Good Health-Related Quality of Life in Older Patients One Year after mTBI despite Incomplete Recovery: An Indication of the Disability Paradox?

Background: Older adults (OAs) with mild traumatic brain injury (OA-mTBI) are a growing population, but studies on long-term outcomes and quality of life are scarce. Our aim was to determine the health-related quality of life (HRQoL) in OA-mTBI one year after injury and to assess the early predictors of HRQoL. Methods: Data from a prospective follow-up study of 164 older (≥60 years) and 289 younger mTBI patients (<60 years) admitted to the emergency department were analyzed. Post-traumatic complaints, emotional distress and coping were evaluated 2 weeks post-injury using standardized questionnaires. At 12 months post-injury, HRQoL and functional recovery were determined with the abbreviated version of the World Health Organization Quality of Life scale and Glasgow Outcome Scale Extended (GOSE), respectively. Results: One year post-injury, 80% (n = 131) of the OA-mTBI rated their HRQoL as "good" or "very good", which was comparable to younger patients (79% (n = 226), p = 0.72). Incomplete recovery (GOSE <8) was present in 43% (n = 69) of OA-mTBI, with 67% (n = 46) reporting good HRQoL. Two weeks post-injury, fewer OA-mTBI had (≥2) post-traumatic complaints compared to younger patients (68% vs. 80%, p = 0.01). In the multivariable analyses, only depression-related symptoms (OR = 1.20 for each symptom, 95% CI = 1.01-1.34, p < 0.01) were predictors of poor HRQoL in OA-mTBI. Conclusions: Similar to younger patients, most OA-mTBI rated their HRQoL as good at one year after injury, although a considerable proportion showed incomplete recovery according to the GOSE, suggesting a disability paradox. Depression-related symptoms emerged as a significant predictor for poor HRQoL and can be identified as an early target for treatment after mTBI.

Self-Reported Systemic Sclerosis-Related Symptoms Are More Prevalent in Subjects with Raynaud's Phenomenon in the Lifelines Population: Focus on Pulmonary Complications.

Puffy fingers and Raynaud's phenomenon (RP) are important clinical predictors of the development of systemic sclerosis (SSc). We aim to assess the prevalence of SSc-related symptoms, explore pulmonary symptoms, and test the usefulness of skin autofluorescence (SAF) as a non-invasive marker for Advanced Glycation Endproducts (AGEs). Subjects from the Lifelines Cohort Study with known connective tissue disease (CTD) were excluded. Patient characteristics, SAF, self-reported pulmonary symptoms, and spirometry were obtained. Subjects (n = 73,948) were categorized into definite RP (5.3%) with and without SSc-related symptoms and non-RP. Prevalence of at least one potential SSc-related symptom (other than RP) was 8.7%; 23.5% in subjects with RP and 7.1% without RP (p < 0.001). Subjects with RP and additional SSc-related symptoms more frequently reported dyspnea at rest, dyspnea after exertion, and self-reported pulmonary fibrosis, and had the lowest mean forced vital capacity compared to the other groups (RP without SSc-related symptoms and no RP, both p < 0.001). In multivariate regression, dyspnea at rest/on exertion remained associated with an increased risk of SSc-related symptoms in subjects with RP (both p < 0.001). SAF was higher in subjects with RP and SSc-related symptoms compared to the other groups (p < 0.001), but this difference was not significant after correction for potential confounders. The prevalence of SSc-related symptoms was approximately three-fold higher in subjects with RP. Pulmonary symptoms are more prevalent in subjects with RP who also reported additional potential SSc-related symptoms. This might suggest that (suspected) early SSc develops more insidiously than acknowledged. According to this study, SAF is no marker for early detection of SSc.

Release of High-Mobility Group Box-1 after a Raynaud's Attack Leads to Fibroblast Activation and Interferon-γ Induced Protein-10 Production: Role in Systemic Sclerosis Pathogenesis.

Raynaud's Phenomenon (RP) leading to repetitive ischemia and reperfusion (IR) stress, is the first recognizable sign of systemic sclerosis (SSc) leading to increased oxidative stress. High-mobility group box-1 (HMGB1) is a nuclear factor released by apoptotic and necrotic cells after oxidative stress. Since HMGB1 can signal through the receptor for advanced glycation end products (RAGE), we investigated whether an RP attack promotes the release of HMGB1, leading to fibroblast activation and the upregulation of interferon (IFN)-inducible genes. A cold challenge was performed to simulate an RP attack in patients with SSc, primary RP (PRP), and healthy controls. We measured levels of HMGB1 and IFN gamma-induced Protein 10 (IP-10) at different time points in the serum. Digital perfusion was assessed by photoplethysmography. In vitro, HMGB1 or transforming growth factor (TGF-ß1) (as control) was used to stimulate healthy human dermal fibroblasts. Inflammatory, profibrotic, and IFN-inducible genes, were measured by RT-qPCR. In an independent cohort, sera were obtained from 20 patients with SSc and 20 age- and sex-matched healthy controls to determine HMGB1 and IP-10 levels. We found that HMGB1 levels increased significantly 30 min after the cold challenge in SSc compared to healthy controls. In vitro stimulation with HMGB1 resulted in increased mRNA expression of IP-10, and interleukin-6 (IL-6) while TGF-ß1 stimulation promoted IL-6 and Connective Tissue Growth Factor (CTGF). In serum, both HMGB1 and IP-10 levels were significantly higher in patients with SSc compared to healthy controls. We show that cold challenge leads to the release of HMGB1 in SSc patients. HMGB1 induces IP-10 expression in dermal fibroblasts partly through the soluble RAGE (sRAGE) axis suggesting a link between RP attacks, the release of HMGB1 and IFN-induced proteins as a putative early pathogenetic mechanism in SSc.

Systemic Oxidative Stress Is Increased in Postmenopausal Women and Independently Associates with Homocysteine Levels.

Oxidative stress plays a pivotal role in the pathogenesis of cardiovascular diseases (CVD). Postmenopausal women have an increased risk of developing CVD due to decreased estrogen availability, which is accompanied by increased oxidative stress. Serum free thiols (R-SH) provide a robust and powerful read-out of systemic oxidative stress. In this study, we aimed to establish serum levels of free thiols and explore associations between free thiols and demographic, clinical, and biochemical parameters related to obesity and the risk for developing CVD in both pre- and postmenopausal women. Serum free thiols were measured in a cohort consisting of healthy pre- (n = 223) and postmenopausal (n = 118) Omani women. Postmenopausal women had significantly lower levels of serum free thiols as compared to premenopausal women (762.9 ± 85.3 vs. 780 ± 80.9 µM, age-adjusted p < 0.001). Women's age was positively associated with serum free thiol levels in premenopausal women (ß = 0.36, p = 0.002), whereas an inverse association was observed in postmenopausal women (ß = -0.29, p = 0.002). Homocysteine levels were significantly inversely associated with serum free thiol levels in both pre- (ß = -0.19, p = 0.005) and postmenopausal (ß = -0.20, p = 0.032) women, independent from known cardiovascular risk factors. In this study, we show that postmenopausal women are affected by increased systemic oxidative stress, which independently associates with homocysteine levels.

Treatment of resistant Raynaud's phenomenon with single-port thoracoscopic sympathicotomy: a novel minimally invasive endoscopic technique.

OBJECTIVE: To assess the minimally invasive single-port thoracoscopic sympathicotomy feasibility and efficacy in patients with treatment-resistant RP. METHODS: Single-port thoracoscopic sympathicotomy was performed unilaterally on the left side in eight patients with RP (six males, two females, with a median age of 45.2 years). Five patients had primary and three had secondary RP. Perfusion effects in the hands were assessed at baseline and after 1 month by using a cooling and recovery procedure, and by using laser speckle contrast analysis. Number and duration of RP attacks were reported over a 2-week period. RESULTS: Patient satisfaction was 100% after surgery. After surgery, a unilateral improvement in perfusion was observed in the left hand compared with the right hand, with cooling and recovery (P = 0.008) and with laser speckle contrast analysis (P = 0.023). In addition, the number and duration of the attacks in the left hand decreased compared with the right hand (both P = 0.028). No serious adverse events occurred in a follow-up period of at least 10 months. CONCLUSION: Single-port thoracoscopic sympathicotomy is feasible and can be effective in improving hand perfusion in patients with RP. However, long-term efficacy needs to be established. CLINICAL TRIAL REGISTRATION NUMBER: NCT02680509.

The Systemic Redox Status Is Maintained in Non-Smoking Type 2 Diabetic Subjects Without Cardiovascular Disease: Association with Elevated Triglycerides and Large VLDL.

Decreased circulating levels of free thiols (R-SH, sulfhydryl groups) reflect enhanced oxidative stress, which plays an important role in the pathogenesis of cardiometabolic diseases. Since hyperglycemia causes oxidative stress, we questioned whether plasma free thiols are altered in patients with type 2 diabetes mellitus (T2DM) without cardiovascular disease or renal function impairment. We also determined their relationship with elevated triglycerides and very low density lipoproteins (VLDL), a central feature of diabetic dyslipidemia. Fasting plasma free thiols (colorimetric method), lipoproteins, VLDL (nuclear magnetic resonance spectrometry), free fatty acids (FFA), phospholipid transfer protein (PLTP) activity and adiponectin were measured in 79 adult non-smoking T2DM subjects (HbA1c 51 ± 8 mmol/mol, no use of insulin or lipid lowering drugs), and in 89 non-smoking subjects without T2DM. Plasma free thiols were univariately correlated with glucose (r = 0.196, p < 0.05), but were not decreased in T2DM subjects versus non-diabetic subjects (p = 0.31). Free thiols were higher in subjects with (663 ± 84 µmol/L) versus subjects without elevated triglycerides (619 ± 91 µmol/L; p = 0.002). Age- and sex-adjusted multivariable linear regression analysis demonstrated that plasma triglycerides were positively and independently associated with free thiols (ß = 0.215, p = 0.004), FFA (ß = 0.168, p = 0.029) and PLTP activity (ß = 0.228, p = 0.002), inversely with adiponectin (ß = -0.308, p < 0.001) but not with glucose (ß = 0.052, p = 0.51). Notably, the positive association of free thiols with (elevated) triglycerides appeared to be particularly evident in men. Additionally, large VLDL were independently associated with free thiols (ß = 0.188, p = 0.029). In conclusion, circulating free thiols are not decreased in this cohort of non-smoking and generally well-controlled T2DM subjects. Paradoxically, higher triglycerides and more large VLDL particles are likely associated with higher plasma levels of thiols, reflecting lower systemic oxidative stress.

Correction: Abdulle, A.E., et al. Hydrogen Sulfide: A Therapeutic Option in Systemic Sclerosis. Int. J. Mol. Sci. 2018, 19, 4121.

The authors wish to make the following correction to this paper [...].

Rapid free thiol rebound is a physiological response following cold-induced vasoconstriction in healthy humans, primary Raynaud and systemic sclerosis.

Raynaud's phenomenon (RP) is often the first sign of systemic sclerosis (SSc). Molecular mechanisms involved are incompletely understood, but reactive oxygen, nitrogen, and sulfur species are thought to play an important role in the pathogenesis of SSc. Free thiol groups play a protective role against oxidative stress and may represent an attractive therapeutic target. We aimed to investigate the effects of hypothermia-induced vasoconstriction on the responsiveness of redox-related markers. Thirty participants (n = 10/group [SSc, primary Raynaud's phenomenon (PRP), healthy controls (HC)]) were included in this study. Fingertip photoelectric plethysmography was performed during a standardized cooling and recovery experiment. Venous blood was collected at four predetermined time points. Free thiols, NO-derived species (nitros(yl)ated species, nitrite, nitrate), sulfate and endothelin-1 were measured. Lower baseline concentrations of free thiols were observed in PRP and SSc patients (HC: 5.87 [5.41-5.99] µmol/g; PRP: 5.17 [4.74-5.61]; SSc 5.28 [4.75-5.80], P = 0.04). Redox-related markers remained unchanged during cooling. However, an unexpected increase in systemic free thiol concentrations was observed in all groups during the recovery phase. The response of this marker differed between groups, with a higher increase found in SSc patients (HC Δ = 1.30 [1.48-1.17]; PRP Δ = 1.04 [1.06-1.03]; SSc Δ = 1.72 [1.13-1.49], P = 0.04). NO-derived species, sulfate and endothelin-1 levels remained unchanged throughout the recovery phase. This exploratory study sheds light on the rapid responsiveness of systemic free thiol concentrations following reperfusion, which may reflect overall redox balance. The robust response to reperfusion in SSc patients suggests that reductive systems involved in this response are functionally intact in these patients.

Hydrogen Sulfide: A Therapeutic Option in Systemic Sclerosis.

Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related complications. In addition to the well-known detrimental properties of reactive oxygen species (ROS), gasotransmitters (e.g., nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)) are also thought to play an important role in SSc. Accordingly, the diverse physiologic actions of NO and CO and their role in SSc have been previously studied. Recently, multiple studies have also shown the importance of the third gasotransmitter H2S in both vascular physiology and pathophysiology. Interestingly, homocysteine (which is converted into H2S through the transsulfuration pathway) is often found to be elevated in SSc patients; suggesting defects in the transsulfuration pathway. Hydrogen sulfide, which is known to have several effects, including a strong antioxidant and vasodilator effect, could potentially play a prominent role in the initiation and progression of vasculopathy. A better understanding of the actions of gasotransmitters, like H2S, in the development of SSc-related vasculopathy, could help to create early interventions to attenuate the disease course. This paper will review the role of H2S in vascular (patho-)physiology and potential disturbances in SSc. Moreover, current data from experimental animal studies will be reviewed. Lastly, we will evaluate potential interventional strategies.

Early Predictors for Long-Term Functional Outcome After Mild Traumatic Brain Injury in Frail Elderly Patients.

OBJECTIVE: To identify the effect of frailty and early postinjury measures on the long-term outcome after mild traumatic brain injury in elderly patients. SETTING: Patients admitted to 3 Dutch hospitals designated as level 1 trauma centers. PARTICIPANTS: The elderly (≥60 years) with mild traumatic brain injury (N = 161). DESIGN: A prospective observational cohort study. MAIN MEASURES: Posttraumatic complaints and the Hospital Anxiety and Depression Scale determined 2 weeks postinjury; the Glasgow Outcome Scale Extended and Groningen frailty indicator determined 1 to 3 years postinjury. RESULTS: A total of 102 nonfrail (63%) and 59 frail elderly (37%) patients, mean age of 70.8 (6.3) years were included. Most patients (54%; 72% nonfrail and 24% frail) recovered completely 1 to 3 years postinjury. Two weeks postinjury, 81% had posttraumatic complaints (83% frail and 80% nonfrail elderly), and 30% showed emotional distress (50% frail and 20% nonfrail). Frailty (odds ratio, 2.1; 95% confidence interval, 1.59-2.77) and presence of early complaints (odds ratio, 1.13; 95% confidence interval, 1.01-1.27) (Nagelkerke R = 46%) were found to predict long-term outcome, whereas age was not a significant predictor. CONCLUSION: The frail elderly had worse long-term outcome, and early complaints were found to be a stronger predictor of unfavorable outcome than age. Understanding the implications of frailty on outcome could help clinicians recognize patients at risk of a poor outcome and allocate care more efficiently.