BackgroundSignificant fatigue is a frequent reason for seeking medical advice in the general population. Patients, however, commonly feel their complaint is ignored. This situation may be because clinicians perceive fatigue to be benign, unrelated to traditional biomedical outcomes such as premature mortality. The present study aimed to investigate whether an association between significant fatigue and mortality actually exists, and, if so, to identify potential mechanisms of this association.MethodsA population-based cohort of 18,101 men and women aged 40–79 years who completed a measure of fatigue (Short Form 36 vitality domain, SF36-VT) in addition to providing information on possible confounding factors (age, sex, body mass index, marital status, smoking, education level, alcohol consumption, social class, depression, bodily pain, diabetes, use of β blockers, physical activity and diet) and mechanisms (haemoglobin, C-reactive protein and thyroid function) were followed up prospectively for up to 20 years. Mortality from all causes, cancer and cardiovascular disease was ascertained using death certification linkage with the UK Office of National Statistics.ResultsDuring 300,322 person years of follow-up (mean 16.6 years), 4397 deaths occurred. After adjusting for confounders, the hazard ratio (HR) for all-cause mortality was 1.40 (95 % confidence interval [CI] 1.25–1.56) for those reporting the highest fatigue (bottom SF36-VT quartile) compared with those reporting the lowest fatigue (top SF36-VT quartile). This significant association was specifically observed for those deaths related to cardiovascular disease (HR 1.45, 95 % CI 1.18–1.78) but not cancer (HR 1.09, 95 % CI 0.90–1.32). Of the considered mechanisms, thyroid function was most notable for attenuating this association. The risk of all-cause mortality, however, remained significant even after considering all putative confounders and mechanisms (HR 1.26, 95 % CI 1.10–1.45).ConclusionsHigh levels of fatigue are associated with excess mortality in the general population. This commonly dismissed symptom demands greater evaluation and should not automatically be considered benign.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0662-y) contains supplementary material, which is available to authorized users.
A number of environmental exposures are likely to play an important role in the development of the disease; however, current evidence consists mainly of heterogeneous studies with relatively small sample sizes. In the future, multicentre collaborations may help inform preventive strategies.
BackgroundThe inhibitory CTLA-4 molecule is a crucial regulator of immune responses and a target for therapeutic intervention in both autoimmunity and cancer. In particular, CTLA-4 is important in controlling antigen-specific immunity, including responses to autoantigens associated with autoimmune disease. Here, we investigate cytokine responses to a range of lupus-associated autoantigens and assess whether the alternatively spliced isoform of CTLA-4, soluble CTLA-4 (sCTLA-4), contributes to immune regulation of autoantigen-specific immunity in systemic lupus erythematosus (SLE).MethodsThe cell culture supernatant production of sCTLA-4 as well as the cytokines IL-10, IFN-γ, and IL-17 from peripheral blood mononuclear cells (PBMC) from lupus patients and age- and sex-matched healthy volunteer donors were measured in response to previously identified histone and small nuclear ribonucleoprotein (snRNP) autoantigen-derived peptides (H391-105, H471-93, and U170K131-151) by ELISA. We also examined the functional contribution of sCTLA-4 to immune regulation in the context of these autoantigenic peptides following blockade of sCTLA-4 with a selective anti-sCTLA-4 monoclonal antibody, JMW-3B3.ResultsWe identified responses to autoantigenic peptides, which revealed qualitative differences in cytokine (IL-10, IL-17, and IFN-γ) profiles between SLE patients and healthy donors. PBMC from healthy donors responded to each of the lupus peptides by secreting IFN-γ and IL-17, but PBMC from SLE patients produced IL-10. Although we did not observe differences in the levels of serum or PBMC culture supernatant sCTLA-4 in either cohort, blockade of sCTLA-4 in PBMC cultures responding to antigen enhanced the cytokine profiles associated with each group.ConclusionThe results show that lupus autoantigen-derived peptides display varied immunogenicity in lupus versus healthy volunteer donors, while sCTLA-4 acts to regulate the T-cell activity independently of response profile.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1075-1) contains supplementary material, which is available to authorized users.
The term 'osteonecrosis of the jaw' is typically used to describe the exposure of bone within the oral cavity. These lesions are often painful and can result in pathological fracture and disfigurement in severe cases. Infection and dental extractions commonly precede presentation, although lesions can occur spontaneously. There are no clear effective management strategies; surgery often makes the situation worse. The aetiology is far from clear. Historically, it was mainly associated with exposure to 'white phosphorus' contained in safety matches. More recently, it has presented as a complication of head and neck radio-therapy. The vast majority of contemporary reports refer to high-dose intravenous bisphosphonates used in the oncological setting. However, oral bisphosphonates, for the common indication of postmenopausal osteoporosis, have also been implicated, although the number of cases is minuscule considering the number of worldwide prescriptions. Osteonecrosis of the jaw poses a significant problem in oncology, but whether this worry is transferable to metabolic bone disease only time will tell. Certainly, further research into its pathophysiology and management is merited. With regard to management of postmenopausal osteoporosis, practice should not necessarily be altered at this early stage; however, pre-treatment worries regarding dental health should perhaps instigate a precautionary dental review.
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