WAGR syndrome is characterized by Wilm's tumor, aniridia, genitourinary abnormalities and intellectual disabilities. WAGR is caused by a chromosomal deletion that includes the PAX6, WT1 and PRRG4 ...genes. PRRG4 is proposed to contribute to the autistic symptoms of WAGR syndrome, but the molecular function of PRRG4 genes remains unknown. The Drosophila commissureless (comm) gene encodes a short transmembrane protein characterized by PY motifs, features that are shared by the PRRG4 protein. Comm intercepts the Robo axon guidance receptor in the ER/Golgi and targets Robo for degradation, allowing commissural axons to cross the CNS midline. Expression of human Robo1 in the fly CNS increases midline crossing and this was enhanced by co-expression of PRRG4, but not CYYR, Shisa or the yeast Rcr genes. In cell culture experiments, PRRG4 could re-localize hRobo1 from the cell surface, suggesting that PRRG4 is a functional homologue of Comm. Comm is required for axon guidance and synapse formation in the fly, so PRRG4 could contribute to the autistic symptoms of WAGR by disturbing either of these processes in the developing human brain.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Homeostatic synaptic plasticity (HSP) involves compensatory mechanisms employed by neurons and circuits to preserve signaling when confronted with global changes in activity that may occur during ...physiological and pathological conditions. Cholinergic neurons, which are especially affected in some pathologies, have recently been shown to exhibit HSP mediated by nicotinic acetylcholine receptors (nAChRs). In Drosophila central neurons, pharmacological blockade of activity induces a homeostatic response mediated by the Drosophila α7 (Dα7) nAChR, which is tuned by a subsequent increase in expression of the voltage-dependent Kv4/Shal channel. Here, we show that an in vivo reduction of cholinergic signaling induces HSP mediated by Dα7 nAChRs, and this upregulation of Dα7 itself is sufficient to trigger transcriptional activation, mediated by nuclear factor of activated T cells (NFAT), of the Kv4/Shal gene, revealing a receptor-ion channel system coupled for homeostatic tuning in cholinergic neurons.
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•Inhibiting activity induces an increase in mEPSCs and Dα7 nAChR protein•Inhibiting activity induces upregulation of Kv4/Shal mRNA, protein, and current•Increasing Dα7 and/or NACHO is sufficient to induce upregulation of Kv4/Shal•Inactivity-induced upregulation of Kv4/Shal requires transcription factor NFAT
Eadaim et al. show that in vivo reduction of cholinergic signaling in Drosophila neurons induces synaptic homeostasis mediated by Dα7 nAChRs. This upregulation of Dα7 induces Kv4/Shal gene expression mediated by nuclear factor of activated T cells (NFAT), revealing a receptor-ion channel system coupled for homeostatic tuning in cholinergic neurons.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Rheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these "at-risk" stages is not well described. This study ...assessed health-related quality of life (HRQoL), function, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) or RA.
Cross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in patients from the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F. PROMs were compared across CSA, UA and RA and with population averages from the HSE with descriptive statistics. Multivariate linear regression assessed associations between PROMs and clinical and sociodemographic variables.
Of 838 patients included in the analysis, 484 had RA, 200 had CSA and 154 had UA. Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. However, "mean EQ-5D utilities were 0.65 (95%CI: 0.61 to 0.69) in CSA, 0.61 (0.56 to 0.66) in UA and 0.47 (0.44 to 0.50) in RA, which was lower than in general and older (≥ 65 years) background populations." In patients with CSA or UA, HRQoL was comparable to chronic conditions such as heart failure, severe COPD or mild angina. Higher BMI and older age (≥ 60 years) predicted worse depression (PHQ-9: -2.47 (-3.85 to -1.09), P < 0.001) and fatigue (FACIT-F: 5.05 (2.37 to 7.73), P < 0.001). Women were more likely to report worse function (HAQ-DI: 0.13 (0.03 to 0.21), P = 0.01) and fatigue (FACIT-F: -3.64 (-5.59 to -1.70), P < 0.001), and residents of more deprived areas experienced decreased function (HAQ-DI: 0.23 (0.10 to 0.36), P = 0.001), greater depression (PHQ-9: 1.89 (0.59 to 3.18), P = 0.004) and fatigue (FACIT-F: -2.60 (-5.11 to 0.09), P = 0.04). After adjustments for confounding factors, diagnostic category was not associated with PROMs, but disease activity and polypharmacy were associated with poorer performance across all PROMs.
Patient-reported outcomes were associated with disease activity and sociodemographic characteristics. Patients presenting with RA reported a higher health burden than those with CSA or UA, however HRQoL in the pre-RA groups was significantly lower than population averages.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background/Aims
Methotrexate (MTX) is a drug used to treat inflammatory arthropathies. A significant side effect of MTX is liver fibrosis. There are numerous ways to screen for liver ...fibrosis, liver biopsy being the gold-standard, but its invasive nature and accompanying adverse effects limits its utility as a screening tool. Guidelines advise the use of liver function tests, yet liver enzymes and synthetic liver function may be normal even in advanced disease. This leaves the question of the best screening tool for liver fibrosis unanswered. This data collection seeks to explore the utility of FibroScan in the screening of liver fibrosis in rheumatoid arthritis and psoriatic arthritis patients taking long-term methotrexate.
Methods
A hospital-based survey was conducted where electronic records of rheumatoid and psoriatic arthritis patients, who were referred for FibroScan due to being on long-term methotrexate therapy, were reviewed. Long-term MTX therapy was defined as MTX use of greater than ten years. The following data were collected: demographics, BMI, MTX duration, results of FibroScan, and impact on management. The primary outcome was to determine whether FibroScan altered the patients’ management as this has not been tested in the literature previously. ‘Change of management' was defined as reduction of MTX dose or cessation of MTX therapy. Three secondary outcomes were assessed. Firstly, relationship of BMI (body mass index) with FibroScan result. FibroScan result consisted of median elastography and controlled attenuation parameter (CAP). Secondly, relationship of BMI with impact on management. Finally, relationship of MTX therapy duration with impact on management.
Results
A total of 16 patients were identified. With regards to primary outcome, 29.4% of patients had their management changed secondary to FibroScan. In terms of secondary outcomes, positive correlations were found between BMI and median elastography and CAP. Mean BMI was greater in patients who had their management changed. Patients whose MTX was stopped had a greater mean MTX therapy duration.
Conclusion
These data show the utility of FibroScan to screen for liver fibrosis in patients on long-term MTX therapy. It recommends that practitioners consider FibroScan in patients who have been taking MTX for longer than 10 years, especially if they have associated risk factors such as high BMI.
Disclosure
M.H. Amin: None. E. Justice: None.
We present the case of a 49-year-old woman with a seronegative rheumatoid arthritis who developed pustular psoriasis whilst on etanercept and subsequently developed disseminated herpes simplex on ...infliximab.
Our patient presented with an inflammatory arthritis which failed to respond to both methotrexate and leflunomide, and sulphasalazine treatment led to side effects. She was started on etanercept but after 8 months of treatment developed scaly pustular lesions on her palms and soles typical of pustular psoriasis. Following the discontinuation of etanercept, our patient required high doses of oral prednisolone to control her inflammatory arthritis. A second biologic agent, infliximab, was introduced in addition to low-dose methotrexate and 15 mg of oral prednisolone. However, after just 3 infusions of infliximab, she was admitted to hospital with a fever, widespread itchy vesicular rash and worsening inflammatory arthritis. Fluid from skin vesicles examined by polymerase chain reaction showed Herpes Simplex Virus type 1. Blood cultures were negative and her chest X-ray was normal. Her infliximab was discontinued and she was started on acyclovir, 800 mg five times daily for 2 weeks. She made a good recovery with improvement in her skin within 48 hours.She continued for 2 months on a prophylactic dose of 400 mg bd. Her rheumatoid arthritis became increasingly active and a decision was made to introduce adalimumab alongside acyclovir. Acyclovir prophylaxis has been continued but the dose tapered so that she is taking only 200 mg of acyclovir on alternate days. There has been no recurrence of Herpes Simplex Virus lesions despite increasing adalimumab to 40 mg weekly 3 months after starting treatment.
We believe this to be the first reported case of widespread cutaneous Herpes Simplex Virus type 1 infection following treatment with infliximab. We discuss the clinical manifestations of Herpes Simplex Virus infections with particular emphasis on the immunosuppressed patient and the use of prophylactic acyclovir. Pustular psoriasis is now a well recognised but uncommon side effect of antitumour necrosis factor therapy and can lead to cessation of therapy, as in our patient's case.
Abstract
Background
A 49 year old male patient presented to the acute medical unit with history of acute onset high grade fever with polyarthritis involving right knee, left elbow, both ankles and ...small joints of right hand preceded by 2 days of diarrhoea and vomiting. He had temperature of 38°C, BP: 156/77 mmHg, Pulse rate: 98/min. Initial blood tests: CRP: 312, ESR: 51, and leucocytosis (WBC count: 17.9 with neutrophilia: 13.1). The medical team considered diagnosis of multifocal septic arthritis and initiated IV flucloxacillin empirically. He had past medical history of recently treated extra pulmonary tuberculosis three months prior to admission.
Methods
CT thorax abdomen and pelvis scan was organised to rule out reactivation of tuberculosis/Poncet’s arthritis. CT revealed generalised lymphadenopathy and bilateral hip effusions. At this point, a Rheumatology opinion was requested, a synovial fluid aspiration from the right knee, the most affected joint, was performed. The turbid sample had numerous pus cells, but negative gram stain and negative cultures after prolonged culture. AFB stain was negative. He was improving systemically but had intermittent fevers and CRP remained high (155mg/l). Synovial fluid sample was sent for 16S PCR testing and Streptococcus pyogenes ribosomal DNA was detected. Testing for serum ASO titres revealed elevated titres (32000 IU/mL). In conjunction with microbiology team, we augmented antibiotics to IV Gentamicin and IV Ceftriaxone. A careful history revealed transient throat infection of 6 hours duration 10 days prior to onset of arthritis. Urinary dipstick and ACR revealed proteinuria (ACR 84.8). This is under close follow-up with renal team who feel that post Streptococcal Glomerular Nephritis is likely but deferred renal biopsy. 2 DECHO study ruled out valve abnormality. A right inguinal lymph node biopsy was attempted; however, tissue sample was unsuitable. Hepatitis screen was negative and Antibody panel (ANA, ANCA were negative, RF: borderline positive (26) were unremarkable. He received total duration of 31 days of antibiotics. CRP eventually improved to 13, on follow up, in view of persisting arthritis, orals steroids (15mg OD) was prescribed for three weeks.
Results
Thus, we achieved a compelling diagnosis of acute rheumatic fever, with possible focus in the throat and probably bacteraemic spread to the right knee. PCR analysis of synovial fluid in context of negative culture guided antibiotic therapy choice, duration and cautious approach for immunosuppression. The patient’s story evolved with development of proteinuria suggestive of possible post streptococcal glomerulonephritis which is under follow up.
Conclusion
Rheumatologists are faced with challenge of reviewing ill patients with joint effusions in whom empirical antibiotics have been started. In this scenario, joint aspiration yields lower positive culture results. 16S PCR analysis can help in guiding antibiotic choice and duration with negative culture.
Disclosures
A. Desai None. E. Justice None. M. Rahman None. A. Johnson None.
Abstract
Objectives
The value of US-defined tenosynovitis in predicting the persistence of inflammatory arthritis is not well described. In particular, the predictive utility of US-defined ...tenosynovitis of larger tendons is yet to be reported. We assessed the value of US-defined tenosynovitis alongside US-defined synovitis and clinical and serological variables in predicting persistent arthritis in an inception cohort of DMARD-naïve patients with early arthritis.
Methods
One hundred and fifty DMARD-naïve patients with clinically apparent synovitis of one or more joints and a symptom duration of ≤3 months underwent baseline clinical, laboratory and US (of 19 bilateral joints and 16 bilateral tendon compartments) assessments. Outcomes were classified as persistent or resolving arthritis after 18 months’ follow-up. The predictive value of US-defined tenosynovitis for persistent arthritis was compared with those of US-defined synovitis, and clinical and serological variables.
Results
At 18 months, 99 patients (66%) had developed persistent arthritis and 51 patients (34%) had resolving disease. Multivariate logistic regression analysis showed that US-detected digit flexor tenosynovitis odds ratio (OR): 6.6, 95% CI: 2.0 , 22.1, P = 0.002 provided independent predictive data for persistence over and above the presence of US-detected joint synovitis and RF antibodies. In the RF/ACPA-negative subcohort, US-defined digit flexor tenosynovitis remained a significant predictive variable (OR: 4.7, 95% CI: 1.4, 15.8, P = 0.012), even after adjusting for US-defined joint synovitis.
Conclusion
US-defined tenosynovitis provided independent predictive data for the development of persistent arthritis. The predictive role of US-defined digit flexor tenosynovitis should be further assessed; investigators should consider including this tendon site as a candidate variable when designing imaging-based predictive algorithms for persistent inflammatory arthritis development.
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