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Biomedical subjects

K J Murray

Publications and source records attributed to K J Murray.

At least 19 recordsLinked to original sources
PubMed2006

The Juvenile Dermatomyositis National Registry and Repository (UK and Ireland)--clinical characteristics of children recruited within the first 5 yr.

OBJECTIVES: To identify epidemiological, clinical and laboratory characteristics of juvenile dermatomyositis (JDM) in a national multi-centre cohort of patients, and to review recent changes in the understanding of management and prognosis in the light of these data. METHODS: All children with idiopathic inflammatory myositis recruited to the Juvenile Dermatomyositis National Registry and Repository (UK and Ireland) were included. Features at presentation, and later in disease, were assessed and evaluated. A total of 63 out of 175 children with a new diagnosis of myositis were recruited at the time of diagnosis and followed prospectively. Out of the 175 children, 122 diagnosed prior to 2000 were recruited retrospectively, with subsequent data collected prospectively. RESULTS: One patient died (0.7%), which is equivalent to one death per 465 patient years. Data were available at the time of analysis on 151 registered patients. The most common presenting features were characteristic rash, weakness, tiredness, Gottron's patches and myalgia. Muscle biopsy, magnetic resonance imaging and muscle enzymes were frequently, but not always, abnormal. Muscle enzymes and erythrocyte sedimentation rate were not useful markers of disease activity. CONCLUSIONS: The JDM National Registry and Repository captures data on a significant cohort of children with inflammatory myositis. The current study reports the largest European cohort of children with dermatomyositis to date. This powerful resource will help improve our understanding of this rare disease. Prospective data collection will allow a fuller analysis of poor prognostic features, impact of therapy, and variable outcome of childhood myositis.

Adolescent↗
PubMed2006

Alternative donor bone marrow transplant for children with Philadelphia chromosome ALL.

Children with Philadelphia chromosome positive (Ph+) acute lymphocytic leukemia (ALL) have only a 20% event-free survival when treated with chemotherapy alone. Bone marrow transplant (BMT) for patients with matched siblings has been associated with significantly better long-term survival. We asked whether children who lack a matched sibling donor would do as well if an alternative donor was utilized. Between 1987 and 2002, we transplanted 29 children and adolescents using either an unrelated donor (23) or a mismatched family member (six). The conditioning regimen included cytosine-arabinoside, cyclophosphamide and total body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of T-cell depletion (antibody T10B9 or OKT3 and complement) with post transplant cyclosporine (CSA). All patients engrafted. Four developed grades III-IV acute GVHD. Three of 24 evaluable patients developed extensive chronic GVHD. Two patients died of relapse (7%). Two long-term survivors (>6 years) died of malignant glioblastoma multiforme. Event-free survival at 3, 5, and 10 years is 56, 51, and 46%, respectively. Five of six patients in >CR2 or relapse at the time of transplant died. Our data should encourage the use of alternative donor transplants early in the course of disease for children with Ph+ ALL.

Adolescent↗
PubMed2005

Joint hypermobility syndrome in childhood. A not so benign multisystem disorder?

OBJECTIVES: Joint hypermobility (JH) or "ligamentous laxity" is felt to be an underlying risk factor for many types of musculoskeletal presentation in paediatrics, and joint hypermobility syndrome (JHS) describes such disorders where symptoms become chronic, often more generalized and associated with functional impairment. Clinical features are felt to have much in common with more severe disorders, including Ehlers-Danlos syndrome (EDS), osteogenesis imperfecta and Marfan syndrome, although this has not been formally studied in children. We defined the clinical characteristics of all patients with joint hypermobility-related presentations seen from 1999 to 2002 in a tertiary referral paediatric rheumatology unit. METHODS: Patients were identified and recruited from paediatric rheumatology clinic and ward, and a dedicated paediatric rheumatology hypermobility clinic at Great Ormond Street Hospital. Data were collected retrospectively on the patients from the paediatric rheumatology clinics (1999-2002) and prospectively on patients seen in the hypermobility clinic (2000-2002). Specifically, historical details of developmental milestones, musculoskeletal or soft tissue diagnoses and symptoms, and significant past medical history were recorded. Examination features sought included measurements of joint and soft tissue laxity, and associated conditions such as scoliosis, dysmorphic features, cardiac murmurs and eye problems. RESULTS: One hundred and twenty-five children (64 females) were included on whom sufficient clinical data could be identified and who had clinical problems ascribed to JH present for longer than 3 months. Sixty-four were from the paediatric rheumatology clinic and 61 from the hypermobility clinic. No differences were found in any of the measures between the two populations and results are presented in a combined fashion. Three-quarters of referrals came from paediatricians and general practitioners but in only 10% was hypermobility recognized as a possible cause of joint complaint. The average age at onset of symptoms was 6.2 yr and age at diagnosis 9.0 yr, indicating a 2- to 3-yr delay in diagnosis. The major presenting complaint was arthralgia in 74%, abnormal gait in 10%, apparent joint deformity in 10% and back pain in 6%. Mean age at first walking was 15.0 months; 48% were considered "clumsy" and 36% as having poor coordination in early childhood. Twelve per cent had "clicky" hips at birth and 4% actual congenital dislocatable hip. Urinary tract infections were present in 13 and 6% of the female and male cases, respectively. Thirteen and 14%, respectively, had speech and learning difficulties diagnosed. A history of recurrent joint sprains was seen in 20% and actual subluxation/dislocation of joints in 10%. Forty per cent had experienced problems with handwriting tasks, 48% had major limitations of school-based physical education activities, 67% other physical activities and 41% had missed significant periods of schooling because of symptoms. Forty-three per cent described a history of easy bruising. Examination revealed that 94% scored > or =4/9 on the Beighton scale for generalized hypermobility, with knees (92%), elbows (87%), wrists (82%), hand metacarpophalangeal joints (79%), and ankles (75%) being most frequently involved. CONCLUSIONS: JHS is poorly recognized in children with a long delay in the time to diagnosis. Although there is a referral bias towards joint symptoms, a surprisingly large proportion is associated with significant neuromuscular and motor development problems. Our patients with JHS also show many overlap features with genetic disorders such as EDS and Marfan syndrome. The delay in diagnosis results in poor control of pain and disruption of normal home life, schooling and physical activities. Knowledge of the diagnosis and simple interventions are likely to be highly effective in reducing the morbidity and cost to the health and social services.

Adolescent↗
PubMed2004

Isolated inflammatory coxitis associated with protrusio acetabuli: a new form of juvenile idiopathic arthritis?

BACKGROUND: Isolated hip disease in the context of chronic childhood inflammatory arthritis is uncommon. This paper reports 14 children who presented to the rheumatology and orthopaedic departments of our hospitals with severe hip symptoms, and who continued to have primarily hip disease throughout their clinical course. Our aim was to characterize and present the relevant demographic, clinical, investigational, treatment and outcome data from the above cohort. METHODS: All paediatric cases with the diagnosis of protrusio acetabuli, Otto pelvis or idiopathic chondrolysis who were seen in the past 15 yr at Great Ormond Hospital and Middlesex Hospital in London were identified and their case notes were searched retrospectively for relevant information. RESULTS: In 11 cases, the disease progressed to involve no joints other than the contralateral hip. None were considered to have a specific subtype of juvenile idiopathic arthritis (JIA) and all tested were negative for HLA-B27. Elevation of serum inflammatory markers was variable. Protrusio acetabuli was the predominant radiological feature. There were definite inflammatory changes on the gadolinium-enhanced magnetic resonance imaging study in all patients who had this procedure performed (seven cases). Microbiological investigations were all consistently negative. Severe hip disease resulted in considerable ongoing symptoms and disability. Six cases were treated with disease-modifying anti-rheumatic drugs. Total hip replacement has been required in four patients to date, with major functional improvement. CONCLUSIONS: These cases represent severe and disabling primary hip disease with considerable clinical and investigational inflammatory features. Such a mode of presentation has not been described previously in the context of childhood chronic inflammatory arthritides, and may represent a separate oligoarthritis subtype of JIA.

Acetabulum↗
PubMed2004

Quantitative assessment of MRI T2 relaxation time of thigh muscles in juvenile dermatomyositis.

OBJECTIVE: The aim of the study was to examine the validity and reliability of a quantifiable measure of inflammation using magnetic resonance imaging (MRI) in children with juvenile dermatomyositis (JDM). METHODS: Children with active JDM, inactive JDM and healthy children received detailed assessments of recognized measures of muscle inflammation including muscle strength (manual muscle testing and myometry) and function (Childhood Myositis Assessment Scale, Childhood Health Assessment Questionnaire), the muscle enzymes lactate dehydrogenase (LDH) and creatine kinase (CK) and T2-weighted MRI scans of the thigh muscles, and these values were correlated with each other. RESULTS: Ten children with active JDM, 10 with inactive JDM and 20 healthy children completed the study. There was no significant difference in ages between the three groups. The MRI T2 relaxation times were significantly increased in active JDM compared with inactive JDM and healthy children (P = 0.05), indicating a detectable increase in inflammation within the muscles. There were also good correlations between the MRI scores and the measures of muscle strength and function; however, there was no correlation between the MRI and muscle enzymes. CONCLUSIONS: The MRI T2 relaxation time can be used as a quantitative measure of muscle inflammation and it has good correlations with other measures of disease activity.

Adolescent↗
PubMed2004

Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety.

OBJECTIVES: To assess the efficacy and safety of intravenous cyclophosphamide (CYP) used in severe and refractory juvenile dermatomyositis (JDM). METHODS: Retrospective case note review of the outcome of 12 patients. RESULTS: Assessment at 6 months of therapy in 10 of the 12 patients showed a significant improvement in muscle function as assessed by the Childhood Myositis Assessment Scale (CMAS) (P = 0.012), muscle strength (P = 0.008), global extramuscular disease score (P = 0.008), skin disease severity (P = 0.015) and lactate dehydrogenase (P = 0.028). There were reductions in creatine kinase, alanine aminotransferase, prednisolone dose and ESR, but these did not reach statistical significance. Clinical improvement was maintained after CYP until the most recent follow-up (between 6 months and 7 yr) and no severe side-effects were seen. Reversible complications included lymphopenia, herpes zoster infections and alopecia. The median cumulative dose was 4.6 g/m(2) (range 3-9 g/m(2)). The available evidence suggests that, at the doses required, risks of malignancy, infertility and gonadal failure are low. Two patients with severe treatment-resistant disease died after one dose of CYP, both of whom were ventilated prior to commencement of CYP and were thought to have died as a result of their severe disease process, and too early for clinical benefit to be obtained from the drug. CONCLUSIONS: In this cohort of children with severe and refractory JDM, CYP appeared to have provided major clinical benefit with no evidence of serious toxicity in the short term.

Antirheumatic Agents↗
PubMed2004

Advances in paediatric rheumatology: beyond NSAIDs and joint replacement.

Over the previous three decades there have been a number of dramatic changes in our understanding of both the pathogenesis and epidemiology of the rheumatic diseases of childhood. Improvements in the classification of paediatric-onset arthritides and international collaboration in terms of multicentre research have led to the development of new therapeutic agents and better methods of outcome assessment for these chronic and often disabling conditions. Fortunately for children with paediatric rheumatic diseases treatment regimes are now available that provide excellent disease control for many and remission induction for some. Challenges include clearer definition of the genetics and pathogenesis of the diseases, delineation of reliable biological markers for diagnosis and monitoring of disease activity. The future should also herald early identification of those with a poorer prognosis, together with the design of more powerful, safer and cheaper remission-inducing agents, given to the right patients at the right time.

Adolescent↗
PubMed2002

Juvenile-onset localized scleroderma activity detection by infrared thermography.

OBJECTIVE: The aim of this study was to define the clinical utility of infrared thermography in disease activity detection in localized scleroderma (LS). METHODS: We retrospectively reviewed 130 thermal images of 40 children with LS and calculated the sensitivity and specificity of thermography, comparing clinical descriptions of the lesions and contemporary thermographs. The reproducibility of thermography was calculated by using the weighted kappa coefficient to determine the level of agreement between two clinicians who reviewed the thermographs independently. RESULTS: The sensitivity of thermography was 92% and specificity was 68%. Full concordance between the two clinicians was observed in 91% of lesions, with a kappa score of 0.82, implying very high reproducibility of this technique. CONCLUSION: Our results demonstrate that thermography is a promising diagnostic tool when associated with clinical examination in discriminating disease activity, as long as it is applied to lesions without severe atrophy of the skin and subcutaneous fat. Further evaluation is needed to determine whether thermography can predict the future progression of lesions.

Age of Onset↗
PubMed2001

Incidence of and risk factors for diabetic retinopathy in diabetic clinic attenders.

The incidence and risk factors for the development of diabetic retinopathy during a mean (SD) follow-up period of 4.6 (2.9) (range 1-12.4) years have been examined among 3424 patients (1878 males and 1546 females) with diabetes mellitus from three outpatient clinics at the University Hospital, Nottingham. The mean (SD) age of participants was 49.2 (17.9) years with a mean (SD) duration of diabetes of 7.3 (9.0) years at initial registration. Among the 3424 patients free of retinopathy at initial registration who attended the clinic at least twice in the period 1979-1992, the incidence of any retinopathy was 59.6 (57.8 male and 61.8 female) per 1000 person-years based on 15,571 person-years of follow-up. The incidence rate of retinopathy was 72% higher among insulin-treated than among non-insulin-treated noninsulin-dependent diabetes mellitus (NIDDM) clinic attenders. Using a Cox's Proportional Hazards Model for insulin-dependent diabetes (IDDM) and NIDDM (insulin and non-insulin-treated) diabetes separately, longer duration of diabetes, higher systolic blood pressure and poor metabolic control were significant independent predictors of retinopathy for all three groups. Never smoking was a significant independent predictor of retinopathy for the insulin-dependent diabetes groups. Lower body mass index, proteinuria and age were predictors of retinopathy only for non-insulin-treated NIDDM patients. Gender and creatinine had no significant independent association with retinopathy when other covariates were considered. These findings will help the identification of those patients at particular risk of retinopathy so that clinic time for screening of eyes can be appropriately focused.

Ambulatory Care Facilities↗
PubMed2001

Central nervous system complications in two cases of juvenile onset dermatomyositis.

Central nervous system (CNS) complications are rarely reported in either juvenile or adult onset inflammatory myositides, such as dermatomyositis and polymyositis. We report two children, aged 4 and 10 yr respectively, with a diagnosis of juvenile dermatomyositis, both of whom subsequently developed clinical features of severe CNS involvement, possibly consistent with cerebral vasculopathy. One child died from apparent brainstem involvement; the other developed seizures, pseudoseizures and clinical depression which responded to aggressive immunosuppression. Although the vasculopathy or vasculitis underlying this disorder is known to have a systemic distribution, CNS involvement has rarely been reported and may be under-recognized.

Cerebrovascular Disorders↗
PubMed2001

Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders.

AIMS: To review the precipitating events, clinical features, treatment, and outcome of macrophage activation syndrome (MAS). METHODS: Retrospective review of cases of MAS from a prospectively collected database of children with rheumatic diseases from 1980 to 2000. RESULTS: Nine patients (eight girls) were considered to have evidence of MAS. The primary diagnosis was systemic onset juvenile idiopathic arthritis in seven, enthesitis related arthritis in one, and chronic infantile neurological cutaneous articular syndrome in one. Mean age of onset was 5.7 years, and duration prior to MAS, 4.2 years. No medication was identified as a trigger. Eight had infections prior to MAS; specific infectious agents were identified in four. High grade fever, new onset hepatosplenomegaly, and lymphadenopathy were common clinical features. Platelet counts fell dramatically, from an average of 346 to 99 x 10(9)/l. Mean erythrocyte sedimentation rate (in three patients) fell from 115 to 28 mm/h. Eight had abnormal liver function during the disease course, and six had coagulopathy. Bone marrow examination supported the diagnosis with definite haemophagocytosis in four of seven. All received high dose steroids (eight intravenous, one oral), five cyclosporin, two cyclophosphamide, and one antithymocyte globulin. Two of three patients with significant renal impairment died. CONCLUSION: MAS is a rare and potentially fatal complication of childhood rheumatic disorders. Most of our patients were female, and most cases were preceded by infection. Bone marrow studies support the diagnosis. Deranged renal function may be a poor prognostic sign. Aggressive early therapy is essential.

Adolescent↗
PubMed2001

Ligand binding to transmembrane receptors on intact cells or membrane vesicles measured in a homogeneous 1-microliter assay format.

We have developed homogeneous miniaturized assays to measure ligand binding to either intact cells or receptor-containing membrane fragments by analysis of particle brightness. As an example, the affinities and inhibition constants of fluorescently labeled interleukin-8 (IL-8) and a low-molecular-weight antagonist toward the receptors CXCR1 and CXCR2, which belong to the superfamily of G protein-coupled receptors (GPCRs), were determined. Although the results were generally comparable between the two approaches, the cell-based measurements revealed a more complex pattern of both ligand and inhibitor titration curves, pointing to the influence of intracellular regulatory events. Both the vesicle- and cell-based membrane receptor assays were successfully miniaturized to a total volume of 1 microl without compromising their sensitivity, indicating that screening of transmembrane receptors in these formats is feasible. This is the first report of a cellular ligand-binding assay performed in such low volumes. The resulting savings in reagent could potentially enable the use of primary cells for future HTS/ultra-HTS efforts.

Animals↗
PubMed2001

Co-existent sickle cell disease and juvenile rheumatoid arthritis. Two cases with delayed diagnosis and severe destructive arthropathy.

We describe 2 pediatric patients with sickle cell disease (SCD) who developed seropositive juvenile rheumatoid arthritis (JRA). Both patients have severe joint damage, the compound effect of both disease processes. The bone and cartilage destruction, which poses serious therapeutic challenges, highlights the difficulty of making a diagnosis of chronic inflammatory disease in the setting of SCD. There may be a correlation between increased levels of tumor necrosis factor-alpha in the synovial tissue of joints damaged by arthritis and local sickling. The resultant ischemia and corresponding inflammatory infiltrates could in turn worsen existing synovial proliferation and cartilage destruction as well as trigger further sickling.

Adolescent↗
PubMed2001

Juvenile idiopathic polyarticular arthritis and IgA deficiency in the 22q11 deletion syndrome.

Five patients with the 22q11 deletion syndrome (velocardiofacial syndrome) developed chronic inflammatory polyarticular arthritis. These new cases add to 8 previously reported and confirm the association. The arthritis in all cases was moderate to severe, but at least partially responsive to methotrexate and/or corticosteroids, and was clinically indistinguishable from juvenile idiopathic arthritis (JIA). Analysis of the total 13 patients indicates that 2 are rheumatoid factor positive, 6 are antinuclear antibody positive, 5 have subtle T cell deficiencies, and 6 have hypergammaglobulinemia. Of particular interest is the occurrence of IgA deficiency in 4 patients, including 2 from our own series. Although IgA deficiency is seen in both JIA (2-4%) and 22q11 deletion syndrome (2-4%), the prevalence of low IgA in this series (31%) is much greater than expected. This phenomenon and the true association of inflammatory arthritis and a chromosome deletion disorder provides further evidence of important genetic factors in the pathogenesis of JIA.

Adolescent↗
PubMed2000

Importance of the mini-mental status examination in the treatment of patients with brain metastases: a report from the Radiation Therapy Oncology Group protocol 91-04.

PURPOSE: Little information is available on the importance of pretreatment Mini-Mental Status Exam (MMSE) on long-term survival and neurologic function following treatment for unresectable brain metastases. This study examines the importance of the MMSE in predicting outcome in a group of patients treated with an accelerated fractionation regimen of 30 Gy in 10 daily fractions in 2 weeks. MATERIALS AND METHODS: The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastases were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. Two hundred twenty-four patients were entered on the accelerated fractionated arm, and 182 were eligible for analysis (7 patients were judged ineligible, no MMSE information in 29, no survival data in 1, no forms submitted in 1). RESULTS: Average age was 60 years; 58% were male and 25% had a single intracranial lesion on their pretherapy evaluation. KPS was 70 in 32%, 80 in 31%, 90 in 29%, and 100 in 14%. The average MMSE was 26.5, which is the lower quartile for normal in the U.S. population. The range of the MMSE scores was 11-30 with 30 being the maximum. A score of less than 23 indicates possible dementia, which occurred in 16% of the patients prior to treatment. The median time from diagnosis to treatment was 5 days (range, 0-158 days). The median survival was 4.2 months with a 95% confidence interval of 3.7-5.1 months. Thirty-seven percent of the patients were alive at 6 months, and 17% were alive at 1 year. The following variables were examined in a Cox proportional-hazards model to determine their prognostic value for overall survival: age, gender, KPS, baseline MMSE, time until MMSE below 23, time since diagnosis, number of brain metastases, and radiosurgery eligibility. In all Cox model analyses, age, KPS, baseline MMSE, time until MMSE below 23, and time since diagnosis were treated as continuous variables. Statistically significant factors for survival were pretreatment MMSE (p = 0.0002), and KPS (p = 0.02). Age was of borderline significance (p = 0.065) as well as gender (p = 0.074). A poorer outcome is associated with an increasing age, male gender, lower MMSE, and shorter time until MMSE below 23. Improvement in MMSE over time was assessed; 62 patients died prior to obtaining follow-up MMSE, and 30 patients had a baseline MMSE of 30 (the maximum), and, therefore, no improvement could be expected. Of the remaining 88, 48 (54.5%) demonstrated an improvement in their MMSE at any follow-up visit. Lack of decline of MMSE below 23 was seen in long-term survivors, with 81% at 6 months and 66% at 1 year of patients maintaining a MMSE above 23. Analysis of time until death from brain metastases demonstrated that decreasing baseline MMSE (p = 0.003) and primary site (breast vs. lung vs. other p = 0.032) were highly associated with a terminal event. CONCLUSION: While gender and perhaps age remain significant predictors for survival, MMSE is also an important way of assessing a patient's outcome. Accelerated fractionation used in the treatment of brain metastases (30 Gy in 10 fractions) appears to also be associated with an improvement in MMSE and a lack of decline of MMSE below 23 in long-term survivors.

Adult↗
PubMed2000

Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription.

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3. RESULTS: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3alpha in vitro, with K(i)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3beta with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a beta-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase. CONCLUSIONS: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.

Adenosine Triphosphate↗