NK Cell Patterns in Idiopathic Inflammatory Myopathies with Pulmonary Affection.

BACKGROUND: Pulmonary affection (PA) is associated with a substantial increase in morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). However, the underlying immune mechanisms of PA remain enigmatic and prompt deeper immunological analyses. Importantly, the Janus-faced role of natural killer (NK) cells, capable of pro-inflammatory as well as regulatory effects, might be of interest for the pathophysiologic understanding of PA in IIM. METHODS: To extend our understanding of immunological alterations in IIM patients with PA, we compared the signatures of NK cells in peripheral blood using multi-color flow cytometry in IIM patients with (n = 12, of which anti-synthetase syndrome = 8 and dermatomyositis = 4) or without PA (n = 12). RESULTS: We did not observe any significant differences for B cells, CD4, and CD8 T cells, while total NK cell numbers in IIM patients with PA were reduced compared to non-PA patients. NK cell alterations were driven by a particular decrease of CD56dim NK cells, while CD56bright NK cells remained unchanged. Comparisons of the cell surface expression of a large panel of NK receptors revealed an increased mean fluorescence intensity of NKG2D+ on NK cells from patients with PA compared with non-PA patients, especially on the CD56dim subset. NKG2D+ and NKp46+ cell surface levels were associated with reduced vital capacity, serving as a surrogate marker for clinical severity of PA. CONCLUSION: Our data illustrate that PA in IIM is associated with alterations of the NK cell repertoire, suggesting a relevant contribution of NK cells in certain IIMs, which might pave the way for NK cell-targeted therapeutic approaches.

Effect of cognitive and motor dual-task on oropharyngeal swallowing in Parkinson's disease.

BACKGROUND: Dysphagia frequently occurs in patients with Parkinson's disease (PD) and is associated with severe complications. However, the underlying pathology is poorly understood at present. This study investigated the effect of cognitive and motor dual-task interference on oropharyngeal swallowing in PD. METHODS: Thirty PD patients (23 men, mean age 65.90 ± 9.32 years, mean Hoehn and Yahr stage 2.62 ± 0.81, mean UPDRS 18.00 ± 7.18) were examined using flexible endoscopic evaluation of swallowing (FEES). FEES was performed during three paradigms: at baseline without interference, during a cognitive dual-task, and during a motor dual-task. Oropharyngeal swallowing function was rated using a score which was validated to detect changes in PD related dysphagia. The three paradigms were compared using a two-way-repetitive-measures-ANOVA and a post-hoc-analysis. RESULTS: Mean swallowing score in baseline FEES was 10.67 ± 5.89. It significantly increased (worsened) to 15.97 ± 7.62 (p < 0.001) in the motor dual-task and to 14.55 ± 7.49 (p < 0.001) in the cognitive dual-task. Premature bolus spillage and pharyngeal residue both significantly increased during both of the dual-task conditions whereas penetration/aspiration events did not change. CONCLUSION: Oropharyngeal swallowing in patients with PD is not purely reflexive but requires mental capacity. Additional allocation of attentional resources in the central control of swallowing seems to be an effective compensatory mechanism in PD-related dysphagia: The proposed dual-task protocol may be useful to challenge swallowing functional reserve. Conversely, as a therapeutic strategy, it could be beneficial to focus attention on swallowing and to avoid dual-task situations.

Effect of Caffeine and Other Methylxanthines on Aß-Homeostasis in SH-SY5Y Cells.

Methylxanthines (MTX) are alkaloids derived from the purine-base xanthine. Whereas especially caffeine, the most prominent known MTX, has been formerly assessed to be detrimental, this point of view has changed substantially. MTXs are discussed to have beneficial properties in neurodegenerative diseases, however, the mechanisms of action are not completely understood. Here we investigate the effect of the naturally occurring caffeine, theobromine and theophylline and the synthetic propentofylline and pentoxifylline on processes involved in Alzheimer's disease (AD). All MTXs decreased amyloid-ß (Aß) level by shifting the amyloid precursor protein (APP) processing from the Aß-producing amyloidogenic to the non-amyloidogenic pathway. The α-secretase activity was elevated whereas ß-secretase activity was decreased. Breaking down the molecular mechanism, caffeine increased protein stability of the major α-secretase ADAM10, downregulated BACE1 expression and directly decreased ß-secretase activity. Additionally, APP expression was reduced. In line with literature, MTXs reduced oxidative stress, decreased cholesterol and a decreased in Aß1-42 aggregation. In conclusion, all MTXs act via the pleiotropic mechanism resulting in decreased Aß and show beneficial properties with respect to AD in neuroblastoma cells. However, the observed effect strength was moderate, suggesting that MTXs should be integrated in a healthy diet rather than be used exclusively to treat or prevent AD.

Vitamin D and Its Analogues Decrease Amyloid-ß (Aß) Formation and Increase Aß-Degradation.

Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-ß (Aß), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aß-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D2 and D3 analogues decreased Aß-production and increased Aß-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aß-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased ß-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention.

Tocotrienol Affects Oxidative Stress, Cholesterol Homeostasis and the Amyloidogenic Pathway in Neuroblastoma Cells: Consequences for Alzheimer's Disease.

One of the characteristics of Alzheimer´s disease (AD) is an increased amyloid load and an enhanced level of reactive oxidative species (ROS). Vitamin E has known beneficial neuroprotective effects, and previously, some studies suggested that vitamin E is associated with a reduced risk of AD due to its antioxidative properties. However, epidemiological studies and nutritional approaches of vitamin E treatment are controversial. Here, we investigate the effect of α-tocotrienol, which belongs to the group of vitamin E, on AD-relevant processes in neuronal cell lines. In line with the literature, α-tocotrienol reduced the ROS level in SH-SY5Y cells. In the presence of tocotrienols, cholesterol and cholesterol esters, which have been shown to be risk factors in AD, were decreased. Besides the unambiguous positive effects of tocotrienol, amyloid-ß (Aß) levels were increased accompanied by an increase in the activity of enzymes responsible for Aß production. Proteins and gene expression of the secretases and their components remained unchanged, whereas tocotrienol accelerates enzyme activity in cell-free assays. Besides enhanced Aß production, tocotrienols inhibited Aß degradation in neuro 2a (N2a)-cells. Our results might help to understand the controversial findings of vitamin E studies and demonstrate that besides the known positive neuroprotective properties, tocotrienols also have negative characteristics with respect to AD.