A study of the influence of ethnicity on serology and clinical features in lupus

OBJECTIVE: The objective of this study was to review the links between ethnicity, serology and clinical expression in systemic lupus erythematosus (SLE) in a single cohort that was followed over a 36-year period. PATIENTS AND METHODS: Patients with SLE treated at the University College London Hospitals (UCLHs) between January 1978 and December 2013 formed the cohort. We assessed the demographic, clinical and serological data. Standard methods were used for laboratory testing. The Student t test and Mann-Whitney U test were used for the continuous variables; the Fisher's exact test was used for the categorical variables. RESULTS: We studied 624 SLE patients: There were 571 women (91.5%), with a mean age at diagnosis of 29.0 ± 6.5 years; and 53 men (8.5%), with a mean age at diagnosis of 29.4 ± 15.3 years. Ethnically, 369 of the patients were European, 100 were Afro-Caribbean, 77 were East Asian, 56 were South Asian and 21 were of mixed ethnicity. The East Asian patients developed the disease at a younger age than the other ethnic groups (p < 0.0001). The Afro-Caribbean patients were less frequently associated with the presence of rash and photosensitivity, and the non-European patients were more likely to have alopecia and renal involvement. The South Asian patients were significantly associated with musculoskeletal and neurological involvement, serositis, Sicca syndrome and hematological features. The Afro-Caribbean patients had the highest prevalence of anti-Smith, anti-RNP, anti-Ro and anti-La antibodies. Anti-IgG anticardiolipin (aCL) antibodies were significantly associated with the non-East Asian groups; and hypocomplementemia was common in the East Asians. Rash, alopecia, mouth ulcers, serositis, neurological, joint and renal involvement were significantly associated with the presence of anti-Smith and anti-RNP antibodies in the Afro-Caribbean group. We also observed an association of joint involvement and the presence of anti-Ro and anti-La antibodies in this group. CONCLUSIONS: The East Asian patients developed their SLE disease at a younger age than the other ethnic groups. Cutaneous involvement was more frequent in those who were not Afro-Caribbean. Serositis, joint and neurological involvement were more frequently diagnosed in the South Asian patients. Anti-ENA antibodies were frequently associated with the Afro-Caribbean patients

Advances in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a heterogeneous course and systemic involvement. It is the result of a complex pathogenic pathway that culminates in autoantibody formation. The interaction between environmental triggers and genetic susceptibility is key in this process. Genome-wide association study technology has allowed the recognition of > 80 loci associated with SLE that lead to the formation of key proteins, each contributing a small increase to the risk. Advances in the management of the disease include new validated standardized tools to capture disease activity, damage and quality of life, for clinical and research purposes. The prognosis of SLE has much improved in the last 50 years because of better general management and specific treatment, including better use of immunosuppressive agents and development of a new group of drugs – biological therapies

Renal transplantation for lupus nephritis: non-adherence and graft survival

Objectives: Poor adherence to immunosuppressive treatment is common in patients with systemic lupus erythematosus and may identify those with lupus nephritis (LN) who have a poorer prognosis. Non-adherence has also been reported to be a potential adverse outcome predictor in renal transplantation (rTp). We investigated whether non-adherence is associated with increased rTp graft rejection and/or failure in patients with LN. Methods: Patients with LN undergoing rTp in two major London hospitals were retrospectively included. Medical and electronic records were reviewed for documented concerns of non-adherence as well as laboratory biochemical drug levels. The role of non-adherence and other potential predictors of graft rejection/failure including demographics, comorbidities, age at systemic lupus erythematosus and LN diagnosis, type of LN, time on dialysis prior to rTp and medication use were investigated using logistic regression. Results: Out of 361 patients with LN, 40 had rTp. During a median follow-up of 8.7 years, 17/40 (42.5%) of these patients had evidence of non-adherence. A total of 12 (30.0%) patients experienced graft rejection or failure or both. In the adherent group 2/23 (8.7%) had graft rejection, whilst in the non-adherent this rose to 5/17 (29.4%, p = 0.11). Graft failure was seen in 5/23 (21.7%) patients from the adherent group and 4/17 (23.5%) in the non-adherent group (p = 0.89). Non-adherent patients had a trend towards increased graft rejection, hazard ratio 4.38, 95% confidence interval = 0.73–26.12, p = 0.11. Patients who spent more time on dialysis prior to rTp were more likely to be adherent to medication, p = 0.01. Conclusion: Poor adherence to immunosuppressive therapy is common and has been shown to associate with a trend towards increased graft failure in patients with LN requiring rTp. This is the first paper to report that shorter periods on dialysis prior to transplantation might lead to increased non-adherence in lupus patients

Looking inside the spiky bits : a critical review and conceptualisation of entrepreneurial ecosystems

The authors wish to thank the Organisational for Economic Cooperation and Development (OECD) for funding their original research on entrepreneurial ecosystems.The concept of entrepreneurial ecosystems has quickly established itself as one of the latest ‘fads’ in entrepreneurship research. At face value, this kind of systemic approach to entrepreneurship offers a new and distinctive path for scholars and policy makers to help understand and foster growth-oriented entrepreneurship. However, its lack of specification and conceptual limitations has undoubtedly hindered our understanding of these complex organisms. Indeed, the rapid adoption of the concept has tended to overlook the heterogeneous nature of ecosystems. This paper provides a critical review and conceptualisation of the ecosystems concept: it unpacks the dynamics of the concept; outlines its theoretical limitations; measurement approaches and use in policy-making. It sets out a preliminary taxonomy of different archetypal ecosystems. The paper concludes that entrepreneurial ecosystems are a highly variegated, multi-actor and multi-scalar phenomenon, requiring bespoke policy interventions.Publisher PDFPeer reviewe

Musculoskeletal complications of haematological disease

Rheumatological manifestations complicate many benign and malignant blood disorders. Significant advances in haematology, with improved diagnostic techniques and newer musculoskeletal imaging, have occurred in the past two decades. This review focuses on the interrelationship between the major haematological diseases (haemochromatosis, haemophilia, sickle cell disease, thalassaemia, leukaemia, lymphoma, myelodysplastic syndromes, multiple myeloma and cryoglobulinaemia) and rheumatic manifestations

Patient Uncertainty Questionnaire-Rheumatology (PUQ-R): development and validation of a new patient-reported outcome instrument for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in a mixed methods study

Background An in-depth qualitative exploration of uncertainty in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) led to the development of a five-domain conceptual framework of patient uncertainty in these two conditions. The purpose of this study was to develop and evaluate a new patient-reported outcome (PRO) instrument for patient uncertainty in SLE and RA on the basis of this empirically developed conceptual framework. Methods Cognitive debriefing interviews were conducted to pre-test the initial items generated on the basis of the preliminary qualitative exploration of patient uncertainty in SLE and RA. Two separate field tests were conducted in five hospital sites to evaluate the measurement properties of the new instrument; the first to identify and form scales, and the second to assess measurement properties of the final version in an independent sample. Psychometric evaluation was conducted in line with the Rasch Measurement Theory (RMT), examining the extent to which sample to scale targeting was satisfactory, measurement scales were constructed effectively and the sample was measured successfully. Traditional psychometric techniques were also used to provide complementary analyses best understood by clinicians. Results Pre-testing supported the relevance, acceptability and comprehensibility of the initial items. Findings indicated that the Patient Uncertainty Questionnaire for Rheumatology PUQ-R instrument fulfilled the expectations of RMT to a large extent (including person separation index 0.73 – 0.91). The PUQ-R comprises 49 items across five scales; symptoms and flares (14 items), medication (11 items), trust in doctor (8 items), self-management (6 items) and impact (10 items) which further displayed excellent measurement properties as assessed against the traditional psychometric criteria (including Cronbach’s alpha 0.82 – 0.93). Conclusion The PUQ-R has been developed and evaluated specifically for patients with SLE and RA. By quantifying uncertainty, the PUQ-R has the potential to support evidence-based management programmes and research

The 100 most cited articles investigating the radiological staging of oesophageal and junctional cancer: a bibliometric analysis

Objectives Accurate staging of oesophageal cancer (OC) is vital. Bibliometric analysis highlights key topics and publications that have shaped understanding of a subject. The 100 most cited articles investigating radiological staging of OC are identified. Methods The Thomas Reuters Web of Science database with search terms including “CT, PET, EUS, oesophageal and gastro-oesophageal junction cancer” was used to identify all English language, full-script articles. The 100 most cited articles were further analysed by topic, journal, author, year and institution. Results A total of 5,500 eligible papers were returned. The most cited paper was Flamen et al. (n = 306), investigating the utility of positron emission tomography (PET) for the staging of patients with potentially operable OC. The most common research topic was accuracy of staging investigations (n = 63). The article with the highest citation rate (38.00), defined as the number of citations divided by the number of complete years published, was Tixier et al. investigating PET texture analysis to predict treatment response to neo-adjuvant chemo-radiotherapy, cited 114 times since publication in 2011. Conclusion This bibliometric analysis has identified key publications regarded as important in radiological OC staging. Articles with the highest citation rates all investigated PET imaging, suggesting this modality could be the focus of future research

The effects of upper and lower limb exercise on the microvascular reactivity in limited cutaneous systemic sclerosis patients

Background: Aerobic exercise in general and high intensity interval training (HIIT) specifically is known to improve vascular function in a range of clinical conditions. HIIT in particular has demonstrated improvements in clinical outcomes, in conditions that have a strong macroangiopathic component. Nevertheless, the effect of HIIT on microcirculation in systemic sclerosis (SSc) patients is yet to be investigated. Therefore, the purpose of the study was to compare the effects of two HIIT protocols (cycle and arm cranking) on the microcirculation of the digital area in SSc patients. Methods: Thirty four limited cutaneous SSc patients (65.3 ± 11.6 years old) were randomly allocated in three groups (cycling, arm cranking and control group). The exercise groups underwent a twelve-week exercise program twice per week. All patients performed the baseline and post-exercise intervention measurements where physical fitness, functional ability, transcutaneous oxygen tension (ΔtcpO2), body composition and quality of life were assessed. Endothelial-dependent as well as-independent vasodilation were assessed in the middle and index fingers using LDF and incremental doses of acetylcholine (ACh) and sodium nitroprusside (SNP). Cutaneous flux data were expressed as cutaneous vascular conductance (CVC). Results: Peak oxygen uptake increased in both exercise groups (p<0.01, d=1.36). ΔtcpO2 demonstrated an increase in the arm cranking group only, with a large effect, but not found statistically significant,(p=0.59, d=0.93). Endothelial-dependent vasodilation improvement was greater in the arm cranking (p<0.05, d=1.07) in comparison to other groups. Both exercise groups improved life satisfaction (p<0.001) as well as reduced discomfort and pain due to Raynaud's phenomenon (p<0.05). Arm cranking seems to be the preferred mode of exercise for study participants as compared to cycling (p<0.05). No changes were observed in the body composition or the functional ability in both exercise groups. Conclusion: Our results suggest that arm cranking has the potential to improve the microvascular endothelial function in SSc patients. Also notably, our recommended training dose (e.g., a 12-week HIIT program, twice per week), appeared to be sufficient and tolerable for this population. Future research should focus on exploring the feasibility of a combined exercise such as aerobic and resistance training by assessing individual's experience and the quality of life in SSc patients. Trial registration: ClinicalTrials.gov (NCT number): NCT03058887, February 23, 2017, https://clinicaltrials.gov/ct2/show/NCT03058887?term=NCT03058887&rank=1 Key words: High intensity interval training, vascular function, quality of lif

Pharmacologic targeting of renal ischemia-reperfusion injury using a normothermic machine perfusion platform.

Normothermic machine perfusion (NMP) is an emerging modality for kidney preservation prior to transplantation. NMP may allow directed pharmacomodulation of renal ischemia-reperfusion injury (IRI) without the need for systemic donor/recipient therapies. Three proven anti-IRI agents not in widespread clinical use, CD47-blocking antibody (αCD47Ab), soluble complement receptor 1 (sCR1), and recombinant thrombomodulin (rTM), were compared in a murine model of kidney IRI. The most effective agent was then utilized in a custom NMP circuit for the treatment of isolated porcine kidneys, ascertaining the impact of the drug on perfusion and IRI-related parameters. αCD47Ab conferred the greatest protection against IRI in mice after 24 hours. αCD47Ab was therefore chosen as the candidate agent for addition to the NMP circuit. CD47 receptor binding was demonstrated by immunofluorescence. Renal perfusion/flow improved with CD47 blockade, with a corresponding reduction in oxidative stress and histologic damage compared to untreated NMP kidneys. Tubular and glomerular functional parameters were not significantly impacted by αCD47Ab treatment during NMP. In a murine renal IRI model, αCD47Ab was confirmed as a superior anti-IRI agent compared to therapies targeting other pathways. NMP enabled effective, direct delivery of this drug to porcine kidneys, although further efficacy needs to be proven in the transplantation setting

E2F-1 Directly Regulates Thrombospondin 1 Expression

Thrombospondin 1 (TSP1) has been shown to play a critical role in inhibiting angiogenesis, resulting in inhibition of tumor growth and metastases. To figure out TSP1's regulators will lead to reveal its biological function mechanistically. In this study, we show that E2F-1 could activate the transcription of TSP1 by both promoter assays and Northern blot. Analysis of various TSP1 promoter mutant constructs showed that a sequence located −144/−137 up-stream of the transcriptional initiation site, related to the consensus E2F-responsive sequence, is necessary for the activation. In consistence with up-regulation of TSP-1 activity by over-expression of E2F-1, the knockdown of endogenous E2F-1 inhibited TSP-1 promoter activity significantly, implying that E2F-1 mediated regulation of TSP-1 is relevant in vivo. In addition, E2F-1 could also directly bind to the TSP1 promoter region covering −144/−137 region as revealed by ChIP assays. Furthermore, the E2F-1-induced activation of TSP1 gene transcription is suppressed by pRB1 in a dose-dependent manner. Taken together, the results demonstrate that TSP1 is a novel target for E2F1, which might imply that E2F-1 can affect angiogenesis by modulating TSP1 expression