The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation

OBJECTIVE: Spondylarthritis (SpA) and rheumatoid arthritis (RA) have different patterns of bone damage, with more pronounced bone erosions in RA. The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in bone resorption by promoting the maturation and activation of osteoclasts. To assess the potential role of this system in the distinct bone phenotype, we studied the synovial expression of these mediators in SpA and RA peripheral synovitis. METHODS: Synovial biopsy specimens were obtained from the actively inflamed peripheral joints of 35 patients with SpA and 19 patients with RA. Paired synovial biopsy samples were obtained from 24 patients with SpA after tumor necrosis factor alpha (TNFalpha) blockade. Synovial tissue sections were immunostained for RANKL, OPG, RANK, and TRAP and assessed by semiquantitative scoring and digital image analysis. RESULTS: After extensive validation of the reactivity and specificity of the antibodies, we demonstrated the abundant expression of RANKL and OPG in SpA synovitis. RANKL was expressed by both fibroblast-like synoviocytes and sublining T lymphocytes. RANK-positive osteoclast precursors but no mature TRAP-positive osteoclasts were present in the inflamed tissue. The expression of these mediators was not different between patients with nonpsoriatic SpA, patients with psoriatic SpA, and patients with RA, was not related to the degree of systemic or local inflammation, and was not significantly modulated by highly effective treatment with TNFalpha blockers. Only the subset of patients with the best systemic response to TNFalpha blockade had decreased RANKL expression in the intimal lining layer. CONCLUSION: The relative protection against bone erosions in SpA cannot be explained by qualitative or quantitative differences in the synovial expression of RANKL, OPG, and RANK. The abundant expression of these factors in SpA peripheral synovitis is largely disconnected from systemic and local inflammation.     

Lipotoxicity in type 2 diabetic cardiomyopathy

As obesity and type 2 diabetes are becoming an epidemic in westernized countries, the incidence and prevalence of obesity- and diabetes-related co-morbidities are increasing. In type 2 diabetes ectopic lipid accumulation in the heart has been associated with cardiac dysfunction and apoptosis, a process termed lipotoxicity. Since cardiovascular diseases are the main cause of death in diabetic patients, diagnosis and treatment become increasingly important. Although ischaemic heart disease is a major problem in diabetes, non-ischaemic heart disease (better known as diabetic cardiomyopathy) becomes increasingly important with respect to the impairment of cardiac function and mortality in type 2 diabetes. The underlying aetiology of diabetic cardiomyopathy is incompletely understood but is beginning to be elucidated. Various mechanisms have been proposed that may lead to lipotoxicity. Therefore, this review will focus on the mechanisms of cardiac lipid accumulation and its relation to the development of cardiomyopathy.     

Cognitive decline is associated with an accelerated rate of bone loss and increased fracture risk in women: a prospective study from the Canadian Multicentre Osteoporosis Study

Cognitive decline and osteoporosis often coexist and some evidence suggests a causal link. However, there are no data on the longitudinal relationship between cognitive decline, bone loss and fracture risk, independent of aging. This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline (≥3 points) on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged ≥65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Association between cognitive decline and (i) bone loss was estimated using mixed-effects models; and (ii) fracture risk was estimated using adjusted Cox models. Over 95% of participants had normal cognition at baseline (MMSE ≥ 24). The annual % change in MMSE was similar for both genders (women −0.33, interquartile range [IQR] −0.70 to +0.00; and men −0.34, IQR: −0.99 to 0.01). After multivariable adjustment, cognitive decline was associated with bone loss in women (6.5%; 95% confidence interval [CI], 3.2% to 9.9% for each percent decline in MMSE from baseline) but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly (multivariable hazard ratio [HR], 1.61; 95% CI, 1.11 to 2.34). There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women. Further studies are needed to determine mechanisms that link these common conditions. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Fatigue in facioscapulohumeral muscular dystrophy: a qualitative study of people’s experiences

Purpose: The aim of this article is to describe how fatigue affects the lives of people with facioscapulohumeral dystrophy (FSHD), how they experience fatigue, and how they deal with it in order to attune rehabilitation care to patients’ needs.

Method: A qualitative study, consisting of 25 semistructured interviews with patients with FSHD and severe fatigue (as measured with the checklist individual strength (CIS) fatigue questionnaire), was conducted to gain insight into the experiences of patients with fatigue. Data were inductively analyzed.

Results: Patients describe fatigue as an overwhelming and unpredictable experience and they make a distinction between actual experienced fatigue and fear of becoming tired. Fatigue can, according to patients, be the result of weak muscles, physical overachieving or underachieving and stress. But most of the time patients do not know the actual causes of the fatigue, which makes it hard to deal with. The experienced fatigue has a large impact on participation, social contacts, and the quality of life of patients, and patients try to use many strategies to adapt themselves to the constantly changing situations.

Conclusions: Fatigue is a severe problem in FSHD and has a huge impact on patients’ lives. Patients should be helped to reduce fatigue, for instance by offering evidence-based therapies such as aerobic exercise training or cognitive behavioral therapy.

• Implications for Rehabilitation

• Fatigue has significant influence on the quality of lives and participation of people with FSHD.

• Patients with FSHD are insufficient supported in coping with their fatigue.

• More attention for fatigue in patients with FSHD in rehabilitation is needed, for instance by a broader implementation of aerobic exercise training or cognitive behavioral therapy.

     

Am I My Brother’s Keeper? Moral Dimensions of Informal Caregiving in a Neoliberal Society

Within the current Dutch policy context the role of informal care is revalued. Formal care activities are reduced and family and friends are expected to fill this gap. Yet, there is little research on the moral ambivalences that informal care for loved ones who have severe and ongoing mental health problems entails, especially against the backdrop of neoliberal policies. Giving priority to one’s own life project or caring for a loved one with severe problems is not reconciled easily. Using a case study we illustrate the moral ambivalences that persons may experience when they try to shape their involvement and commitment when a relative is in need. The case comes from a research project which explores whether it is possible to reduce coercive measures in psychiatry by organizing a Family Group Conference. The purpose of the article is to explore what theoretical concepts such as ‘communities of fate’, ‘communities of choice’ and ‘personal communities’ add in understanding how persons shape their involvement and commitment when a family member experiences recurrent psychiatric crises.     

Researchers' opinions towards the communication of results of biobank research: a survey study

Eighty Dutch investigators (response 41%) involved in biobank research responded to a web-based survey addressing communication of results of biobank research to individual participants. Questions addressed their opinion towards an obligation to communicate results and related issues such as ownership of blood samples, privacy, therapeutic relationship, costs and implications for participants. Most researchers (74%) indicated that participants only have to be informed when results have implications for treatment or prevention. Researchers were generally not inclined to provide more feedback to patients as compared with healthy participants, nor were they inclined to provide feedback in return for participants' contribution to the biobank. Our results demonstrate major and significant differences in opinion about the feedback of individual results within the community of biobank researchers.     

LPS-induced release of IL-1beta, IL-1Ra, IL-6, and TNF-alpha in whole blood from patients with familial hypercholesterolemia: no effect of cholesterol-lowering treatment.

Proinflammatory cytokines, such as interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha), are suggested to have an important role in the process of atherosclerosis. Patients with heterozygous familial hypercholesterolemia (FH) have a marked elevation in the plasma level of low-density lipoproteins (LDL), and they show early development of atherosclerosis. The aim of the present study was to test with a whole blood culture system if hyperlipoproteinemia is associated with increased cytokine production capacity in these patients and if treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors influences this production capacity of blood cells, at both the protein and mRNA levels. The capacity of blood cells in a whole blood culture to produce IL-1beta, IL-6, TNF-alpha, IL-12, IL-18, and IL-1 receptor antagonist (IL-1Ra) in response to lipopolysaccharide (LPS) appeared to be similar for heterozygous FH patients and healthy volunteers. Furthermore, the capacity to produce IL-1beta, IL-6, and TNF-alpha in response to LPS was not modified by cholesterol synthesis inhibitors at the level of mRNA expression or at the level of release. On the other hand, the release of IL-1Ra was significantly increased after treatment with HMG-CoA reductase inhibitors, although only at the protein level. This suggests a possible beneficial anti-inflammatory role for this therapy.