Statins research unfinished saga: desirability versus feasibility

Aims

Resistin is an adipocyte-derived factor implicated in obesity-associated type 2 diabetes (T2DM). This study examines the association between human serum resistin, T2DM and coronary heart disease.

Methods

One hundred and fourteen Saudi Arabian patients (male: female ratio 46:68; age 51.4 (mean ± SD)11.7 years; median and range: 45.59 (11.7) years and BMI: 27.1 (mean ± SD) 8.1 Kgm² median and range: 30.3 (6.3) were studied. Serum resistin and C-reactive protein (CRP), a marker of inflammation CRP levels, were measured in all subjects. (35 patients had type 2 diabetes mellitus (T2DM); 22 patients had coronary heart disease (CHD).

Results

Serum resistin levels were 1.2-fold higher in type 2 diabetes and 1.3-fold higher in CHD than in controls (p = 0.01). In addition, CRP was significantly increased in both T2DM and CHD patients (p = 0.007 and p = 0.002 respectively). The use of regression analysis also determined that serum resistin correlated with CRP levels (p = 0.04, R² 0.045).

Conclusion

The findings from this study further implicate resistin as a circulating protein associated with T2DM and CHD. In addition this study also demonstrates an association between resistin and CRP, a marker of inflammation in type 2 diabetic patients.     

RANKL inhibition by osteoprotegerin prevents bone loss without affecting local or systemic inflammation parameters in two rat arthritis models: comparison with anti-TNFα or anti-IL-1 therapies

Introduction

Rat adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) feature bone loss and systemic increases in TNFα, IL-1β, and receptor activator of NF-κB ligand (RANKL). Anti-IL-1 or anti-TNFα therapies consistently reduce inflammation in these models, but systemic bone loss often persists. RANKL inhibition consistently prevents bone loss in both models without reducing joint inflammation. Effects of these therapies on systemic markers of bone turnover and inflammation have not been directly compared.

Methods

Lewis rats with established AIA or CIA were treated for 10 days (from day 4 post onset) with either PBS (Veh), TNFα inhibitor (pegsunercept), IL-1 inhibitor (anakinra), or RANKL inhibitor (osteoprotegerin (OPG)-Fc). Local inflammation was evaluated by monitoring hind paw swelling. Bone mineral density (BMD) of paws and lumbar vertebrae was assessed by dual X-ray absorptiometry. Markers and mediators of bone resorption (RANKL, tartrate-resistant acid phosphatase 5b (TRACP 5B)) and inflammation (prostaglandin E₂ (PGE₂), acute-phase protein alpha-1-acid glycoprotein (α₁AGP), multiple cytokines) were measured in serum (day 14 post onset).

Results

Arthritis progression significantly increased paw swelling and ankle and vertebral BMD loss. Anti-TNFα reduced paw swelling in both models, and reduced ankle BMD loss in AIA rats. Anti-IL-1 decreased paw swelling in CIA rats, and reduced ankle BMD loss in both models. Anti-TNFα and anti-IL-1 failed to prevent vertebral BMD loss in either model. OPG-Fc reduced BMD loss in ankles and vertebrae in both models, but had no effect on paw swelling. Serum RANKL was elevated in AIA-Veh and CIA-Veh rats. While antiTNFα and anti-IL-1 partially normalized serum RANKL without any changes in serum TRACP 5B, OPG-Fc treatment reduced serum TRACP 5B by over 90% in both CIA and AIA rats. CIA-Veh and AIA-Veh rats had increased serum α₁AGP, IL-1β, IL-8 and chemokine (C-C motif) ligand 2 (CCL2), and AIA-Veh rats also had significantly greater serum PGE₂, TNFα and IL-17. Anti-TNFα reduced systemic α₁AGP, CCL2 and PGE₂ in AIA rats, while anti-IL-1 decreased systemic α₁AGP, IL-8 and PGE₂. In contrast, RANKL inhibition by OPG-Fc did not lessen systemic cytokine levels in either model.

Conclusions

Anti-TNFα or anti-IL-1 therapy inhibited parameters of local and systemic inflammation, and partially reduced local but not systemic bone loss in AIA and CIA rats. RANKL inhibition prevented local and systemic bone loss without significantly inhibiting local or systemic inflammatory parameters.     

Serum resistin in older patients with hip fracture: Relationship with comorbidity and biochemical determinants of bone metabolism

Objectives

To determine the relationship of serum resistin concentrations to biochemical determinants of bone metabolism, comorbidity and outcomes in patients with hip fracture (HF).

Methods

In 256 consecutive patients (mean age 81.9 ± 7.8 years; 71.1% women) serum levels of resistin (determined by ELISA), biochemical parameters of bone turnover and mineral metabolism as well as routine haematological and biochemical parameters were measured. Clinical data were recorded prospectively.

Results

In multivariate analysis cervical HF (OR = 1.81; 95% CI 1.05–3.11), diabetes (OR = 2.60; 95% CI 1.23–5.51) and history of stroke (OR = 2.67; 95% CI 1.17–6.13) were significant independent predictors of higher resistin levels (?16.26 ng/ml, median value). The independent correlates of serum resistin levels in patients with cervical HF were serum osteocalcin and magnesium (both negatively associated) and in patients with trochanteric HF, serum PTH, calcium and age (all positively associated). Resistin and glomerular filtration rate were the only independent (inverse) predictors of serum osteocalcin. Resistin levels on admission did not predict short-term outcomes.

Conclusions

In older patients with HF there is a significant association of higher resistin levels with cervical fracture, type 2 diabetes and history of stroke, which is partly influenced by the reciprocal interaction between resistin and osteocalcin. However, the design of the study does not prove causality and further prospective studies are needed to clarify these relationships.     

Type-2 diabetes-induced changes in vascular extracellular matrix gene expression: Relation to vessel size

Introduction

Inflammation contributes to cardiovascular disease and is exacerbated with increased adiposity, particularly omental adiposity; however, the role of epicardial fat is poorly understood.

Methods

For these studies the expression of inflammatory markers was assessed in epicardial fat biopsies from coronary artery bypass grafting (CABG) patients using quantitative RT-PCR. Further, the effects of chronic medications, including statins, as well as peri-operative glucose, insulin and potassium infusion, on gene expression were also assessed. Circulating resistin, CRP, adiponectin and leptin levels were determined to assess inflammation.

Results

The expression of adiponectin, resistin and other adipocytokine mRNAs were comparable to that in omental fat. Epicardial CD45 expression was significantly higher than control depots (p < 0.01) indicating significant infiltration of macrophages. Statin treated patients showed significantly lower epicardial expression of IL-6 mRNA, in comparison with the control abdominal depots (p < 0.001). The serum profile of CABG patients showed significantly higher levels of both CRP (control: 1.28 ± 1.57 μg/mL vs CABG: 9.11 ± 15.7 μg/mL; p < 0.001) and resistin (control: 10.53 ± 0.81 ng/mL vs CABG: 16.8 ± 1.69 ng/mL; p < 0.01) and significantly lower levels of adiponectin (control: 29.1 ± 14.8 μg/mL vs CABG: 11.9 ± 6.0 μg/mL; p < 0.05) when compared to BMI matched controls.

Conclusion

Epicardial and omental fat exhibit a broadly comparable pathogenic mRNA profile, this may arise in part from macrophage infiltration into the epicardial fat. This study highlights that chronic inflammation occurs locally as well as systemically potentially contributing further to the pathogenesis of coronary artery disease.     

Elevated serum triglycerides is the strongest single indicator for the presence of metabolic syndrome in patients with type 2 diabetes

Objectives

South-Asians have lower adiponectin levels compared to Caucasians. It was not clear however, if this intrinsic feature is related to aspects of glucose metabolism. This study aims to determine the relationship between body fat distribution and adipocytokine in South-Asian subjects by measuring serum adipocytokines, adiposity, insulinemia, and glucose tolerance levels.

Methods

In this cross-sectional study, 150 South-Asians (80 males, 70 females) were included, 60 had NGT (Control group, Age 51.33 ± 11.5, BMI 27 ± 2.3), 60 had IGT (Age 57.7 ± 12.5, BMI 27.2 ± 2.7), 30 had type 2 DM (Age 49.5 ± 10.9, BMI 28 ± 1.7). Measures of adiposity, adipocytokines and other metabolic parameters were determined. Parameters were measured using the following: a) Plasma glucose by glucose oxidase method b) CRP by immunoturbidimetric method (Roche/Hitachi analyser) c) insulin by Medgenix INS-ELISA immunoenzymetric assay by Biosource (Belgium) d) Leptin, Adiponectin by radioimmunoassay kits by Linco Research (St. Charles MO) e) Resistin by immunoassay kits by Phoenix Pharmaceuticals INC (530 Harbor Boulevard, Belmont CA 94002, USA).

Results

Adiponectin concentrations were highest in NGT, decreased in IGT and lowest in DMT2, (both p < 0.01). Leptin was significantly higher in DMT2 than IGT and NGT p = 0.02 and 0.04 respectively. There was a significant positive relationships between log adiponectin and 2-hr insulin values, p = 0.028 and history of hypertensions and a ischemic heart disease p = 0.008 with R = 0.65. There was a significant inverse correlation between log adiponectin and resistin, p < 0.01.

Conclusion

Resistin levels had an inverse correlation with adiponectin levels, indicating an inverse relationship between pro-inflammatory cytokines and adiponectin. Adiponectin levels were related to glucose tolerance.     

TLR7 single-nucleotide polymorphisms in the 3' untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women: a case-control association study

Introduction

The Toll-like receptor 7 (TLR7) gene, encoded on human chromosome Xp22.3, is crucial for type I interferon production. A recent multicenter study in East Asian populations, comprising Chinese, Korean and Japanese participants, identified an association of a TLR7 single-nucleotide polymorphism (SNP) located in the 3' untranslated region (3' UTR), rs3853839, with systemic lupus erythematosus (SLE), especially in males, although some difference was observed among the tested populations. To test whether additional polymorphisms contribute to SLE in Japanese, we systematically analyzed the association of TLR7 with SLE in a Japanese female population.

Methods

A case-control association study was conducted on eight tag SNPs in the TLR7 region, including rs3853839, in 344 Japanese females with SLE and 274 healthy female controls.

Results

In addition to rs3853839, two SNPs in intron 2, rs179019 and rs179010, which were in moderate linkage disequilibrium with each other (r ² = 0.53), showed an association with SLE (rs179019: P = 0.016, odds ratio (OR) 2.02, 95% confidence interval (95% CI) 1.15 to 3.54; rs179010: P = 0.018, OR 1.75, 95% CI 1.10 to 2.80 (both under the recessive model)). Conditional logistic regression analysis revealed that the association of the intronic SNPs and the 3' UTR SNP remained significant after we adjusted them for each other. When only the patients and controls carrying the risk genotypes at the 3' UTR SNPpositionwere analyzed, the risk of SLE was significantly increased when the individuals also carried the risk genotypes at both of the intronic SNPs (P = 0.0043, OR 2.45, 95% CI 1.31 to 4.60). Furthermore, the haplotype containing the intronic risk alleles in addition to the 3' UTR risk allele was associated with SLE under the recessive model (P = 0.016, OR 2.37, 95% CI 1.17 to 4.80), but other haplotypes were not associated with SLE.

Conclusions

The TLR7 intronic SNPs rs179019 and rs179010 are associated with SLE independently of the 3' UTR SNP rs3853839 in Japanese women. Our findings support a role of TLR7 in predisposition for SLE in Asian populations.     

Better assessment of physical function: item improvement is neglected but essential

Introduction

Cardiovascular disease (CVD) is a major cause of premature mortality among Systemic lupus erythematosus (SLE) patients. Many studies have measured and evaluated risk factors for premature subclinical atherosclerosis, but few studies are prospective and few have evaluated risk factors for hard endpoints, i.e. clinically important cardiovascular events (CVE). We investigated the impact of traditional and lupus associated risk factors for the first ever CVE in a longitudinal cohort of SLE patients.

Methods

A total of 182 SLE patients (mean age 43.9 years) selected to be free of CVE were included. Cardiovascular and autoimmune biomarkers were measured on samples collected after overnight fasting at baseline. Clinical information was collected at baseline and at follow up. End point was the first ever CVE (ischemic heart, cerebrovascular or peripheral vascular disease or death due to CVD). Impact of baseline characteristics/biomarkers on the risk of having a first CVE was evaluated with Cox regression.

Results

Follow up was 99.5% after a mean time of 8.3 years. Twenty-four patients (13%) had a first CVE. In age-adjusted Cox regression, any positive antiphospholipid antibody (aPL), elevated markers of endothelial activation (von Willebrand factor (vWf), soluble vascular cellular adhesion molecule-1 (sVCAM-1)) and fibrinogen predicted CVEs. Of SLE manifestations, arthritis, pleuritis and previous venous occlusion were positively associated with future CVEs while thrombocytopenia was negatively associated. Among traditional risk factors only age and smoking were significant predictors. In a multivariable Cox regression model age, any positive aPL, vWf and absence of thrombocytopenia were all predictors of the first CVE.

Conclusions

In addition to age, positive aPL, biomarkers indicating increased endothelial cell activity/damage, and absence of thrombocytopenia were independent predictors of CVEs in this prospective study. Our results indicate that activation of the endothelium and the coagulation system are important features in SLE related CVD. Furthermore, we observed that the risk of CVEs seems to differ between subgroups of SLE patients.     

Reduced trabecular bone mineral density and cortical thickness accompanied by increased outer bone circumference in metacarpal bone of rheumatoid arthritis patients: a cross-sectional study

Introduction

The objective of this study was to assess three-dimensional bone geometry and density at the epiphysis and shaft of the third meta-carpal bone of rheumatoid arthritis (RA) patients in comparison to healthy controls with the novel method of peripheral quantitative computed tomography (pQCT).

Methods

PQCT scans were performed in 50 female RA patients and 100 healthy female controls at the distal epiphyses and shafts of the third metacarpal bone, the radius and the tibia. Reproducibility was determined by coefficient of varia-tion. Bone densitometric and geometric parameters were compared between the two groups and correlated to disease characteristics.

Results

Reproducibility of different pQCT parameters was between 0.7% and 2.5%. RA patients had 12% to 19% lower trabecular bone mineral density (BMD) (P ≤ 0.001) at the distal epiphyses of radius, tibia and metacarpal bone. At the shafts of these bones RA patients had 7% to 16% thinner cortices (P ≤ 0.03). Total cross-sectional area (CSA) at the metacarpal bone shaft of pa-tients was larger (between 5% and 7%, P < 0.02), and relative cortical area was reduced by 13%. Erosiveness by Ratingen score correlated negatively with tra-becular and total BMD at the epiphyses and shaft cortical thickness of all measured bones (P < 0.04).

Conclusions

Reduced trabecular BMD and thinner cortices at peripheral bones, and a greater bone shaft diameter at the metacarpal bone suggest RA spe-cific bone alterations. The proposed pQCT protocol is reliable and allows measuring juxta-articular trabecular BMD and shaft geometry at the metacarpal bone.     

The peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate maintains bone mass, while the PPAR gamma agonist pioglitazone exaggerates bone loss, in ovariectomized rats

Background

Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats.

Methods

Fifty-five female Sprague-Dawley rats were assigned to five groups. One group was sham-operated and given vehicle (methylcellulose), the other groups were ovariectomized and given vehicle, fenofibrate, Wyeth 14643 and pioglitazone, respectively, daily for four months. Whole body and femoral BMD were measured by dual X-ray absorptiometry (DXA), and biomechanical testing of femurs, and micro-computed tomography (microCT) of the femoral shaft and head, were performed.

Results

Whole body and femoral BMD were significantly higher in sham controls and ovariectomized animals given fenofibrate, compared to ovariectomized controls. Ovariectomized rats given Wyeth 14643, maintained whole body BMD at sham levels, while rats on pioglitazone had lower whole body and femoral BMD, impaired bone quality and less mechanical strength compared to sham and ovariectomized controls. In contrast, cortical volume, trabecular bone volume and thickness, and endocortical volume were maintained at sham levels in rats given fenofibrate.

Conclusions

The PPARalpha agonist fenofibrate, and to a lesser extent the PPARaplha agonist Wyeth 14643, maintained BMD and bone architecture at sham levels, while the PPARgamma agonist pioglitazone exaggerated bone loss and negatively affected bone architecture, in ovariectomized rats.     

Les manifestations hématologiques du lupus érythémateux systémique. A propos de 70 cas dans une série de 80 LES

Abstract

Systemic lupus erythematosus is a non-organ specific auto-immune disease which commonly has haematological manifestations. The aim of this study was to assess the epidemiological aspects of haematological manifestations among 80 patients with systemic lupus erythematosus (SLE).

Methods

A retrospective study of 80 SLE patients covering the period between 1990 and May 2005.

Results

From among the 80 patients with SLE, 70 had haematological manifestations, of which 65 women and 5 men. Average age was 32.41 years. The most commonly-observed haematological manifestation was anaemia (83.75%), followed by bicytopaenia (63.75%) then leukocytopaenia and/or lymphocytopaenia (62.5).     

Ibandronate increases cortical bone density in patients with systemic lupus erythematosus on long-term glucocorticoid

Introduction

The purpose of this research is to assess the effects of oral ibandronate on bone microarchitecture by using high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with systemic lupus erythematosus (SLE) taking a long-term glucocorticoid.

Methods

In this double-blind placebo-controlled study, 40 Chinese female SLE patients taking prednisolone were randomly assigned to receive either monthly oral ibandronate (150 mg) or placebo with daily 1-hydroxycholecalciferol (Alfacalcidol; 1 μg) and calcium supplement for 12 months. Assessments of bone microarchitecture by using HR-pQCT and area bone mineral density (aBMD) of the lumbar spine and hip with dual-energy x-ray absorptiometry (DXA) were performed at baseline and 12 months.

Results

No differences in baseline characteristics were found between the two groups. After 12 months, no statistical differences were noted in any of the bone densities, microarchitectural parameters, or percentage changes of these parameters, as measured with HR-pQCT or DXA between the two groups. However, within the active group, the percentage improvement was significant in cortical bone density (P = 0.023) which was absent in the placebo group. Improvement was also seen in the aBMD of both the lumbar spine (P < 0.0001) and the hip (P < 0.005). In the placebo group, the percentage increase in trabecular separation was significant (P = 0.04), and the percentage improvement in aBMD in the spine also was significant (P = 0.049).

Conclusions

Oral ibandronate treatment improves microarchitecture in SLE patients taking long-term glucocorticoid assessed with HR-pQCT, and this new technology may have a role in assessing bony changes in future longitudinal studies in SLE patients.

Trial registration

ClinicalTrials.gov identifier: NCT00668330.     

Resistin in idiopathic inflammatory myopathies

Introduction

The purpose of this study was to evaluate and compare the serum levels and local expression of resistin in patients with idiopathic inflammatory myopathies to controls, and to determine the relationship between resistin levels, inflammation and disease activity.

Methods

Serum resistin levels were determined in 42 patients with inflammatory myopathies and 27 healthy controls. The association among resistin levels, inflammation, global disease activity and muscle strength was examined. The expression of resistin in muscle tissues from patients with inflammatory myopathies and healthy controls was evaluated. Gene expression and protein release from resistin-stimulated muscle and mononuclear cells were assessed.

Results

In patients with inflammatory myopathies, the serum levels of resistin were significantly higher than those observed in controls (8.53 ± 6.84 vs. 4.54 ± 1.08 ng/ml, P < 0.0001) and correlated with C-reactive protein (CRP) levels (r = 0.328, P = 0.044) and myositis disease activity assessment visual analogue scales (MYOACT) (r = 0.382, P = 0.026). Stronger association was observed between the levels of serum resistin and CRP levels (r = 0.717, P = 0.037) as well as MYOACT (r = 0.798, P = 0.007), and there was a trend towards correlation between serum resistin and myoglobin levels (r = 0.650, P = 0.067) in anti-Jo-1 positive patients. Furthermore, in patients with dermatomyositis, serum resistin levels significantly correlated with MYOACT (r = 0.667, P = 0.001), creatine kinase (r = 0.739, P = 0.001) and myoglobin levels (r = 0.791, P = 0.0003) and showed a trend towards correlation with CRP levels (r = 0.447, P = 0.067). Resistin expression in muscle tissue was significantly higher in patients with inflammatory myopathies compared to controls, and resistin induced the expression of interleukins (IL)-1β and IL-6 and monocyte chemoattractant protein (MCP)-1 in mononuclear cells but not in myocytes.

Conclusions

The results of this study indicate that higher levels of serum resistin are associated with inflammation, higher global disease activity index and muscle injury in patients with myositis-specific anti-Jo-1 antibody and patients with dermatomyositis. Furthermore, up-regulation of resistin in muscle tissue and resistin-induced synthesis of pro-inflammatory cytokines in mononuclear cells suggest a potential role for resistin in the pathogenesis of inflammatory myopathies.     

Distinguishing fibromyalgia from rheumatoid arthritis and systemic lupus in clinical questionnaires: an analysis of the revised Fibromyalgia Impact Questionnaire (FIQR) and its variant, the Symptom Impact Questionnaire (SIQR), along with pain locations

Introduction

The purpose of this study was to explore a data set of patients with fibromyalgia (FM), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who completed the Revised Fibromyalgia Impact Questionnaire (FIQR) and its variant, the Symptom Impact Questionnaire (SIQR), for discriminating features that could be used to differentiate FM from RA and SLE in clinical surveys.

Methods

The frequency and means of comparing FM, RA and SLE patients on all pain sites and SIQR variables were calculated. Multiple regression analysis was then conducted to identify the significant pain sites and SIQR predictors of group membership. Thereafter stepwise multiple regression analysis was performed to identify the order of variables in predicting their maximal statistical contribution to group membership. Partial correlations assessed their unique contribution, and, last, two-group discriminant analysis provided a classification table.

Results

The data set contained information on the SIQR and also pain locations in 202 FM, 31 RA and 20 SLE patients. As the SIQR and pain locations did not differ much between the RA and SLE patients, they were grouped together (RA/SLE) to provide a more robust analysis. The combination of eight SIQR items and seven pain sites correctly classified 99% of FM and 90% of RA/SLE patients in a two-group discriminant analysis. The largest reported SIQR differences (FM minus RA/SLE) were seen for the parameters "tenderness to touch," "difficulty cleaning floors" and "discomfort on sitting for 45 minutes." Combining the SIQR and pain locations in a stepwise multiple regression analysis revealed that the seven most important predictors of group membership were mid-lower back pain (29%; 79% vs. 16%), tenderness to touch (11.5%; 6.86 vs. 3.02), neck pain (6.8%; 91% vs. 39%), hand pain (5%; 64% vs. 77%), arm pain (3%; 69% vs. 18%), outer lower back pain (1.7%; 80% vs. 22%) and sitting for 45 minutes (1.4%; 5.56 vs. 1.49).

Conclusions

A combination of two SIQR questions ("tenderness to touch" and "difficulty sitting for 45 minutes") plus pain in the lower back, neck, hands and arms may be useful in the construction of clinical questionnaires designed for patients with musculoskeletal pain. This combination provided the correct diagnosis in 97% of patients, with only 7 of 253 patients misclassified.     

Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)α agonist fenofibrate and the PPARγ agonist pioglitazone

Background

All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARγ agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARα agonist fenofibrate (FENO) and the PPARγ agonist pioglitazone (PIO) on bone in intact female rats.

Methods

Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied.

Results

The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1.

Conclusion

We show opposite skeletal effects of PPARα and γ agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARα activation.     

Only one independent genetic association with rheumatoid arthritis within the KIAA1109-TENR-IL2-IL21 locus in Caucasian sample sets: confirmation of association of rs6822844 with rheumatoid arthritis at a genome-wide level of significance

Introduction

To investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years.

Methods

In 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years.

Results

68% of the patients had accelerated hand BMD loss (>-0.003 g/cm²) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage.

Conclusions

In the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year.     

Which measuring site in ankylosing spondylitis is best to detect bone loss and what predicts the decline: results from a 5-year prospective study

Background

Studies have shown increased prevalence of osteoporosis and increased risk for vertebral fractures in patients with ankylosing spondylitis (AS). Measurements of bone mineral density (BMD) in the lumbar spine anterior-posterior (AP) projection may be difficult to interpret due to the ligamentous calcifications, and the lateral projection might be a better measuring site. Our objectives were to investigate BMD changes after 5 years at different measuring sites in patients with AS and to evaluate disease-related variables and medications as predictors for BMD changes.

Methods

In a longitudinal study, BMD in Swedish AS patients, 50?±?13 years old, was measured with dual-energy x-ray absorptiometry (DXA) at the hip, the lumbar spine AP and lateral projections, and the total radius at baseline and after 5 years. Patients were assessed with questionnaires, blood samples, and spinal radiographs for grading of AS-related alterations in the spine with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and assessment of vertebral fractures by the Genant score. Multiple linear regression analyses were used to investigate predictors for BMD changes.

Results

Of 204 patients included at baseline, 168 (82%) were re-examined after 5 years (92 men and 76 women). BMD decreased significantly at the femoral neck and radius and increased significantly at the lumbar spine, both for AP and lateral projections. Mean C-reactive protein during follow-up predicted a decrease in the femoral neck BMD (change in %, β?=?–0.15, p?=?0.046). Use of bisphosphonates predicted an increase in BMD at all measuring sites (p?<?0.001 to 0.013), except for the total radius. Use of tumor necrosis factor inhibitors (TNFi) predicted an increase in AP spinal BMD (β?=?3.15, p?=?0.012).

Conclusion

The current study (which has a long follow-up, many measuring sites, and is the first to longitudinally assess the lateral projection of the spine in AS patients) surprisingly showed that lateral projection spinal BMD increased. This study suggests that the best site to assess bone loss in AS patients is the femoral neck and that inflammation has an adverse effect, and the use of bisphosphonates and TNFi has a positive effect, on BMD in AS patients.

     

Early repolarization with horizontal ST segment may be associated with aborted sudden cardiac arrest: a retrospective case control study

Background

Patients with systemic lupus erythematosus (SLE) have increased cardiovascular morbidity and mortality. Although autopsy studies have documented that the heart is affected in most SLE patients, clinical manifestations occur in less than 10%. QT dispersion is a new parameter that can be used to assess homogeneity of cardiac repolarization and autonomic function. We compared the increase in QT dispersion in SLE patients with high disease activity and mild or moderate disease activity.

Methods and Results

One hundred twenty-four patients with SLE were enrolled in the study. Complete history and physical exam, ECG, echocardiography, exercise test and SLE disease activity index (SLEDAI) were recorded. Twenty patients were excluded on the basis of our exclusion criteria. The patients were divided to two groups based on SLEDAI: 54 in the high-score group (SLEDAI > 10) and 50 in the low-score group (SLEDAI < 10). QT dispersion was significantly higher in high-score group (58.31 ± 18.66 vs. 47.90 ± 17.41 respectively; P < 0.004). QT dispersion was not significantly higher in patients who had received hydroxychloroquine (54.17 ± 19.36 vs. 50.82 ± 15.96, P = 0.45) or corticosteroids (53.58 ± 19.16 vs. 50.40 + 11.59, P = 0.47). There was a statistically significant correlation between abnormal echocardiographic findings (abnormalities of pericardial effusion, pericarditis, pulmonary hypertension and Libman-Sacks endocarditis) and SLEADI (P < 0.004).

Conclusions

QT dispersion can be a useful, simple noninvasive method for the early detection of cardiac involvement in SLE patients with active disease. Concerning high chance of cardiac involvement, cardiovascular evaluation for every SLE patient with a SLEDAI higher than 10 may be recommended.

Trial registration

Clinicaltrial.gov registration NCT01031797     

Osteoporosis in ankylosing spondylitis - prevalence, risk factors and methods of assessment

Introduction

Osteoporosis can be a complication of ankylosing spondylitis (AS), but diagnosing spinal osteoporosis can be difficult since pathologic new bone formation interferes with the assessment of the bone mineral density (BMD). The aims of the current study were to investigate prevalence and risk factors for reduced BMD in a Swedish cohort of AS patients, and to examine how progressive ankylosis influences BMD with the use of dual-energy x-ray absorptiometry (DXA) of the lumbar spine in different projections.

Methods

Methods of assessment were questionnaires, back mobility tests, blood samples, lateral spine radiographs for syndesmophyte grading (mSASSS), DXA of the hip, radius and lumbar spine in anteroposterior (AP) and lateral projections with estimation of volumetric BMD (vBMD).

Results

AS patients (modified New York criteria), 87 women and 117 men, mean age 50 ± 13 years and disease duration 15 ± 11 years were included. According to World Health Organization (WHO) criteria 21% osteoporosis and 44% osteopenia was diagnosed in patients > = 50 years. Under age 50 BMD below expected range for age was found in 5%. Interestingly lateral lumbar DXA showed significantly lower BMD and revealed significantly more cases with osteoporosis as compared with AP DXA. Lumbar vBMD was not different between sexes, but women had significantly more lumbar osteoporosis measured with AP DXA (P < 0.001). Men had significantly higher mSASSS (P < 0.001). Low BMD was associated with high age, disease duration, mSASSS, Bath Ankylosing Spondylitis Metrology Index (BASMI), inflammatory parameters and low body mass index (BMI). Increasing mSASSS correlated significantly with decreasing lateral and volumetric lumbar BMD, while AP lumbar BMD showed tendency to increase.

Conclusions

Osteoporosis and osteopenia is common in AS and associated with high disease burden. Lateral and volumetric lumbar DXA are more sensitive than AP DXA in detecting osteoporosis and are less affected by syndesmophyte formation.     

Ablation of prion protein immunoreactivity by heating in saturated calcium hydroxide

Background

Depression is common among diabetic subjects. We conducted the present study to estimate the prevalence of depression in subjects with type 2 diabetes (T2D) in Greece.

Methods

The study sample consisted of 320 T2D subjects without overt macrovascular disease attending the diabetes outpatient clinic of our hospital, from June 2007 to December 2007. Depressive symptoms were measured using the 21-item Beck Depression Inventory, modified for use in diabetic subjects.

Results

Of the study subjects 107 (33.4%) reported elevated depressive symptoms. More women than men with diabetes reported symptoms of depression (48.4% vs. 12.7%, P < 0.001). In the female study group, depressive symptoms were correlated with HbA_1c (P = 0.04), and duration of diabetes (P = 0.004). In the male study group, univariate linear regression analysis showed no significant relationships between depressive symptoms and the testing variables.

Conclusion

The prevalence of depression in Greek T2D subjects is high. Diabetic female subjects showed increased levels of depressive symptoms compared with male subjects. Independent risk factors of depressive symptoms in diabetic female subjects were diabetes duration and glycemic control.