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1.  Lymphoma risk in systemic lupus: effects of disease activity versus treatment 
Annals of the rheumatic diseases  2013;73(1):10.1136/annrheumdis-2012-202099.
To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE).
We performed case–cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogren’s syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses.
We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls.
In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.
PMCID: PMC3855611  PMID: 23303389
4.  Exogenous Proline and Glycine Betaine Mediated Upregulation of Antioxidant Defense and Glyoxalase Systems Provides Better Protection against Salt-Induced Oxidative Stress in Two Rice (Oryza sativa L.) Varieties 
BioMed Research International  2014;2014:757219.
The present study investigates the roles of exogenous proline (Pro, 5 mM) and glycine betaine (GB, 5 mM) in improving salt stress tolerance in salt sensitive (BRRI dhan49) and salt tolerant (BRRI dhan54) rice (Oryza sativa L.) varieties. Salt stresses (150 and 300 mM NaCl for 48 h) significantly reduced leaf relative water (RWC) and chlorophyll (chl) content and increased endogenous Pro and increased lipid peroxidation and H2O2 levels. Ascorbate (AsA), glutathione (GSH) and GSH/GSSG, ascorbate peroxidae (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), glutathione reductase (GR), glutathione peroxidase (GPX), catalase (CAT), and glyoxalase I (Gly I) activities were reduced in sensitive variety and these were increased in tolerant variety due to salt stress. The glyoxalase II (Gly II), glutathione S-transferase (GST), and superoxide dismutase (SOD) activities were increased in both cultivars by salt stress. Exogenous Pro and GB application with salt stress improved physiological parameters and reduced oxidative damage in both cultivars where BRRI dhan54 showed better tolerance. The result suggests that exogenous application of Pro and GB increased rice seedlings' tolerance to salt-induced oxidative damage by upregulating their antioxidant defense system where these protectants rendered better performance to BRRI dhan54 and Pro can be considered as better protectant than GB.
PMCID: PMC4065706  PMID: 24991566
5.  Cancer risk in systemic lupus: An updated international multi-centre cohort study 
Journal of autoimmunity  2013;42:130-135.
To update estimates of cancer risk in SLE relative to the general population.
A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers.
Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkin’s lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61–0.88), endometrial (SIR 0.44, 95% CI 0.23–0.77), and possibly ovarian cancers (0.64, 95% CI 0.34–1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23).
These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.
PMCID: PMC3646904  PMID: 23410586
Systemic Lupus Erythematosus; Epidemiology; Treatment; Disease Activity
6.  Pathogenic autoantibodies from patients with lupus nephritis cause reduced tyrosine phosphorylation of podocyte proteins, including tubulin 
Lupus Science & Medicine  2014;1(1):e000013.
The tertiary structure of normal podocytes prevents protein from leaking into urine. Patients with lupus nephritis (LN) develop proteinuria, and kidney biopsies from these patients display a number of podocyte abnormalities including retraction of podocyte processes. Autoantibodies have been shown to deposit in the kidneys of patients and mice with LN and are believed to play a key role in causing renal inflammation and dysfunction. The objective of this research was to study the effects of IgG antibodies from patients with LN on cultured human podocytes.
We exposed a human podocyte cell line to heat-inactivated (HI) plasma and purified polyclonal IgG from the following groups of subjects; patients with LN, patients with lupus without nephritis, patients with rheumatoid arthritis and healthy controls. We measured expression and intracellular distribution of podocyte-specific proteins and global phosphorylation of tyrosine. We then used mass spectrometry to identify the major protein targets of this phosphorylation.
HI LN plasma did not alter expression or cellular distribution of podocyte-specific proteins but caused a significant reduction in podocyte protein tyrosine phosphorylation compared with plasma from healthy controls (p=0.0008). This result was replicated using purified IgG but was not seen with plasma from rheumatoid arthritis or non-renal lupus patients. The dominant tyrosine phosphorylated protein in podocytes was 55 kDa in size and was identified as tubulin.
Since tubulin is an important component of podocyte major processes, these results suggest that autoantibodies from LN patients may exert an important pathogenic effect by dephosphorylation of this protein in podocytes.
PMCID: PMC4225730  PMID: 25396061
nephritis; podocyte; phosphorylation
7.  Population-Based Incidence of Severe Acute Respiratory Virus Infections among Children Aged <5 Years in Rural Bangladesh, June–October 2010 
PLoS ONE  2014;9(2):e89978.
Better understanding the etiology-specific incidence of severe acute respiratory infections (SARIs) in resource-poor, rural settings will help further develop and prioritize prevention strategies. To address this gap in knowledge, we conducted a longitudinal study to estimate the incidence of SARIs among children in rural Bangladesh.
During June through October 2010, we followed children aged <5 years in 67 villages to identify those with cough, difficulty breathing, age-specific tachypnea and/or danger signs in the community or admitted to the local hospital. A study physician collected clinical information and obtained nasopharyngeal swabs from all SARI cases and blood for bacterial culture from those hospitalized. We tested swabs for respiratory syncytial virus (RSV), influenza viruses, human metapneumoviruses, adenoviruses and human parainfluenza viruses 1–3 (HPIV) by real-time reverse transcription polymerase chain reaction. We calculated virus-specific SARI incidence by dividing the number of new illnesses by the person-time each child contributed to the study.
We followed 12,850 children for 279,029 person-weeks (pw) and identified 141 SARI cases; 76 (54%) at their homes and 65 (46%) at the hospital. RSV was associated with 7.9 SARI hospitalizations per 100,000 pw, HPIV3 2.2 hospitalizations/100,000 pw, and influenza 1.1 hospitalizations/100,000 pw. Among non-hospitalized SARI cases, RSV was associated with 10.8 illnesses/100,000 pw, HPIV3 1.8/100,000 pw, influenza 1.4/100,000 pw, and adenoviruses 0.4/100,000 pw.
Respiratory viruses, particularly RSV, were commonly associated with SARI among children. It may be useful to explore the value of investing in prevention strategies, such as handwashing and respiratory hygiene, to reduce respiratory infections among young children in such settings.
PMCID: PMC3934972  PMID: 24587163
8.  Serum nitrated nucleosome levels in patients with systemic lupus erythematosus: a retrospective longitudinal cohort study 
Circulating nucleosomes released from apoptotic cells are important in the pathogenesis of systemic lupus erythematosus (SLE). Both nucleosomes and anti-nucleosome antibodies are deposited in inflamed tissues in patients with SLE. Active inflammation promotes nitration of tyrosine residues on serum proteins. Our hypothesis was that levels of nitrated nucleosomes would be elevated in patients with SLE and could be associated with disease activity. We therefore carried out a retrospective longitudinal study to investigate factors affecting levels of nitrated nucleosomes (NN) in patients with SLE.
A novel serum ELISA was developed to measure serum NN and modified to measure serum nitrated albumin (NA). Levels of both NN and NA were measured in 397 samples from 49 patients with SLE followed through periods of disease flare and remission for a mean of 89 months. Anti-nucleosome antibody (anti-nuc) levels were measured in the same samples. The effects of 24 different clinical, demographic and serological variables on NN, NA and anti-nuc levels were assessed by univariable and multivariable analysis.
Patients with SLE had higher mean NN than healthy controls or patients with other autoimmune rheumatic diseases (P =0.01). Serum samples from 18 out of 49 (36.7%) of SLE patients were never positive for NN. This group of 18 patients was characterized by lower anti-double stranded DNA antibodies (anti-dsDNA), disease activity and use of immunosuppressants. In the remaining 63.3%, NN levels were variable. High NN was significantly associated with anti-Sm antibodies, vasculitis, immunosuppressants, hydroxychloroquine and age at diagnosis. NN levels were raised in neuropsychiatric flares. NN levels did not completely parallel NA results, thus providing additional information over measuring nitration status alone. NN levels were not associated with anti-nuc levels.
NN are raised in a subset of patients with SLE, particularly those who are anti-Sm positive. Elevated NN may be a marker of vascular activation and neuropsychiatric flares in these patients.
PMCID: PMC3978622  PMID: 24502558
9.  Data‐driven modeling reconciles kinetics of ERK phosphorylation, localization, and activity states 
Molecular Systems Biology  2014;10(1):718.
The extracellular signal‐regulated kinase (ERK) signaling pathway controls cell proliferation and differentiation in metazoans. Two hallmarks of its dynamics are adaptation of ERK phosphorylation, which has been linked to negative feedback, and nucleocytoplasmic shuttling, which allows active ERK to phosphorylate protein substrates in the nucleus and cytosol. To integrate these complex features, we acquired quantitative biochemical and live‐cell microscopy data to reconcile phosphorylation, localization, and activity states of ERK. While maximal growth factor stimulation elicits transient ERK phosphorylation and nuclear translocation responses, ERK activities available to phosphorylate substrates in the cytosol and nuclei show relatively little or no adaptation. Free ERK activity in the nucleus temporally lags the peak in nuclear translocation, indicating a slow process. Additional experiments, guided by kinetic modeling, show that this process is consistent with ERK's modification of and release from nuclear substrate anchors. Thus, adaptation of whole‐cell ERK phosphorylation is a by‐product of transient protection from phosphatases. Consistent with this interpretation, predictions concerning the dose‐dependence of the pathway response and its interruption by inhibition of MEK were experimentally confirmed.
PMCID: PMC4023404  PMID: 24489118
growth factor receptors; mathematical model; mitogen‐activated protein kinases; negative feedback; nucleocytoplasmic shuttling
10.  Pain management for chronic musculoskeletal conditions: the development of an evidence-based and theory-informed pain self-management course 
BMJ Open  2013;3(11):e003534.
To devise and test a self-management course for chronic pain patients based on evidence and underpinned by theory using the Medical Research Council (MRC) framework for developing complex interventions.
We used a mixed method approach. We conducted a systematic review of the effectiveness of components and characteristics of pain management courses. We then interviewed chronic pain patients who had attended pain and self-management courses. Behavioural change theories were mapped onto our findings and used to design the intervention. We then conducted a feasibility study to test the intervention.
Primary care in the inner city of London, UK.
Adults (18 years or older) with chronic musculoskeletal pain.
Related disability, quality of life, coping, depression, anxiety, social integration and healthcare resource use.
The systematic reviews indicated that group-based courses with joint lay and healthcare professional leadership and that included a psychological component of short duration (<8 weeks) showed considerable promise. The qualitative research indicated that participants liked relaxation, valued social interaction and course location, and that timing and good tutoring were important determinants of attendance. We used behavioural change theories (social learning theory and cognitive behaviour approaches (CBA)) to inform course content. The course addressed: understanding and accepting pain, mood and pain, unhelpful thoughts and behaviour, problem solving, goal setting, action planning, movement, relaxation and social integration/reactivation. Attendance was 85%; we modified the recruitment of patients, the course and the training of facilitators as a result of testing.
The MRC guidelines were helpful in developing this intervention. It was possible to train both lay and non-psychologists to facilitate the courses and deliver CBA. The course was feasible and well received.
PMCID: PMC3831098  PMID: 24231458
11.  PEGylated drugs in rheumatology—why develop them and do they work? 
Rheumatology (Oxford, England)  2013;53(3):391-396.
Lack of efficacy and drug-related adverse effects are important reasons for the discontinuation of treatment in patients with rheumatic diseases. The development of new biologic therapies seeks to address these problems by specifically targeting the pathogenic mechanisms of disease. Most current biologics are proteins (particularly antibodies and enzymes) administered parenterally. It is important to optimize properties such as serum half-life, immunogenicity and solubility. Companies have thus begun to modify the drugs by conjugate chemistry, binding inert molecules such as polyethylene glycol (PEG) to biologic molecules to improve their pharmacodynamic properties. The use of PEG to alter these properties has to be weighed against the negative aspects of PEGylation, such as decreased activity and heterogeneity. This review focuses on the currently available PEGylated drugs used in rheumatological diseases, their efficacy, drawbacks and the current clinical trial evidence supporting their use.
PMCID: PMC3930883  PMID: 23962623
PEGylation; gout; rheumatoid arthritis; clinical trials
12.  Derivation and Validation of Systemic Lupus International Collaborating Clinics Classification Criteria for Systemic Lupus Erythematosus 
Arthritis and rheumatism  2012;64(8):2677-2686.
The Systemic Lupus Collaborating Clinics (SLICC) revised and validated the American College of Rheumatology (ACR) SLE classification criteria in order to improve clinical relevance, meet stringent methodology requirements and incorporate new knowledge in SLE immunology.
The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. SLICC validated the classification criteria in a new validation sample of 690 SLE patients and controls.
Seventeen criteria were identified. The SLICC criteria for SLE classification requires: 1) Fulfillment of at least four criteria, with at least one clinical criterion AND one immunologic criterion OR 2) Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications than the current ACR classification criteria (49 versus 70, p=0.0082), had greater sensitivity (94% versus 86%, p<0.0001) and equal specificity (92% versus 93%, p=0.39). In the validation set, the SLICC Classification criteria resulted in fewer misclassifications (62 versus 74, p=0.24), had greater sensitivity (97% versus 83%, p<0.0001) but less specificity (84% versus 96%, p<0.0001).
The new SLICC classification criteria performed well on a large set of patient scenarios rated by experts. They require that at least one clinical criterion and one immunologic criterion be present for a classification of SLE. Biopsy confirmed nephritis compatible with lupus (in the presence of SLE autoantibodies) is sufficient for classification.
PMCID: PMC3409311  PMID: 22553077
13.  Can measuring urinary biomarkers improve the management of lupus nephritis? 
Although renal biopsy is the most accurate way of assessing renal inflammation in patients with lupus nephritis (LN), the technique is invasive and cannot be performed frequently. Currently used blood and urine biomarkers have limited utility in monitoring the activity of nephritis. In a previous issue of Arthritis Research and Therapy, Singh and colleagues showed that measuring urinary levels of vascular cell adhesion molecule 1 could be useful in both diagnosing and monitoring LN. These levels are higher in patients with lupus than controls, are higher in lupus patients who have active renal disease compared with those who do not, and correlate significantly with the histological activity index in renal biopsies of patients with LN.
PMCID: PMC3674604  PMID: 23256781
14.  Prevalence and impact of chronic widespread pain in the Bangladeshi and White populations of Tower Hamlets, East London 
Clinical Rheumatology  2013;32(9):1375-1382.
The prevalence and impact of chronic pain differ between ethnic groups. We report a study of the comparative prevalence and impact of chronic pain in Bangladeshi, British Bangladeshi and White British/Irish people. We posted a short questionnaire to a random sample of 4,480 patients registered with 16 general practices in the London Borough of Tower Hamlets and conducted a longer questionnaire with patients in the waiting areas at those practices. We distinguished between Bangladeshi participants who were born in the UK or had arrived in the UK at the age of 14 or under (British Bangladeshi) and those who arrived in UK at the age of over 14 (Bangladeshi). We obtained 1,223/4,480 (27 %) responses to the short survey and 600/637 (94 %) to the long survey. From the former, the prevalence of chronic pain in the White, British Bangladeshi and Bangladeshi groups was 55, 54 and 72 %, respectively. The corresponding figures from the long survey were 49, 45 and 70 %. Chronic widespread pain was commoner in the Bangladeshi (16 %) than in the White (10 %) or British Bangladeshi (9 %) groups. People with chronic pain experienced poorer quality of life (odds ratio for scoring best possible health vs. good health (or good vs. poor health) 5.6 (95 % confidence interval 3.4 to 9.8)), but we found no evidence of differences between ethnic groups in the impact of chronic pain on the quality of life. Chronic pain is commoner and, of greater severity, in Bangladeshis than in Whites. On most measures in this study, British Bangladeshis resembled the Whites more than the Bangladeshis.
Electronic supplementary material
The online version of this article (doi:10.1007/s10067-013-2286-3) contains supplementary material, which is available to authorized users.
PMCID: PMC3751214  PMID: 23719834
Chronic pain; Comparative prevalence; Ethnicity; Quality of life
15.  Sleep Deprivation Impairs Spatial Retrieval but Not Spatial Learning in the Non-Human Primate Grey Mouse Lemur 
PLoS ONE  2013;8(5):e64493.
A bulk of studies in rodents and humans suggest that sleep facilitates different phases of learning and memory process, while sleep deprivation (SD) impairs these processes. Here we tested the hypothesis that SD could alter spatial learning and memory processing in a non-human primate, the grey mouse lemur (Microcebus murinus), which is an interesting model of aging and Alzheimer's disease (AD). Two sets of experiments were performed. In a first set of experiments, we investigated the effects of SD on spatial learning and memory retrieval after one day of training in a circular platform task. Eleven male mouse lemurs aged between 2 to 3 years were tested in three different conditions: without SD as a baseline reference, 8 h of SD before the training and 8 h of SD before the testing. The SD was confirmed by electroencephalographic recordings. Results showed no effect of SD on learning when SD was applied before the training. When the SD was applied before the testing, it induced an increase of the amount of errors and of the latency prior to reach the target. In a second set of experiments, we tested the effect of 8 h of SD on spatial memory retrieval after 3 days of training. Twenty male mouse lemurs aged between 2 to 3 years were tested in this set of experiments. In this condition, the SD did not affect memory retrieval. This is the first study that documents the disruptive effects of the SD on spatial memory retrieval in this primate which may serve as a new validated challenge to investigate the effects of new compounds along physiological and pathological aging.
PMCID: PMC3661499  PMID: 23717620
16.  Effectiveness and cost-effectiveness of a novel, group self-management course for adults with chronic musculoskeletal pain: study protocol for a multicentre, randomised controlled trial (COPERS) 
BMJ Open  2013;3(1):e002492.
Chronic musculoskeletal pain is a common condition that often responds poorly to treatment. Self-management courses have been advocated as a non-drug pain management technique, although evidence for their effectiveness is equivocal. We designed and piloted a self-management course based on evidence for effectiveness for specific course components and characteristics.
COPERS (coping with persistent pain, effectiveness research into self-management) is a pragmatic randomised controlled trial testing the effectiveness and cost-effectiveness of an intensive, group, cognitive behavioural-based, theoretically informed and manualised self-management course for chronic pain patients against a control of best usual care: a pain education booklet and a relaxation CD. The course lasts for 15 h, spread over 3 days, with a –2 h follow-up session 2 weeks later. We aim to recruit 685 participants with chronic musculoskeletal pain from primary, intermediate and secondary care services in two UK regions. The study is powered to show a standardised mean difference of 0.3 in the primary outcome, pain-related disability. Secondary outcomes include generic health-related quality of life, healthcare utilisation, pain self-efficacy, coping, depression, anxiety and social engagement. Outcomes are measured at 6 and 12 months postrandomisation. Pain self-efficacy is measured at 3 months to assess whether change mediates clinical effect.
Ethics approval was given by Cambridgeshire Ethics 11/EE/046. This trial will provide robust data on the effectiveness and cost-effectiveness of an evidence-based, group self-management programme for chronic musculoskeletal pain. The published outcomes will help to inform future policy and practice around such self-management courses, both nationally and internationally.
Trial registration
PMCID: PMC3563130  PMID: 23358564
Randomised Controlled Trial; Protocol; Chronic Pain; Self Management
17.  Association of antenatal care with facility delivery and perinatal survival – a population-based study in Bangladesh 
Antenatal Care (ANC) during pregnancy can play an important role in the uptake of evidence-based services vital to the health of women and their infants. Studies report positive effects of ANC on use of facility-based delivery and perinatal mortality. However, most existing studies are limited to cross-sectional surveys with long recall periods, and generally do not include population-based samples.
This study was conducted within the Health and Demographic Surveillance System (HDSS) of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) in Matlab, Bangladesh. The HDSS area is divided into an icddr,b service area (SA) where women and children receive care from icddr,b health facilities, and a government SA where people receive care from government facilities. In 2007, a new Maternal, Neonatal, and Child Health (MNCH) program was initiated in the icddr,b SA that strengthened the ongoing maternal and child health services including ANC. We estimated the association of ANC with facility delivery and perinatal mortality using prospectively collected data from 2005 to 2009. Using a before-after study design, we also determined the role of ANC services on reduction of perinatal mortality between the periods before (2005 – 2006) and after (2008–2009) implementation of the MNCH program.
Antenatal care visits were associated with increased facility-based delivery in the icddr,b and government SAs. In the icddr,b SA, the adjusted odds of perinatal mortality was about 2-times higher (odds ratio (OR) 1.91; 95% confidence intervals (CI): 1.50, 2.42) among women who received ≤1 ANC compared to women who received ≥3 ANC visits. No such association was observed in the government SA. Controlling for ANC visits substantially reduced the observed effect of the intervention on perinatal mortality (OR 0.64; 95% CI: 0.52, 0.78) to non-significance (OR 0.81; 95% CI: 0.65, 1.01), when comparing cohorts before and after the MNCH program initiation (Sobel test of mediation P < 0.001).
ANC visits are associated with increased uptake of facility-based delivery and improved perinatal survival in the icddr,b SA. Further testing of the icddr,b approach to simultaneously improving quality of ANC and facility delivery care is needed in the existing health system in Bangladesh and in other low-income countries to maximize health benefits to mothers and newborns.
PMCID: PMC3495045  PMID: 23066832
18.  Economic Consequences of Post–Kala-Azar Dermal Leishmaniasis in a Rural Bangladeshi Community 
Post–kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis. Bangladesh national treatment guidelines during the study period called for 120 intramuscular injections of sodium antimony gluconate (SAG). We assessed care-seeking behavior, diagnosis and treatment costs, and coping strategies among 134 PKDL patients; 56 (42%) patients had been treated with SAG, and 78 (58%) remained untreated. The median direct cost per patient treated was US$367 (interquartile range [IQR] = 90–284), more than two times the estimated per capita annual income for the study population. The most common coping strategy was to take a loan; the median amount borrowed was US$98 (IQR = 71–150), with a median interest of US$32 (IQR = 16–95). Households lost a median of 123 work-days per patient treated. The current regimen for PKDL imposes a significant financial burden, reinforcing the link between poverty and visceral leishmaniasis. More practical shorter-course regimens for PKDL are urgently needed to achieve national and regional visceral leishmaniasis elimination goals.
PMCID: PMC3163879  PMID: 21896817
19.  The BILAG-2004 systems tally—a novel way of representing the BILAG-2004 index scores longitudinally 
Rheumatology (Oxford, England)  2012;51(11):2099-2105.
Objective. This was an exploratory analysis to develop a new way of representing BILAG-2004 system scores longitudinally that would be clinically meaningful and easier to analyse in comparison with multiple categorical variables.
Methods. Data from a multicentre longitudinal study of SLE patients (the BILAG-2004 index and therapy collected at every visit) were used. External responsiveness analysis of the index suggested the possibility of using counts of systems with specified transitions in scores as a basis to analyse the system scores. Exploratory analyses with multinomial logistic regression were used to examine the appropriateness of this new method of analysing BILAG-2004 system scores. Receiver operating characteristic (ROC) curve analysis was used to assess the performance of this approach.
Results. There were 1414 observations from 347 patients. A novel method was devised based on counts of systems with defined transitions in score (BILAG-2004 systems tally, BST). It has six components (systems with major deterioration, systems with minor deterioration, systems with persistent significant activity, systems with major improvement, systems with minor improvement and systems with persistent minimal or no activity). This was further simplified (simplified BST, sBST) into three components (systems with active/worsening disease, systems with improving disease and systems with persistent minimal or no activity). Both versions had expected associations with change in therapy. ROC curve analyses demonstrated that both versions had similar good performance characteristics (areas under the curve >0.80) in predicting increase in therapy.
Conclusion. The BST and sBST provide alternative approaches to representing BILAG-2004 disease activity longitudinally. Further validation of their use is required.
PMCID: PMC3475981  PMID: 22908329
BILAG-2004; SLE; disease activity; longitudinal study; BILAG-2004 systems tally; BST; sBST
21.  Maternal Cadmium Exposure during Pregnancy and Size at Birth: A Prospective Cohort Study 
Environmental Health Perspectives  2011;120(2):284-289.
Background: Cadmium (Cd) is an embryotoxic and teratogenic metal in a variety of animal species, but data from humans are limited.
Objectives: The aim of the present study was to assess the effects of maternal Cd exposure in pregnancy on size at birth.
Methods: This prospective cohort study was nested in a population-based nutritional supplementation trial in pregnancy conducted in rural Bangladesh. We selected women recruited from February 2002 through January 2003 who had a singleton birth with measurements of size at birth and had donated a urine sample in early pregnancy for Cd analyses (n = 1,616). Urinary Cd was measured with inductively coupled plasma mass spectrometry and adjusted for specific gravity.
Results: Multiple linear regression analyses adjusted for sex and other potential confounders showed that maternal urinary Cd (median, 0.63 μg/L) was significantly negatively associated with birth weight [unstandardized regression coefficient B = –31.0; 95% confidence interval (CI): –59, –2.8] and head circumference (B = –0.15; 95% CI: –0.27, –0.026). However, associations appeared to be limited to girls, with little evidence of effects in boys. A 1-μg/L increase in Cd in maternal urine was associated with a 0.26-cm (95% CI: –0.43, –0.088 cm) and 0.24-cm (95% CI: –0.44, –0.030 cm) decrease in girls’ head and chest circumferences, respectively, and a 45-g (95% CI: –82.5, 7.3 g) decrease in birth weight. Quantile regression analyses indicated that associations with maternal Cd were similar for girls of smaller (25th percentile) and larger (50th and 75th percentiles) sizes at birth.
Conclusion: We found evidence of a sex difference in the association between maternal Cd exposure and birth size, which was apparent only in girls. Results add support for the need to reduce Cd pollution to improve public health.
PMCID: PMC3279440  PMID: 21862444
arsenic; birth weight; cadmium; sex; urine
22.  Effectiveness of an integrated approach to reduce perinatal mortality: recent experiences from Matlab, Bangladesh 
BMC Public Health  2011;11:914.
Improving perinatal health is the key to achieving the Millennium Development Goal for child survival. Recently, several reviews suggest that scaling up available effective perinatal interventions in an integrated approach can substantially reduce the stillbirth and neonatal death rates worldwide. We evaluated the effect of packaged interventions given in pregnancy, delivery and post-partum periods through integration of community- and facility-based services on perinatal mortality.
This study took advantage of an ongoing health and demographic surveillance system (HDSS) and a new Maternal, Neonatal and Child Health (MNCH) Project initiated in 2007 in Matlab, Bangladesh in half (intervention area) of the HDSS area. In the other half, women received usual care through the government health system (comparison area). The MNCH Project strengthened ongoing maternal and child health services as well as added new services. The intervention followed a continuum of care model for pregnancy, intrapartum, and post-natal periods by improving established links between community- and facility-based services. With a separate pre-post samples design, we compared the perinatal mortality rates between two periods--before (2005-2006) and after (2008-2009) implementation of MNCH interventions. We also evaluated the difference-of-differences in perinatal mortality between intervention and comparison areas.
Antenatal coverage, facility delivery and cesarean section rates were significantly higher in the post- intervention period in comparison with the period before intervention. In the intervention area, the odds of perinatal mortality decreased by 36% between the pre-intervention and post-intervention periods (odds ratio: 0.64; 95% confidence intervals: 0.52-0.78). The reduction in the intervention area was also significant relative to the reduction in the comparison area (OR 0.73, 95% CI: 0.56-0.95; P = 0.018).
The continuum of care approach provided through the integration of service delivery modes decreased the perinatal mortality rate within a short period of time. Further testing of this model is warranted within the government health system in Bangladesh and other low-income countries.
PMCID: PMC3257323  PMID: 22151276
23.  Imaging Assessment of Cardiovascular Disease in Systemic Lupus Erythematosus 
Systemic lupus erythematosus is a multisystem, autoimmune disease known to be one of the strongest risk factors for atherosclerosis. Patients with SLE have an excess cardiovascular risk compared with the general population, leading to increased cardiovascular morbidity and mortality. Although the precise explanation for this is yet to be established, it seems to be associated with the presence of an accelerated atherosclerotic process, arising from the combination of traditional and lupus-specific risk factors. Moreover, cardiovascular-disease associated mortality in patients with SLE has not improved over time. One of the main reasons for this is the poor performance of standard risk stratification tools on assessing the cardiovascular risk of patients with SLE. Therefore, establishing alternative ways to identify patients at increased risk efficiently is essential. With recent developments in several imaging techniques, the ultimate goal of cardiovascular assessment will shift from assessing symptomatic patients to diagnosing early cardiovascular disease in asymptomatic patients which will hopefully help us to prevent its progression. This review will focus on the current status of the imaging tools available to assess cardiac and vascular function in patients with SLE.
PMCID: PMC3202117  PMID: 22110536
24.  Evaluating the conformation of recombinant domain I of β2-glycoprotein I and its interaction with human monoclonal antibodies 
Molecular Immunology  2011;49(1-2):56-63.
► Bacterial expressed human recombinant DI has a structure consistent with that of DI in the published β2GPI crystal structure. ► Mutating residues D8/D9 and R39 do not alter the overall DI protein fold but cause local changes in surface contour. ► Monoclonal aPL-derived antibodies and DI of β2GPI interactions are influenced by specific arginine residues in aPL and particular epitopes in DI.
Pathogenic antiphospholipid antibodies (aPL) cause the antiphospholipid syndrome (APS) by interacting with domain I (DI) of beta-2-glycoprotein I (β2GPI). The aPL/β2GPI complex then exerts pathogenic effects on target cells. We previously described periplasmic bacterial expression of native and mutated variants of DI, and reported the presence of immunodominant epitopes at positions 8–9 (D8/D9) and position 39 (R39). Mutations at these positions strongly influenced the ability of recombinant DI to bind patient-derived IgG aPL and to inhibit pathogenic effects of these aPL in a mouse model of APS.
We now describe an improved cytoplasmic bacterial expression system allowing higher yield of DI. We demonstrate that the nuclear magnetic resonance (NMR) spectra of a 15N,13C-isotope-labelled sample of the recombinant DI protein exhibit properties consistent with the structure of DI in crystal structure of intact β2GPI. Mutations at D8/D9 and R39 had limited impact on the NMR spectrum of DI indicating maintenance of the overall fold of the DI domain.
We investigated interactions between five variants of DI and ten monoclonal human IgG antibodies, all derived from the IgG aPL antibody IS4 by sequence manipulation and in vitro expression. Arginine residues at positions 100 and 100g in IS4VH CDR3 play a particularly important role in binding to DI, but this is unlikely to be due to electrostatic interactions with negatively charged amino acids on DI. Both the strength of binding to DI and the ability to discriminate different DI variants varies between the different IgG antibodies tested. There was no simple relationship between these binding properties and antibody pathogenicity.
PMCID: PMC3268385  PMID: 21899894
aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; β2GPI, beta-2-glycoprotein I; CL, cardiolipin; DI, domain I of β2GPI; E. coli, Escherichia coli; His6-tag, hexahistidine tag; HSQC, 15N,1H-heteronuclear single quantum correlation; NMR, nuclear magnetic resonance; PL, phospholipids; VH, variable heavy chain of Ig; VL, variable light chain of Ig; Antiphospholipid antibodies; Beta-2-glycoprotein I; Domain I; Nuclear magnetic resonance spectroscopy
25.  Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis 
Rheumatology (Oxford, England)  2010;49(5):960-971.
Objectives. Clinical and laboratory markers in current use have limited specificity and sensitivity for predicting the development of renal disease in lupus patients. In this longitudinal study, we investigated whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) predicts active nephritis and renal flares in lupus patients with and without a history of biopsy-proven lupus nephritis.
Methods. Renal disease activity and flare status was determined by SLEDAI and BILAG scores. Random effects models were used to determine whether uNGAL was a significant predictor for renal disease activity in SLE patients, and for renal flares in patients with established nephritis. To assess the predictive performance of uNGAL, receiver operating characteristic (ROC) curves were constructed using the previous visit’s uNGAL level. These curves were then compared with curves constructed with currently used biomarkers. Cut-offs determined by ROC curves were tested in an independent validation cohort.
Results. uNGAL was found to be a significant predictor of renal disease activity in all SLE patients, and a significant predictor for flare in patients with a history of biopsy-proven nephritis, in multivariate models adjusting for age, race, sex and anti-double-stranded (ds)DNA antibody titres. As a predictor of renal flare in patients with biopsy-proven nephritis, uNGAL outperformed anti-dsDNA antibody titres. These results were confirmed in an independent validation cohort.
Conclusions. uNGAL predicts renal flare in patients with a history of biopsy-proven nephritis with high sensitivity and specificity. Furthermore, uNGAL is a more sensitive and specific forecaster of renal flare in patients with a history of lupus nephritis than anti-dsDNA antibody titres.
PMCID: PMC2853702  PMID: 20144927
Systemic lupus erythematosus; Lupus nephritis; Neutrophil gelatinase-associated lipocalin; Systemic Lupus Erythematosus Disease Activity Index; British Isles Lupus Assessment Group; Biomarkers

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