Mitochondrial dysfunction happens in both idiopathic (iPD) and LRRK2-related Parkinson's disease (LRRK2-PD). Nonetheless, previous studies suggested that a different type of mitochondrial pathology ...underlies the neurodegeneration in these two disorders. To further explore this hypothesis, we developed a novel multiplex digital PCR assay that allows the absolute quantification of cell-free mitochondrial DNA (cf-mtDNA) copy number and deletion ratio directly in cerebrospinal fluid (CSF) by simultaneously measuring two opposed regions of the mtDNA circular molecule, one of them in the commonly deleted major arc. The results confirmed that the content of cf-mtDNA in CSF was statistically significantly different between iPD and LRRK2-PD patients. Moreover, we found high cf-mtDNA deletion levels in CSF from patients with iPD, but not LRRK2-PD. The high cf-mtDNA deletion frequency in iPD was validated in an independent cohort. These results indicated that the content and deletion ratio of cf-mtDNA may differentiate iPD from LRRK2-PD, and provides further evidence of the different mitochondrial pathophysiology between these two forms of the disease.
•Quantification of cell-free mitochondrial DNA deletions in cerebrospinal fluid.•High content of integral cell-free mitochondrial DNA in LRRK2 Parkinson's disease.•High cell-free mitochondrial DNA deletions in idiopathic Parkinson's disease.
The Digital Transformation of the Fitness Sector highlights the challenges and opportunities of the digitalization of the fitness sector in the wake of recent global challenges in countries around ...the world.
Summary
Background
A dramatic rise in the incidence rates of basal cell carcinoma (BCC) in young women has been reported.
Objectives
We investigate potential risk factors (RF) for sporadic BCC in ...young patients and the current distribution of such RF in the general population of Catalonia, comparing the differences among men and women.
Patients and Methods
A case‐control study was performed, 69 BCCs diagnosed in patients ≤ 45 years of age vs. 69 healthy controls. Afterward, 1,078 participants from the general population completed an RF questionnaire.
Results
Repeated sunburns were more frequent in instances of early‐onset BCC in covered skin than in sun‐exposed skin (P = 0.029). In the general population, 39.1 % of participants reported sunbed use (50.1 % in women, 10.9 % in men). Sunbed use was the only relevant RF more predominant in women than men, favoring the trend to female predominance of BCCs above other RF. Additionally, we found a significant trend in young participants for reduced sunbed use (P < 0.001), although they had the same percentage of repeated sunburns. Repeated sunburns are the most relevant RF for early‐onset BCCs that can be targeted in prevention campaigns.
Conclusions
We should be aware of the more relevant RF for early‐onset BCCs and their distribution among the general population to address preventive campaigns.
The analysis of tumor interstitial fluid (TIF) composition is a valuable procedure to identify antimetastatic targets, and different laboratories have set up techniques for TIF isolation and ...proteomic analyses. However, those methods had never been compared in samples from the same tumor and patient. In this work, we compared the two most used methods, elution and centrifugation, in pieces of the same biopsy samples of cutaneous squamous cell carcinoma (cSCC). First, we established that high G-force (10 000g) was required to obtain TIF from cSCC by centrifugation. Second, we compared the centrifugation method with the elution method in pieces of three different cSCC tumors. We found that the mean protein intensities based in the number of peptide spectrum matches was significantly higher in the centrifuged samples than in the eluted samples. Regarding the robustness of the methods, we observed higher overlapping between both methods (77–80%) than among samples (50%). These results suggest that there exists an elevated consistence of TIF composition independently of the method used. However, we observed a 3-fold increase of extracellular proteins in nonoverlapped proteome obtained by centrifugation. We therefore conclude that centrifugation is the method of choice to study the proteome of TIF from cutaneous biopsies.
(CA) infections have been associated with psoriasis onset or disease flares. However, the integrated immune response against this fungus is still poorly characterized in psoriasis. We studied ...specific immunoglobulins in plasma and the CA response in cocultures of circulating memory CD45RA
cutaneous lymphocyte antigen (CLA)
T cell with autologous epidermal cells from plaque and guttate psoriasis patients (cohort 1,
= 52), and also healthy individuals (
= 17). A complete proteomic profile was also evaluated in plaque psoriasis patients (cohort 2,
= 114) regarding their anti-CA IgA levels. Increased anti-CA IgA and IgG levels are present in the plasma from plaque but not guttate psoriasis compared to healthy controls. CA cellular response is confined to CLA
T cells and is primarily Th17. The levels of anti-CA IgA are directly associated with CLA
Th17 response in plaque psoriasis. Proteomic analysis revealed distinct profiles in psoriasis patients with high anti-CA IgA. C-C motif chemokine ligand 18, chitinase-3-like protein 1 and azurocidin were significantly elevated in the plasma from plaque psoriasis patients with high anti-CA levels and severe disease. Our results indicate a mechanism by which
exposure can trigger a clinically relevant IL-17 response in psoriasis. Assessing anti-CA IgA levels may be useful in order to evaluate chronic psoriasis patients.
Initial SE-dipping slow subduction of the Ligurian–Tethys lithosphere beneath Africa from Late Cretaceous to middle Oligocene twisting to a later faster E-dipping subduction of the subcrustal ...lithosphere is proposed as an efficient geodynamic mechanism to structure the arcuate Betic–Rif orogenic system. This new subduction-related geodynamic scenario is supported by a kinematic model constrained by well-dated plate reconstructions, tectonic, sedimentary and metamorphic data sets. The slow initial SE-dipping subduction of the Ligurian–Tethys realm beneath the Malaguide upper plate unit is sufficient to subduct Alpujarride and Nevado-Filabride rocks to few tens of kilometers of depth in middle Eocene times. The shift from SE- to E-dipping subduction during latest Oligocene–early Miocene was possibly caused by both the inherited geometry of the highly segmented Ligurian–Tethys domain and by the fast roll-back of the subducted lithospheric slab. The early Miocene rather synchronous multiple crustal and subcrustal processes comprising the collision along the Betic front, the exhumation of the HP/LT metamorphic complexes, the opening of the Alboran basin, its flooring by HP Alpujarride rocks and subsequent HT imprint, can be explained by the fast NW- and W-directed roll-back of the Ligurian–Tethys subcrustal lithospheric slab. The W retreat of the Ligurian–Tethys lithosphere in middle–late Miocene times could partly explain the initiation of its lateral tear and consequent subcrustal processes. From latest Miocene onward the Betic–Rif system evolved under both the northerly push of Africa resulting in tightening at crustal and subcrustal levels and by the distinct current dynamics of the steep lithospheric slab. The SW-directed scape of the Rif fold belt is one of the most striking evidences linked to the recent evolution of the squeezed Betic–Rif system between Africa and Iberia.
► Kinematic model for the Betic–Rif orogen with initial SE-dipping subduction ► Highly stretched Ligurian–Tethys lithosphere subducted beneath N-moving Africa ► Late Cretaceous to mid Oligocene slow subduction and HP metamorphic peak ► Subduction shifted to E-dipping in late Oligocene due to ocean segmentation. ► Coeval roll-back, Alboran back-arc extension and exhumation of HP rocks
Zusammenfassung
Hintergrund
Es gibt Berichte über einen dramatischen Anstieg der Inzidenz von Basalzellkarzinomen (BZK) bei jungen Frauen.
Ziele
Wir untersuchten potenzielle Risikofaktoren (RF) für ...sporadische BZK bei jungen Patienten sowie die gegenwärtige Verteilung dieser RF in der Allgemeinbevölkerung Kataloniens. Dabei verglichen wir Männer und Frauen.
Patienten und Methodik
Es wurde eine Fall‐Kontroll‐Studie mit 69 Patienten ≤ 45 Jahren mit BZK‐Diagnose und 69 gesunden Kontrollen durchgeführt. Anschließend füllten 1078 Teilnehmer aus der Allgemeinbevölkerung einen RF‐Fragebogen aus.
Ergebnisse
Wiederholte Sonnenbrände waren bei BZK mit frühem Beginn an bedeckter Haut häufiger als an sonnenexponierten Hautbereichen (p = 0,029). In der Allgemeinbevölkerung gaben 39,1 % der Teilnehmer an, Solarien zu nutzen (50,1 % der Frauen, 10,9 % der Männer). Die Solariumnutzung war der einzige relevante RF, der bei Frauen häufiger auftrat als bei Männern und dementsprechend den Trend zu einer weiblichen Prädominanz bei BZK mehr als andere RF begünstigt. Zudem ermittelten wir bei jungen Teilnehmern einen signifikanten Trend hin zu verringerter Solariumnutzung (p < 0,001). Der Prozentsatz wiederholter Sonnenbrände war jedoch unverändert. Wiederholter Sonnenbrand war der wichtigste RF für BZK mit frühem Beginn, der mittels Präventionskampagnen gezielt angegangen werden kann.
Schlussfolgerungen
Wir sollten uns der wichtigsten RF für BZK mit frühem Beginn sowie ihrer Verteilung in der Allgemeinbevölkerung bewusst sein, um sie in Präventionskampagnen anzugehen.
Neuroinflammation is a potential player in neurodegenerative conditions, particularly the aggressive ones, such as multiple system atrophy (MSA). Previous reports on cytokine levels in MSA using ...serum or cerebrospinal fluid (CSF) have been inconsistent, including small samples and a limited number of cytokines, often without comparison to Parkinson's disease (PD), a main MSA differential diagnosis.
Cross-sectional study of CSF levels of 38 cytokines using a multiplex assay in 73 participants: 39 MSA patients (19 with parkinsonian type MSAp, 20 with cerebellar type MSAc; 31 probable, 8 possible), 19 PD patients and 15 neurologically unimpaired controls. None of the participants was under non-steroidal anti-inflammatory drugs at the time of the lumbar puncture.
There were not significant differences in sex and age among participants. In global non-parametric comparisons FDR-corrected for multiple comparisons, CSF levels of 5 cytokines (FGF-2, IL-10, MCP-3, IL-12p40, MDC) differed among the three groups. In pair-wise FDR-corrected non-parametric comparisons 12 cytokines (FGF-2, eotaxin, fractalkine, IFN-α2, IL-10, MCP-3, IL-12p40, MDC, IL-17, IL-7, MIP-1β, TNF-α) were significantly higher in MSA vs. non-MSA cases (PD + controls pooled together). Of these, MCP-3 and MDC were the most significant ones, also differed in MSA vs. PD, and were significant MSA-predictors in binary logistic regression models and ROC curves adjusted for age. CSF levels of fractalkine and MIP-1α showed a strong and significant positive correlation with UMSARS-2 scores.
Increased CSF levels of cytokines such as MCP-3, MDC, fractalkine and MIP-1α deserve consideration as potential diagnostic or severity biomarkers of MSA.
•CSF levels of 12 cytokines were higher in MSA (n = 39) vs. PD + controls (n = 19 & 15).•Younger age and increasing CSF levels of MCP-3 and MDC were MSA predictors in adjusted models.•CSF levels of fractalkine and MIP-1α correlated with UMSARS-2 scores.•CSF levels of these cytokines might be diagnostic or severity MSA biomarkers.
Abstract LRRK2 mutations are the most common genetic cause of Parkinson's disease (PD). We performed a whole-genome RNA profiling of putamen tissue from idiopathic PD (IPD), LRRK2- associated PD ...(G2019S mutation), neurologically healthy controls and one asymptomatic LRRK2 mutation carrier, by using the Genechip Human Exon 1.0-ST Array. The differentially expressed genes found in IPD revealed an alteration of biological pathways related to long-term potentiation (LTP), GABA receptor signalling, and calcium signalling pathways, among others. These pathways are mainly related with cell signalling cascades and synaptic plasticity processes. They were also altered in the asymptomatic LRRK2 mutation carrier but not in the LRRK2 -associated PD group. The expression changes seen in IPD might be attributed to an adaptive consequence of a dysfunction in the dopamine transmission. The lack of these altered molecular pathways in LRRK2 -associated PD patients suggests that these cases could show a different molecular response to dopamine transmission impairment.
In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 ...gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC).
A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD.
Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC.
Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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