rheumatologists and orthopaedic surgeons to communicate well with patients and to determine the validity of a structured proforma used to assess medical students' communication skills. METHODS: Seventy new patient appointments with consultant rheumatologists and orthopaedic surgeons were assessed for communication skills exhibited by the consultants and patient satisfaction. Communication skills were assessed using a proforma previously used to examine medical students, and patient ratings were obtained using visual analogue scales. RESULTS: Median scores attained using the structured proforma for rheumatology, elective orthopaedic and fracture clinic consultations were 17, 15 and 14 out of 20 (P < 0.05). Patient satisfaction scores were high in all three domains measured. Scores were statistically significantly higher for rheumatology appointments than in fracture clinic (median scores 29.5, 29.5 and 28 out of 30). Consultation durations varied, with a median of 23 min for rheumatology and 10.5 and 4 min for orthopaedic surgeons in clinic and fracture clinic, respectively. CONCLUSIONS: Consultant rheumatologists and orthopaedic surgeons demonstrate good communication skills, according to a tool used to assess medical students. These scores correlate with patient views, suggesting that teaching and assessment of communication skills at medical schools may address concerns of patients. Scores and satisfaction correlate with the duration of the consultation.


Subject(s)
Clinical Competence , Communication , Orthopedics/standards , Physician-Patient Relations , Rheumatology/standards , Education, Medical , Educational Measurement/methods , England , Hospital Units/standards , Humans , Linear Models , Patient Satisfaction , Referral and Consultation/standards , Reproducibility of Results , Time Factors
18.
Ann Rheum Dis ; 62(1): 20-6, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12480664

ABSTRACT

BACKGROUND: Although disease-specific health status measures are available for ankylosing spondylitis (AS), no instrument exists for assessing quality of life (QoL) in the condition. OBJECTIVE: To produce an AS-specific QoL measure that would be relevant and acceptable to respondents, valid, and reliable. METHODS: The ASQoL employs the needs-based model of QoL and was developed in parallel in the UK and the Netherlands (NL). Content was derived from interviews with patients in each country. Face and content validity were assessed through patient field test interviews (UK and NL). A postal survey in the UK produced a more efficient version of the ASQoL, which was tested for scaling properties, reliability, internal consistency, and validity in a further postal survey in each country. RESULTS: A 41 item questionnaire was derived from interview transcripts. Field testing interviews confirmed acceptability. Rasch analysis of data from the first survey (n=121) produced a 26 item questionnaire. Rasch analysis of data from the second survey (UK: n=164; NL: n=154) showed some item misfit, but showed that items formed a hierarchical order and were stable over time. Problematic items were removed giving an 18 item scale. Both language versions had excellent internal consistency (alpha=0.89-0.91), test-retest reliability (r(s)=0.92 UK and r(s)=0.91 NL), and validity. CONCLUSIONS: The ASQoL provides a valuable tool for assessing the impact of interventions for AS and for evaluating models of service delivery. It is well accepted by patients, taking about four minutes to complete, and has excellent scaling and psychometric properties.


Subject(s)
Quality of Life , Spondylitis, Ankylosing/psychology , Adult , Aged , Female , Health Status , Humans , Interviews as Topic , Male , Middle Aged , Sensitivity and Specificity , Surveys and Questionnaires
20.
Med Teach ; 23(6): 585-590, 2001 Oct.
Article in English | MEDLINE | ID: mdl-12098480

ABSTRACT

The objective was to determine whether routinely available textbooks describe the core musculoskeletal examination skills for medical students. Textbooks were evaluated for content against a list of 27 core examination skills as perceived by rheumatologists, orthopaedic surgeons and general practitioners. The study took place in Newcastle upon Tyne, libraries of the rheumatology department, teaching hospital and medical school. The main outcome was the inclusion of a description of examination skills by available textbooks. Median score for each textbook was only 19 (range 1-24) of a possible 27 core skills. Screening examination was not included in general texts. General principles were well covered but detail was insufficient, particularly in texts aimed at students taking final examinations. It is not easy for students to access adequate information about core items of musculoskeletal examination from textbooks readily available to them. This may reflect a general view of the lack of importance of musculoskeletal clinical examination skills.

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