Associations of B cell-activating factor (BAFF) and anti-BAFF autoantibodies with disease activity in multi-ethnic Asian systemic lupus erythematosus patients in Singapore.

To measure the levels of B cell-activating factor (BAFF) and endogenous anti-BAFF autoantibodies in a cohort of multi-ethnic Asian systemic lupus erythematosus (SLE) patients in Singapore, to determine their correlation with disease activity. Serum samples from 121 SLE patients and 24 age- and sex-matched healthy controls were assayed for BAFF and anti-BAFF immunoglobulin (Ig)G antibody levels by enzyme-linked immunosorbent assay (ELISA). The lowest reliable detection limit for anti-BAFF-IgG antibody levels was defined as 2 standard deviations (s.d.) from blank. Correlation of serum BAFF and anti-BAFF IgG levels with disease activity [scored by SLE Activity Measure revised (SLAM-R)], and disease manifestations were determined in these 121 patients. SLE patients had elevated BAFF levels compared to controls; mean 820 ± 40 pg/ml and 152 pg ± 45/ml, respectively [mean ± standard error of the mean (s.e.m.), P < 0·01], which were correlated positively with anti-dsDNA antibody levels (r = 0·253, P < 0·03), and SLAM-R scores (r = 0·627, P < 0·01). In addition, SLE patients had significantly higher levels of anti-BAFF IgG, which were correlated negatively with disease activity (r = -0·436, P < 0·01), levels of anti-dsDNA antibody (r = -0·347, P < 0·02) and BAFF (r = -0·459, P < 0·01). The majority of patients in this multi-ethnic Asian SLE cohort had elevated levels of BAFF and anti-BAFF antibodies. Anti-BAFF autoantibody levels correlated negatively with clinical disease activity, anti-dsDNA and BAFF levels, suggesting that they may be disease-modifying. Our results provide further information about the complexity of BAFF pathophysiology in different SLE disease populations and phenotypes, and suggest that studies of the influence of anti-cytokine antibodies in different SLE populations will be required when selecting patients for trials using targeted anti-cytokine therapies.

Heterogeneity of Mesp1+ mesoderm revealed by single-cell RNA-seq.

Mesp1 is a transcription factor that promotes differentiation of pluripotent cells into different mesoderm lineages including hematopoietic, cardiac and skeletal myogenic. This occurs via at least two transient cell populations: a common hematopoietic/cardiac progenitor population and a common cardiac/skeletal myogenic progenitor population. It is not established whether Mesp1-induced mesoderm cells are intrinsically heterogeneous, or are simply capable of multiple lineage decisions. In the current study, we applied single-cell RNA-seq to analyze Mesp1+ mesoderm. Initial whole transcriptome analysis showed a surprising homogeneity among Mesp1-induced mesoderm cells. However, this apparent global homogeneity masked an intrinsic heterogeneity revealed by interrogating a panel of early mesoderm patterning factors. This approach enabled discovery of subpopulations primed for hematopoietic or cardiac development. These studies demonstrate the heterogeneic nature of Mesp1+ mesoderm.

Clock-controlled emission of single-electron wave packets in a solid-state circuit.

We demonstrate the energy- and time-resolved detection of single-electron wave packets from a clock-controlled source transmitted through a high-energy quantum Hall edge channel. A quantum dot source is loaded with single electrons which are then emitted ~150 meV above the Fermi energy. The energy spectroscopy of emitted electrons indicates that at high magnetic field these electrons can be transported over several microns without inelastic electron-electron or electron-phonon scattering. Using a time-resolved spectroscopic technique, we deduce the wave packet size at picosecond resolution. We also show how this technique can be used to switch individual electrons into different electron waveguides (edge channels).

Quantum conductance in silicon oxide resistive memory devices.

Resistive switching offers a promising route to universal electronic memory, potentially replacing current technologies that are approaching their fundamental limits. In many cases switching originates from the reversible formation and dissolution of nanometre-scale conductive filaments, which constrain the motion of electrons, leading to the quantisation of device conductance into multiples of the fundamental unit of conductance, G0. Such quantum effects appear when the constriction diameter approaches the Fermi wavelength of the electron in the medium - typically several nanometres. Here we find that the conductance of silicon-rich silica (SiOx) resistive switches is quantised in half-integer multiples of G0. In contrast to other resistive switching systems this quantisation is intrinsic to SiOx, and is not due to drift of metallic ions. Half-integer quantisation is explained in terms of the filament structure and formation mechanism, which allows us to distinguish between systems that exhibit integer and half-integer quantisation.

Discordant assessment of lupus activity between patients and their physicians: the Singapore experience.

Patients with systemic lupus erythematosus often assess their disease activity differently from their physicians. We studied the factors associated with this discordance. The data provided by 534 systemic lupus erythematosus patients were analyzed. We compared the physician and patient assessments of lupus activity on a visual-assessment scale from the same visit. We collected clinical data and scores from MOS 36-Item Short-Form Health Survey, Systemic Lupus Erythematosus Quality-of-Life Questionnaire, Rheumatology Attitudes Index, Systemic Lupus Erythematosus Disease Activity Index, and revised Systemic Lupus Activity Measure. Patients tended to score their disease activity higher than do their physicians, when these factors were present: poorer general health assessment, presence of thrombocytopenia, hypertension and urinary sediments, and difficulty in carrying groceries. Physicians tended to score the disease activity higher than do the patients in these circumstances proteinuria, hemolysis, use of azathioprine or cyclophosphamide, tiredness, photosensitivity, higher revised Systemic Lupus Activity Measure score, casturia, and patient report of being more easily ill than are other patients. There was only moderate correlation between the discordance in the baseline and the subsequent visits. The physician assessment of disease activity at baseline correlated better with an objective measure of disease activity (revised Systemic Lupus Activity Measure) in the subsequent visit than the patient assessment. In conclusion, discordance in the perception of disease activity between patients and physicians may be amenable to intervention.

Enhanced expression of interferon-inducible protein-10 correlates with disease activity and clinical manifestations in systemic lupus erythematosus.

Our objective was to investigate the serum levels of interferon-inducible protein-10 (IP-10) in systemic lupus erythematosus (SLE) and their correlation with disease activity and organ manifestations. Serum IP-10 levels were assessed in 464 SLE patients and 50 healthy donors. Disease activity was assessed by the revised SLE Activity Measure, and the concomitant active organ manifestations, anti-ds DNA antibody titres, complement levels and erythrocyte sedimentation rates recorded. Peripheral blood mononuclear cell (PBMC) synthesis of IP-10 in SLE patients and controls was determined by in vitro cultures stimulated with mitogen or lipopolysaccharide. Elevated serum IP-10 levels were observed in SLE patients, which were significantly higher in the presence of active haematological and mucocutaneous manifestations. SLE PBMCs exhibited enhanced spontaneous IP-10 production in vitro. Serial IP-10 levels correlated with longitudinal change in SLE activity, even at low levels where anti-dsDNA antibody and complement levels remain unchanged. These data demonstrate that IP-10 levels are increased in SLE and serum IP-10 may represent a more sensitive marker for monitoring disease activity than standard serological tests.

Development and preliminary validation of a systemic lupus erythematosus-specific quality-of-life instrument (SLEQOL).

OBJECTIVES: Systemic lupus erythematosus (SLE), a chronic illness with an unpredictable and variable course, profoundly affects the quality of life (QOL). General health questionnaires are used to assess QOL in SLE, but a disease-specific instrument could offer enhanced responsiveness and content validity. We detail the steps we took to develop and validate a new SLE-specific QOL instrument, SLEQOL. METHODS: Rheumatology professionals nominated items that they felt were important determinants of QOL of SLE patients. One hundred SLE patients were asked to assess the importance and frequency of occurrence of these items and to suggest those that had not been listed. Item reduction was performed using Rasch model and factor analyses to create a new questionnaire in English. This final questionnaire was administered to a cohort of 275 patients to study its psychometric properties. RESULTS: Fifty-one items covering a wide range of QOL concerns were identified. The patients' responses led to the elimination of 11. The new questionnaire of 40 items was found to have Cronbach's alpha of 0.95 and to consist of eight domains covering physical, mental and social QOL issues. It has good test-retest reliability, poor to fair cross-sectional correlation with the SF-36, with poor correlation with lupus activity or damage indices. The SLEQOL was more responsive to change than the SF-36. CONCLUSIONS: We have developed a new 40-item SLEQOL in English and showed that it is valid for use in SLE patients in Singapore. It offers better content validity and responsiveness to change than the SF-36.

Transforming growth factor beta-1 and gene polymorphisms in oriental ankylosing spondylitis.

OBJECTIVES: To study serum levels of transforming growth factor beta-1 (TGFbeta1) and the expression of TGFbeta1 in in vitro peripheral blood mononuclear cell (PBMC) cultures in oriental ankylosing spondylitis (AS) patients, and to determine their association with codon 10 and 25 TGFB1 gene polymorphisms. METHODS: Serum levels of TGFbeta1 were measured by enzyme-linked immunosorbent assay (ELISA). The ability of PBMCs to synthesize TGFbeta1 and other cytokines was assessed by in vitro cultures stimulated with mitogen. Genomic DNA was extracted from PBMCs of AS patients (n=72) or unrelated healthy controls (n=96). The codon 10 and 25 polymorphisms in the TGFB1 gene were analysed using standard polymerase chain reaction-based methods. RESULTS: AS patients had significantly higher serum TGFbeta1 levels than controls (P<0.001). There was no difference in the distribution of codon 10 and 25 TGFB1 genotypes between AS patients and controls. Incubation of AS and control PBMC with phytohaemagglutinin (PHA) led to upregulation of TGFbeta1, interleukin-10, tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) assessed by ELISA. Importantly, PHA-induced TGFbeta1 production was significantly enhanced in AS patients compared with normal controls whereas the production of the pro-inflammatory cytokines TNFalpha and IFNgamma was reduced. CONCLUSIONS: Our results show that AS patients express significantly higher levels of serum TGFbeta1 independent of the codon 10 and 25 genotype. Activation of AS PBMCs led to enhanced TGFbeta1 production accompanied by reduction of TNFalpha and IFNgamma while the converse was observed in normal controls.

Anaplastic thyroid carcinoma with destructive thyrotoxicosis in a patient with preexisting multinodular goiter.

Presentation of anaplastic thyroid carcinoma with thyrotoxicosis is extremely rare and its occurrence in a patient with Wegener's granulomatosis has not been reported previously. We describe an elderly lady with Wegener's granulomatosis who developed a rapidly growing anaplastic thyroid carcinoma in a preexisting multinodular goiter and discuss the mechanism of thyrotoxicosis in this patient.

Cerebral infarct mimicking glioma in Sjogren's syndrome.

A 50-year-old Chinese woman with a chronic 20-year history of ataxic gait associated with dry eyes and mouth, was admitted to hospital after a single episode of syncope. Magnetic resonance imaging scans showed a large left frontal hypodense lesion suggestive of a glioma. Craniotomy was performed and the lesion excised, with histology showing only infarcted tissue and no malignant cells. Further diagnostic evaluation revealed that the patient had primary Sjogren's syndrome, with demyelinating polyneuropathy. In the absence of risk factors for stroke, it was considered likely that the cerebral infarct was secondary to autoimmune-related vasculitis. Functional neuroimaging, such as magnetic resonance spectroscopy, should be considered in evaluating doubtful or unusual brain lesions in patients with autoimmune disease.

Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends.

BACKGROUND: The American Cancer Society, the National Cancer Institute (NCI), the North American Association of Central Cancer Registries, and the Centers for Disease Control and Prevention, including the National Center for Health Statistics (NCHS), collaborate to provide an annual update on cancer occurrence and trends in the United States. This year's report contains a special feature that focuses on cancers with recent increasing trends. METHODS: From 1992 through 1998, age-adjusted rates and annual percent changes are calculated for cancer incidence and underlying cause of death with the use of NCI incidence and NCHS mortality data. Joinpoint analysis, a model of joined line segments, is used to examine long-term trends for the four most common cancers and for those cancers with recent increasing trends in incidence or mortality. Statistically significant findings are based on a P value of.05 by use of a two-sided test. State-specific incidence and death rates for 1994 through 1998 are reported for major cancers. RESULTS: From 1992 through 1998, total cancer death rates declined in males and females, while cancer incidence rates declined only in males. Incidence rates in females increased slightly, largely because of breast cancer increases that occurred in some older age groups, possibly as a result of increased early detection. Female lung cancer mortality, a major cause of death in women, continued to increase but more slowly than in earlier years. In addition, the incidence or mortality rate increased in 10 other sites, accounting for about 13% of total cancer incidence and mortality in the United States. CONCLUSIONS: Overall cancer incidence and death rates continued to decline in the United States. Future progress will require sustained improvements in cancer prevention, screening, and treatment.

Life-threatening angioedema in systemic lupus erythematosus.

Life-threatening angioedema involving the upper respiratory tract is an uncommon manifestation in systemic lupus erythematosus (SLE). We report three patients in their late adolescence who had laryngeal oedema causing airway obstruction and requiring mechanical ventilation during active disease following symptoms of a respiratory tract infection. All of them had major organ involvement from lupus and none had a family history of hereditary angioedema (HAE). The mechanisms of angioedema in SLE are heterogeneous. There has been little evidence so far of anti-Cl inhibitor (Cl INH) autoantibody in SLE patients with angioedema. These are the first three cases reported in the literature of life-threatening angioedema following respiratory tract infection in SLE.

Non-thyphoidal salmonellosis in patients with systemic lupus erythematosus. A study of fifty patients and a review of the literature.

The objective of this study was to characterize the clinical profile of lupus patients with non-typhoidal salmonellosis. A retrospective review of the clinical charts of lupus patients diagnosed with bacteriologically proven non-typhoidal salmonellosis over the last 20 y was undertaken, paying special attention to risk factors, clinical presentation and treatment outcome. Most episodes were bacteraemic without a localizing focus; and some patients were afebrile. They usually occurred in patients prone to opportunistic infections, and at times of increased immunosuppression given for lupus flares (especially nephritis). However, salmonellosis also occurred in some patients presenting with lupus. The C-reactive protein level was found to be significantly higher during the infective episodes compared to episodes of non-infective febrile lupus flare. All isolates were sensitive to the usual first-line antibiotics and eminently treatable with 3 weeks of appropriate antibiotics without recurrence/persistence or significant morbidity/mortality, the exceptions being spinal osteomyelitis and septic arthritis involving deformed joints requiring surgical debridement and prolonged antibiotic therapy for eradication. Mortality occurred in the setting of septic shock from mixed-microbial sepsis and major organ failure from active lupus. There is a high association of non-epidemic, non-typhoidal salmonellosis with SLE, especially in patients with active disease on intensified immunosuppression. The C-reactive protein value may be helpful in distinguishing between fever from a pure lupus flare and one complicated by infection.

A comparative study of the clinical manifestations of systemic lupus erythematosus in Caucasians in Rochester, Minnesota, and Chinese in Singapore, from 1980 to 1992.

OBJECTIVE: To examine the relationship between ethnicity and major organ involvement at and after diagnosis in community-based cohorts of Caucasian and Chinese systemic lupus erythematosus (SLE) patients resident in Rochester, Minnesota, and Singapore, respectively. METHODS: Clinical manifestations at and after diagnosis were compared in Caucasian and Chinese SLE patients. The association between ethnicity and disease manifestations at and after diagnosis was determined using logistic regression and Cox proportional hazards models, respectively, adjusting for the influence of demographic, socioeconomic, disease-related, and therapy-related factors. RESULTS: At diagnosis, Caucasian SLE patients were 3 times more likely than Chinese SLE patients to have serositis (odds ratio [OR] 3.11, 95% confidence interval [CI] 1.01-9.71), nearly 7 times more likely to have a hematologic disorder (OR 6.95, 95% CI 2.20-21.97), and far less likely to have a malar rash (OR 0.19, 95% CI 0.07-0.54) or positive antinuclear antibodies (OR 0.11, 95% CI 0.03-0.52). Ethnicity was not associated with the prevalence of proteinuria or central nervous system (CSN) and other major organ involvement at diagnosis. After diagnosis, there was a trend toward less development of proteinuria and other major organ involvement in Caucasians (relative risk [RR] 0.47, 95% CI 0.19-1.15, and RR 0.22, 95% CI 0.05-1.04, respectively). CONCLUSION: Chinese SLE patients are far less likely to have serositis or a hematologic disorder at diagnosis and may be more likely to develop proteinuria or CNS or other major organ involvement over the course of the disease, compared with Caucasian SLE patients. This may contribute to the increased mortality seen in Chinese SLE patients.

The annual report to the nation on the status of cancer, 1973-1997, with a special section on colorectal cancer.

BACKGROUND: This annual report to the nation addresses progress in cancer prevention and control in the U.S. with a special section on colorectal cancer. This report is the joint effort of the American Cancer Society, the National Cancer Institute (NCI), the North American Association of Central Cancer Registries (NAACCR), and the Centers for Disease Control and Prevention (CDC), including the National Center for Health Statistics (NCHS). METHODS: Age-adjusted rates were based on cancer incidence data from the NCI and NAACCR and underlying cause of death as compiled by NCHS. Joinpoint analysis was based on NCI Surveillance, Epidemiology, and End Results (SEER) program incidence rates and NCHS death rates for 1973-1997. The prevalence of screening examinations for colorectal cancer was obtained from the CDC's Behavioral Risk Factor Surveillance System and the NCHS's National Health Interview Survey. RESULTS: Between 1990-1997, overall cancer incidence and death rates declined. Joinpoint analyses of cancer incidence and death rates confirmed the declines described in earlier reports. The incidence trends for colorectal cancer have shown recent steep declines for whites in contrast to a leveling off of the rates for blacks. State-to-state variations occurred in colorectal cancer screening prevalence as well as incidence and death rates. CONCLUSIONS: The continuing declines in overall cancer incidence and death rates are encouraging. However, a few of the top ten incidence or mortality cancer sites continued to increase or remained level. For many cancer sites, whites had lower incidence and mortality rates than blacks but higher rates than Hispanics, Asian and Pacific Islanders, and American Indians/Alaska Natives. The variations in colorectal cancer incidence and death rates by race/ethnicity, gender, age, and geographic area may be related to differences in risk factors, demographic characteristics, screening, and medical practice. New efforts currently are underway to increase awareness of screening benefits and treatment for colorectal cancer.

Cross cultural adaptation and validation of the Chinese Health Assessment Questionnaire for use in rheumatoid arthritis.

OBJECTIVE: The Health Assessment Questionnaire - Disability Index (HAQ), used as a disability and outcome measurement in rheumatoid arthritis (RA), has been validated in several languages, but not in Chinese. Our aim was to validate the Chinese version of HAQ (Chinese-HAQ) to suit the needs of Chinese speaking patients with RA in an Asian setting. METHODS: The original HAQ was modified in the context of Chinese culture and translated into Chinese by 2 translators aware of the objective of the questionnaire. The Chinese HAQ was self-administered by 42 patients with RA during their routine followup visit and one week later. RESULTS: The test-retest reliability assessed using Spearman's correlation coefficient was 0.84. Between dimensions measured in the HAQ, the highest test-retest reliability was observed for walking (Spearman correlation coefficient rs=0.80) and the lowest was for eating (rs=0.54). The internal consistency of the scale using Cronbach's alpha was high at 0.86. In terms of criterion validity, the Chinese-HAQ score was found to correlate well with American College of Rheumatology functional status (rs=0.501, p=0.01). The Chinese-HAQ scores also correlated well with markers of disease activity such as patient's perception of pain measured on a visual analog scale (rs=0.55, p < 0.001), grip strength in mm Hg (rs=-0.55. p < 0.001 ), and physician's assessment of disease activity (rs=0.59, p < 0.001). CONCLUSION: The Chinese HAQ is a reliable and valid instrument for studies measuring disability of patients with RA in Singapore.