Molecular response of a sub-antarctic population of the blue mussel (Mytilus edulis platensis) to a moderate thermal stress.

The Kerguelen Islands (49°26'S, 69°50'E) represent a unique environment due to their geographical isolation, which protects them from anthropogenic pollution. The ability of the endemic mussel, part of the Mytilus complex, to cope with moderate heat stress was explored using omic tools. Transcripts involved in six major metabolic functions were selected and the qRT-PCR data indicated mainly changes in aerobic and anaerobic energy metabolism and stress response. Proteomic comparisons revealed a typical stress response pattern with cytoskeleton modifications and elements suggesting increased energy metabolism. Results also suggest conservation of protein homeostasis by the long-lasting presence of HSP while a general decrease in transcription is observed. The overall findings are consistent with an adaptive response to moderate stresses in mussels in good physiological condition, i.e. living in a low-impact site, and with the literature concerning this model species. Therefore, local blue mussels could be advantageously integrated into biomonitoring strategies, especially in the context of Global Change.

The prevalence and determinants of anti-DFS70 autoantibodies in an international inception cohort of systemic lupus erythematosus patients.

Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7-8.8%), while only 1.1% (95% CI: 0.6-1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-ß2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0-2.8%) and was associated with musculoskeletal activity and anti-ß2 glycoprotein 1 autoantibodies. However, 'monospecific' anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.

Breast cancer in systemic lupus.

Objective There is a decreased breast cancer risk in systemic lupus erythematosus (SLE) versus the general population. We assessed a large sample of SLE patients, evaluating demographic and clinical characteristics and breast cancer risk. Methods We performed case-cohort analyses within a multi-center international SLE sample. We calculated the breast cancer hazard ratio (HR) in female SLE patients, relative to demographics, reproductive history, family history of breast cancer, and time-dependent measures of anti-dsDNA positivity, cumulative disease activity, and drugs, adjusted for SLE duration. Results There were 86 SLE breast cancers and 4498 female SLE cancer-free controls. Patients were followed on average for 7.6 years. Versus controls, SLE breast cancer cases tended to be white and older. Breast cancer cases were similar to controls regarding anti-dsDNA positivity, disease activity, and most drug exposures over time. In univariate and multivariate models, the principal factor associated with breast cancers was older age at cohort entry. Conclusions There was little evidence that breast cancer risk in this SLE sample was strongly driven by any of the clinical factors that we studied. Further search for factors that determine the lower risk of breast cancer in SLE may be warranted.

A majority of parents of children with peanut allergy fear using the epinephrine auto-injector.

Prompt epinephrine administration is crucial in managing anaphylaxis, but epinephrine auto-injectors (EAIs) are underutilized by patients and their families. Children with peanut allergy were recruited from the Allergy Clinics at the Montreal Children's Hospital, food allergy advocacy organizations and organizations providing products to allergic individuals. Parents of children who had been prescribed an EAI were queried on whether they were fearful of using it and on factors that may contribute to fear. A majority of parents (672/1209 = 56%) expressed fear regarding the use of the EAI. Parents attributed the fear to hurting the child, using the EAI incorrectly or a bad outcome. Parents whose child had longer disease duration or a severe reaction and parents who were satisfied with the EAI training or found it easy to use were less likely to be afraid. Families may benefit from simulation training and more education on the recognition and management of anaphylaxis.

Application of a nomogram for exercise capacity in women with systemic lupus erythematosus.

The aim of this study is to examine the exercise capacity in women with systemic lupus erythematosus (SLE). Women with SLE underwent exercise testing; their performance was compared to nomogram predictions. We assessed the potential effects of disease activity and cumulative damage on exercise capacity. We evaluated 52 female SLE patients aged >35 years. The mean workload achieved was somewhat higher than the nomogram predictions. However, over one fifth of the women performed at a very poor level, which in the general population is associated with a twofold increased risk of cardiovascular disease. Compared to other subjects, participants who did poorly tended toward higher disease activity, higher body mass index, and greater smoking prevalence, although the results were not definitive. Exercise testing may be used to identify a subpopulation of lupus patients with a low level of fitness. Extrapolating from general population data, these individuals are likely at particular risk for cardiovascular disease and may, therefore, benefit the most from aggressive cardiovascular risk factor reduction.

SLE patients with renal damage incur higher health care costs.

OBJECTIVES: To compare costs and quality of life (QoL) between SLE patients with and without renal damage. METHODS: Seven hundred and fifteen patients were surveyed semi-annually over 4 yrs on health care use and productivity loss and annually on QoL. Cumulative direct and indirect costs (2006 Canadian dollars) and QoL (average annual change in SF-36) were compared between patients with and without renal damage [Systemic Lupus International Collaborating Clinics/ACR Damage Index (SLICC/ACR DI)] using simultaneous regressions. RESULTS: At study conclusion, for patients with the renal subscale of the SLICC/ACR DI = 0 (n = 634), 1 (n = 54), 2 (n = 15) and 3 (n = 12), mean 4-yr cumulative direct costs per patient (95% CI) were $20,337 ($18,815, $21,858), $27,869 ($19,230, $36,509), $51,191 ($23,463, $78,919) and $99,544 ($57,102, $141,987), respectively. In a regression where the renal subscale of the SLICC/ACR DI was a single indicator variable, on average (95% CI), each unit increase in renal damage was associated with a 24% (15%, 33%) increase in direct costs. In a regression where each level in the renal subscale was an indicator variable, patients with end-stage renal disease incurred 103% (65%, 141%) higher direct costs than those without renal damage. Cumulative indirect costs and annual change in the SF-36 summary scores did not differ between patients. CONCLUSIONS: SLE patients with renal damage incurred higher direct costs, but did not experience a poorer QoL. QoL may be more influenced by concurrent renal activity than accumulated renal damage, which can occur at any time and patients may gradually habituate to their compromised health state.

Triggering of T-cell leukemia and dissemination of T-cell lymphoma in MMP-9-deficient mice.

Previous studies have shown that high levels of MMP-9 can be detected in the serum of patients with various lymphoid malignancies and in leukemia/lymphoma culture supernatants. Indeed, aggressive forms of lymphoma constitutively produce MMP-9 and its elevated levels in the serum or in tissues correlate with advanced stage and poor patient survival. In vitro, MMP-9, which is also produced by the host peritumoral cells in response to the presence of tumors, plays an important role in migration of tumor cells through artificial basement membranes or endothelial cells. In this study, using MMP-9-deficient mice, we show that absence of MMP-9 does not prevent the development of primary T-cell leukemia. Furthermore, MMP-9-deficient cell lines retained their tumorigenic potential, as shown by their ability to induce thymic lymphoma in young syngeneic wild-type animals. In addition, these MMP-9-deficient tumor cells disseminate in normal mice, or mice that are deficient for MMP-9, indicating that tumor growth and dissemination can occur in total absence of MMP-9. These results show for the first time than lymphoma growth can occur in total absence of MMP-9 and have consequences for therapy of invasive cancers with inhibitors of MMPs.

Mortality in systemic lupus erythematosus.

OBJECTIVE: To examine mortality rates in the largest systemic lupus erythematosus (SLE) cohort ever assembled. METHODS: Our sample was a multisite international SLE cohort (23 centers, 9,547 patients). Deaths were ascertained by vital statistics registry linkage. Standardized mortality ratio (SMR; ratio of deaths observed to deaths expected) estimates were calculated for all deaths and by cause. The effects of sex, age, SLE duration, race, and calendar-year periods were determined. RESULTS: The overall SMR was 2.4 (95% confidence interval 2.3-2.5). Particularly high mortality was seen for circulatory disease, infections, renal disease, non-Hodgkin's lymphoma, and lung cancer. The highest SMR estimates were seen in patient groups characterized by female sex, younger age, SLE duration <1 year, or black/African American race. There was a dramatic decrease in total SMR estimates across calendar-year periods, which was demonstrable for specific causes including death due to infections and death due to renal disorders. However, the SMR due to circulatory diseases tended to increase slightly from the 1970s to the year 2001. CONCLUSION: Our data from a very large multicenter international cohort emphasize what has been demonstrated previously in smaller samples. These results highlight the increased mortality rate in SLE patients compared with the general population, and they suggest particular risk associated with female sex, younger age, shorter SLE duration, and black/African American race. The risk for certain types of deaths, primarily related to lupus activity (such as renal disease), has decreased over time, while the risk for deaths due to circulatory disease does not appear to have diminished.

Non-Hodgkin's lymphoma in systemic lupus erythematosus.

BACKGROUND: Recent evidence supports an association between systemic lupus erythematosus (SLE) and non-Hodgkin's lymphoma (NHL). OBJECTIVES: To describe demographic factors, subtypes, and survival of patients with SLE who develop NHL. METHODS: A multi-site cohort of 9547 subjects with definite SLE was assembled. Subjects at each centre were linked to regional tumour registries to determine cancer cases occurring after SLE diagnosis. For the NHL cases ascertained, descriptive statistics were calculated, and NHL subtype frequency and median survival time of patients determined. RESULTS: 42 cases of NHL occurred in the patients with SLE during the 76,948 patient-years of observation. The median age of patients at NHL diagnosis was 57 years. Thirty six (86%) of the 42 patients developing NHL were women, reflecting the female predominance of the cohort. In the patients, aggressive histological subtypes appeared to predominate, with the most commonly identified NHL subtype being diffuse large B cell (11 out of 21 cases for which histological subtype was available). Twenty two of the patients had died a median of 1.2 years after lymphoma diagnosis. CONCLUSIONS: These data suggest aggressive disease in patients with SLE who develop NHL. Continuing work should provide further insight into the patterns of presentation, prognosis, and aetiology of NHL in SLE.

An international cohort study of cancer in systemic lupus erythematosus.

OBJECTIVE: There is increasing evidence in support of an association between systemic lupus erythematosus (SLE) and malignancy, but in earlier studies the association could not be quantified precisely. The present study was undertaken to ascertain the incidence of cancer in SLE patients, compared with that in the general population. METHODS: We assembled a multisite (23 centers) international cohort of patients diagnosed as having SLE. Patients at each center were linked to regional tumor registries to determine cancer occurrence. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. Cancers expected were determined by multiplying person-years in the cohort by the geographically matched age, sex, and calendar year-specific cancer rates, and summing over all person-years. RESULTS: The 9,547 patients from 23 centers were observed for a total of 76,948 patient-years, with an average followup of 8 years. Within the observation interval, 431 cancers occurred. The data confirmed an increased risk of cancer among patients with SLE. For all cancers combined, the SIR estimate was 1.15 (95% confidence interval [95% CI] 1.05-1.27), for all hematologic malignancies, it was 2.75 (95% CI 2.13-3.49), and for non-Hodgkin's lymphoma, it was 3.64 (95% CI 2.63-4.93). The data also suggested an increased risk of lung cancer (SIR 1.37; 95% CI 1.05-1.76), and hepatobiliary cancer (SIR 2.60; 95% CI 1.25, 4.78). CONCLUSION: These results support the notion of an association between SLE and cancer and more precisely define the risk of non-Hodgkin's lymphoma in SLE. It is not yet known whether this association is mediated by genetic factors or exogenous exposures.

The systemic lupus erythematosus tri-nation study: longitudinal changes in physical and mental well-being.

OBJECTIVE: We have shown that SLE patients in Canada and the UK incurred 20% and 13% lower health costs than those in the US, respectively, but did not experience worse outcomes as expressed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We now compare change in quality of life in these patients. PATIENTS AND METHODS: Seven hundred and fifteen SLE patients (Canada 231, US 269, UK 215) completed the SF-36 annually over four years. The annual change in the SF-36 Physical and Mental Component Summary (PCS and MCS) scores over the course of the study were summarized by estimating a linear trend for each individual patient using hierarchical modelling. Cross-country comparison of the slopes in the PCS and MCS scores was then performed using simultaneous regressions. RESULTS: The estimated mean annual changes (95% credible interval [CrI]) in the PCS scores in Canada, the US, and the UK were 0.18 (-0.07, 0.43), -0.05 (-0.27, 0.17), and 0.03 (-0.20, 0.27), respectively; the mean annual changes in the MCS scores were 0.15 (-0.04, 0.34), 0.23 (0.09, 0.37), and 0.08 (-0.10, 0.27), respectively. Regression results showed that the mean annual changes in PCS and MCS scores did not substantially differ across countries. CONCLUSION: Quality of life remained stable across countries. Despite Canadian and British patients incurring lower health costs, on average, patients experienced similar changes in physical and mental well-being.

The systemic lupus erythematosus Tri-nation Study: absence of a link between health resource use and health outcome.

OBJECTIVE: Health consumption and health status in SLE in three countries with different health funding structures were compared. METHODS: Seven hundred and fifteen SLE patients (Canada 231, USA 269, UK 215) were surveyed semi-annually over 4 yr for health resource utilization and health status. Cross-country comparisons of (i) cumulative health expenditure (calculated by applying 2002 Canadian prices to resources in all countries) and (ii) disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SLICC/ACR DI) at study conclusion were performed after adjustment. Missing expenditure and damage data were managed through multiple imputation using best predictive regressions with all available data from all patients as potential covariates. RESULTS: Four hundred and eighty-five patients provided data at study entry and conclusion and at least four resource questionnaires (Canada 162, USA 157, UK 166); 41 died (Canada 13, USA 18, UK 10); 189 withdrew, were lost to follow-up or provided data at entry and conclusion but fewer than four resource questionnaires (Canada 56, USA 94, UK 39). At conclusion, after imputation, in Canada, the USA and the UK respectively, mean cumulative costs per patient over 4 yr [95% confidence interval (CI)] were $15,845 (13,509, 18,182), $20,244 (17,764, 22,724) and $17,647 (15,557, 19,737) and mean changes in SLICC/ACR DI were 0.49 (0.39, 0.60), 0.63 (0.52, 0.74) and 0.48 (0.39, 0.57). After adjustment for baseline differences, on average (95% CI), Canadian and British patients utilized 20% (8%, 32%) and 13% (1%, 24%) less resources than patients in the USA respectively, but experienced similar health outcomes. CONCLUSION: Despite patients in the USA incurring higher health expenditures, they did not experience superior health outcomes.

Upregulation of galectin-7 in murine lymphoma cells is associated with progression toward an aggressive phenotype.

We have previously shown that ICAM-1-deficient mice were resistant to lymphoma dissemination of intravenously injected 164T2 lymphoma cells. Highly aggressive variants of this cell line, however, could overcome this resistance. To discern the complex pattern of gene expression involved in the evolution of aggressiveness in lymphoma cells, we compared the transcriptome of 164T2 cells with that of their aggressive variants using cDNA arrays. We identified several genes that were differentially expressed in nonmetastatic lymphoma cells and their metastatic variants. Galectin-7, associated with the development of chemically induced mammary carcinoma, was one such gene whose expression was significantly upregulated. We showed that it was constitutively expressed in aggressive variants, at both mRNA and protein levels. Galectin-7 expression in aggressive lymphoma cells was induced upon in vivo selection in several organs, including the thymus, the spleen and kidneys. We also showed that treatment of nonaggressive lymphoma cells with 5-aza-2'-deoxycytidine was sufficient to induce galectin-7 gene expression. This report is the first to show that galectin-7 is expressed in aggressive lymphoma.

Altered organ accumulation of oligonucleotides using polyethyleneimine grafted with poly(ethylene oxide) or pluronic as carriers.

Passive targeting provides a simple strategy based on natural properties of the carriers to deliver DNA molecules to desired compartments. Polyethylenimine (PEI) is a potent non-viral system that has been known to deliver efficiently both plasmids and oligonucleotides (ODNs) in vitro. However, in vivo systemic administration of DNA/PEI complexes has encountered significant difficulties because these complexes are toxic and have low biodistribution in target tissues. This study evaluates PEI grafted with poly(ethylene oxide) (PEO(8K)-g-PEI(2K)) and PEI grafted with non-ionic amphiphilic block copolymer, Pluronic P85 (P85-g-PEI(2K)) as carriers for systemic delivery of ODNs. Following i.v. injection an antisense ODN formulated with PEO(8K)-g-PEI(2K) accumulated mainly in kidneys, while the same ODN formulated with P85-g-PEI(2K) was found almost exclusively in the liver. Furthermore, in the case of the animals injected with the P85-g-PEI(2K)-based complexes most of the ODN was found in hepatocytes, while only a minor portion of ODN was found in the lymphocyte/monocyte populations. The results of this study suggest that formulating ODN with PEO(8K)-g-PEI(2K) and P85-g-PEI(2K) carriers allows targeting of the ODN to the liver or kidneys, respectively. The variation in the tissue distribution of ODN observed with the two carriers is probably due to the different hydrophilic-lipophilic balance of the polyether chains grafted to PEI in these molecules. Therefore, polyether-grafted PEI carriers provide a simple way to enhance ODN accumulation in a desired compartment without the need of a specific targeting moiety.

Inducing neutrophil recruitment in the liver of ICAM-1-deficient mice using polyethyleneimine grafted with Pluronic P123 as an organ-specific carrier for transgenic ICAM-1.

Coordinated expression of cell adhesion molecules and chemokines on the surface of vascular endothelium is responsible for the homing of immune effector cells to targeted sites. One way to attract non-activated immune cells to targeted organs is to use transgenically expressed adhesion molecules responsible for leukocyte recruitment. We have previously shown that polyethyleneimine (PEI) grafted with non-ionic amphiphilic Pluronic P123 block copolymer (P123PEI) modifies biodistribution of plasmid DNA toward the liver. In the present study, a P123PEI-formulated plasmid carrying the gene encoding for the murine ICAM-1 molecule was injected i.v. into transgenic ICAM-1-deficient mice. The RT-PCR analysis of ICAM-1 mRNA expression showed that P123PEI induced a dose-dependent expression of ICAM-1 in the liver. Furthermore, this expression of ICAM-1 induced neutrophil invasion in the liver, while no such invasion was observed in mice injected with formulated control plasmid or naked DNA. These results suggest that P123PEI allows functional transgene expression in the liver following i.v. injection and that ICAM-1 could be used to enhance immune response locally by attracting immune effector cells.

Radiographic damage in rheumatoid arthritis correlates with functional disability but not direct medical costs.

OBJECTIVE: Few longitudinal data exist on the relationship between radiographic damage and self-reported functional disability and direct medical costs in rheumatoid arthritis (RA). We assessed these relationships. METHODS: One hundred thirty patients with RA (at time of the first available radiograph, mean age 56.6 yrs, 16.9% male, mean disease duration 16.8 yrs) were followed for up to 13.4 years. Semiannually, they reported on functional disability (0 = no difficulty, 3 = unable to do), global severity (0 = very well, 100 = very poor), pain (0 = no pain, 3 = severe pain), and health services utilization through completion of the Stanford Health Assessment Questionnaire (HAQ). Concurrent hand radiographs were scored for erosions and joint space narrowing using the Genant method and a single score summing both erosions and joint space narrowing for both hands was calculated (0 = no damage, 200 = maximum damage). The univariate association of functional disability, global severity, pain, or direct medical costs with concurrent radiographic damage was assessed through Spearman correlations and hierarchical regression models. The hierarchical models permit exploitation of the between-patient and within-patient variation present in our longitudinal data. RESULTS: At the time of the first available radiograph, mean (SD) levels of functional disability, global severity, and pain were 1.3 (0.7), 39.4 (21.0), and 1.1 (0.7), respectively. At entry into the study, the average radiograph score was 49.7 and upon leaving the study it was 66.9. Patients were followed an average of 6.7 years, with radiograph scores increasing at an average rate of 2.5 units/yr. The Spearman correlation [95% confidence interval (CI)] between average per-patient radiograph score and average per-patient HAQ disability index, average per-patient global severity, average per-patient pain score, and average per-patient direct medical costs was, respectively, 0.42 (0.26, 0.55), 0.23 (0.06, 0.39), 0.20 (0.03, 0.36), and 0.06 (-0.11, 0.23). The mean slope (95% CI) for disability on radiograph score was 0.0186 (0.0132, 0.0226), for severity on radiographs 0.1889 (0.1295, 0.2498), and for pain on radiographs 0.0057 (0.0027, 0.0084). As an example, over 10 years, a 25 unit (i.e., 50%) increase in radiograph scores would, on average, be associated with a 0.46 unit (i.e., 35%) increase in disability, a 4.72 unit (12%) increase in global severity score, and a 0.14 unit (13%) increase in pain, all expressed on the HAQ scales. There was little association between radiograph score and direct medical costs. CONCLUSION: A clinically meaningful association exists between radiographic damage and self-reported functional disability, suggesting that interventions that slow radiographic progression may improve the patient's health status. Such a relationship was not observed between radiographic damage and direct medical costs.

Leukocyte elastase in murine and human non-Hodgkin lymphomas.

Extracellular proteases play a crucial role in the invasive behavior of normal and transformed leukocytes. Thus far, however, most of the attention has been focused on members of the family of matrix metalloproteinases. In this work, we show that lymphoma cells can express leukocyte elastase (LE) and recruit the enzyme at their surface via ICAM-1. The expression of LE by lymphoma cells was augmented significantly by stimulation with IL-6 and IL-13, both of which also induced the expression of MMP-9. Although LE and IL-13 transcripts were detected in several non-Hodgkin's lymphomas, immunohistochemical analysis of lymphoma tissues also showed that LE was strongly expressed in infiltrating leukocytes. Given the spectrum of key molecules that can be cleaved by LE and that LE and MMP-9 are involved in the invasive behavior of normal or transformed leukocytes, our results raise the hypothesis that LE plays a crucial role in the multistep processes of inflammation and lymphoma metastasis.

HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway.

It has been previously shown that the HIV-1 envelope glycoprotein 120 (gp120) activates cell signaling by CXCR4, independently of CD4. The present study examines the involvement of different intracellular signaling pathways and their physiopathologic consequences following the CD4-independent interaction between CXCR4 or CCR5 and gp120 in different cell types: primary T cells, CD4(-)/CXCR4(+)/CCR5(+) T cells, or glioma cells. These interactions were compared with those obtained with natural ligands, stromal cell-derived factor 1 alpha (SDF-1alpha) (CXCL12) and macrophage inflammatory protein 1 beta (MIP-1beta) (CCL4) of their respective coreceptors. Thus, both p38 and SAPK/Jun N-terminal kinase mitogen-activated protein kinases (MAPKs) are activated on stimulation of these cells with either T- or M-tropic gp120, as well as with SDF-1alpha or MIP-1beta. In contrast, extracellular signal-related kinase 1 and 2 MAPKs are only activated by MIP-1beta but not by M-tropic gp120. Importantly, T- and M-tropic gp120 are able to induce the secretion of matrix metalloproteinase 9 (MMP-9), an extracellular metalloproteinase present in cerebrospinal fluid of patients with HIV-1 by T cells or glioma cells. Specific inhibition of MAPK p38 activation resulted in a complete abrogation of the induction of the MMP-9 pathogenic factor expression by gp120 or chemokines in both cell types. Because neurodegenerative features in acquired immune deficiency syndrome dementia may involve demyelinization by MMP-9, the specific targeting of p38 could provide a novel means to control HIV-induced cytopathogenic effects and cell homing to viral replication sites. (Blood. 2001;98:541-547)