Biofluid Markers for Prodromal Parkinson's Disease:Evidence From a Catecholaminergic Perspective

Parkinson's disease (PD) is the most frequent of all Lewy body diseases, a family of progressive neurodegenerative disorders characterized by intra-neuronal cytoplasmic inclusions of α-synuclein. Its most defining features are bradykinesia, tremor, rigidity and postural instability. By the time PD manifests with motor signs, 70% of dopaminergic midbrain neurons are lost, and the disease is already in the middle or late stage. However, there are various non-motor symptoms occurring up to 20 years before the actual parkinsonism that are closely associated with profound deficiency of myocardial noradrenaline content and peripheral sympathetic denervation, as evidenced by neuroimaging experiments in recent years. Additionally, there is an inherent autotoxicity of catecholamines in the neuronal cells in which they are produced, forming toxic catecholaldehyde intermediates that make α-synuclein prone to aggregation, initiating a cascade of events that ultimately leads to neuronal death. The etiopathogenesis of PD and related synucleinopathies thus may well be a prototypical example of a catecholamine-regulated neurodegeneration, given that the synucleinopathy in PD spreads in synergy with central and peripheral catecholaminergic dysfunction from the earliest phases onward. That is why catecholamines and their metabolites, precursors, or derivatives in cerebrospinal fluid or plasma could be of particular interest as biomarkers for prodromal and de novo PD. Because there is great demand for such markers, this mini-review summarizes all catecholamine-related studies to date, in addition to providing profound neurochemical evidence on a systemic and cellular level to further emphasize this hypothesis and with emphasis on extracellular vesicles as a novel diagnostic and therapeutic incentive

The 1 : √2 mode interaction and heteroclinic networks in Boussinesq convection

Copyright © 2007 Elsevier. NOTICE: This is the author’s version of a work accepted for publication by Elsevier. Changes resulting from the publishing process, including peer review, editing, corrections, structural formatting and other quality control mechanisms, may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Physica D, Vol 234, Issue 1, October 2007, DOI: 10.1016/j.physd.2007.06.024Methods of equivariant bifurcation theory are applied to Boussinesq convection in a plane layer with stress-free horizontal boundaries and an imposed square lattice periodicity in the horizontal directions. We consider the problem near the onset of instability of the uniform conducting state where spatial roll patterns with two different wavelengths in the ratio 1 : √2 become simultaneously unstable at a mode interaction. Centre manifold reduction yields a normal form on C4 with very rich dynamical behavior. For a fixed Prandtl number P the mode interaction occurs at an isolated point in the parameter plane (R,L) (where R is the Rayleigh number and L the length of the horizontal periodicities) and acts as an organizing center for many nearby bifurcations. The normal form predicts appearance of many steady states and travelling waves, which are classified by their symmetries. It also predicts the appearance of robust heteroclinic networks involving steady states with several different symmetries, and robust attractors of generalized heteroclinic type that include connections from equilibria to subcycles. This is the first example of a heteroclinic network in a fluid dynamical system that has ‘depth’ greater than one. The normal form dynamics is in good correspondence (both quantitatively and qualitatively) with direct numerical simulations of the full convection equations

Low ficolin-3 levels in early follow-up serum samples are associated with the severity and unfavorable outcome of acute ischemic stroke

<p>Abstract</p> <p>Background</p> <p>A number of data indicate that the lectin pathway of complement activation contributes to the pathophysiology of ischemic stroke. The lectin pathway may be triggered by the binding of mannose-binding lectin (MBL), ficolin-2 or ficolin-3 to different ligands. Although several papers demonstrated the significance of MBL in ischemic stroke, the role of ficolins has not been examined.</p> <p>Methods</p> <p>Sera were obtained within 12 hours after the onset of ischemic stroke (admission samples) and 3-4 days later (follow-up samples) from 65 patients. The control group comprised 100 healthy individuals and 135 patients with significant carotid stenosis (patient controls). The concentrations of ficolin-2 and ficolin-3, initiator molecules of the lectin complement pathway, were measured by ELISA methods. Concentration of C-reactive protein (CRP) was also determined by a particle-enhanced immunturbidimetric assay.</p> <p>Results</p> <p>Concentrations of both ficolin-2 and ficolin-3 were significantly (p < 0.001) decreased in both the admission and in the follow-up samples of patients with definite ischemic stroke as compared to healthy subjects. Concentrations of ficolin-2 and ficolin-3 were even higher in patient controls than in healthy subjects, indicating that the decreased levels in sera during the acute phase of stroke are related to the acute ischemic event. Ficolin-3 levels in the follow-up samples inversely correlated with the severity of stroke indicated by NIH scale on admission. In follow-up samples an inverse correlation was observed between ficolin-3 levels and concentration of S100β, an indicator of the size of cerebral infarct. Patients with low ficolin-3 levels and high CRP levels in the follow up samples had a significantly worse outcome (adjusted ORs 5.6 and 3.9, respectively) as measured by the modified Rankin scale compared to patients with higher ficolin-3 and lower CRP concentrations. High CRP concentrations were similarly predictive for worse outcome, and the effects of low ficolin-3 and high CRP were independent.</p> <p>Conclusions</p> <p>Our findings indicate that ficolin-mediated lectin pathways of complement activation contribute to the pathogenesis of ischemic stroke and may be additive to complement-independent inflammatory processes.</p

Entrainment maps considering hydrological conditions for mass movement runout modelling: Application to debris-flow bulking at Pizzo Cengalo

Debris flows entrain sediments and water along their flow path and grow significantly in size. Because the entrainment process isn’t well understood and data is rare, hazard and risk assessment with numerical models is challenging. It is known, however, that both for debris flows and rock avalanches, interstitial pore water in flow path substrate can cause increases in pore water pressures when overridden by the flow, which enhances erosion. The entrained water likely also plays a role in the process transition from rock avalanche to debris flow, like in the Pizzo Cengalo event in 2017. We present a framework for producing entrainment maps serving as an input for runout modelling, here illustrated using RAMMS. The entrainment maps consist of spatially-distributed entities with properties such as max erosion depth, and soil water content inferred from land cover and lithology maps. This study serves as a basis for producing duration curves of subsurface water available for entrainment and include it into the entrainment maps. Such hydrologically-informed entrainment maps will be useful to assess the probability of certain runout distances

Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy.

OBJECTIVE: Long-term results of surgical vessel reconstruction are compromised by restenosis caused by neointimal hyperplasia. Recent studies suggest that reduced cyclic guanosine monophosphate signaling is associated with neointima formation. In a rat model of endarterectomy, we investigated the effect of pharmacologic inhibition of cyclic guanosine monophosphate degradation on neointima formation by using the selective phosphodiesterase-5 inhibitor vardenafil. METHODS: Carotid endarterectomy was performed in male Sprague-Dawley rats by means of incision of the right common carotid artery with removal of intima. Four groups were studied: unoperated control rats (n = 4), sham-operated rats (n = 9), control rats with endarterectomy (n = 9), or endarterectomized rats treated with vardenafil (10 mg/kg/day) postoperatively (n = 9). After 3 weeks, vessel compartment areas were measured by means of conventional microscopy with hematoxylin and eosin staining. Immunohistochemical analysis was performed to confirm neointima formation and the local cyclic guanosine monophosphate content. Plasma levels of cyclic guanosine monophosphate were determined by means of enzyme immunoassay. Student's t test was used for statistical evaluation. RESULTS: Immunohistochemical analysis demonstrated intensive staining for transforming growth factor beta1 and alpha-smooth muscle actin in the control neointima. Vardenafil significantly reduced the stenosis grade (24.64% +/- 7.46% vs 54.12% +/- 10.30% in the control group, P < .05) and expression of transforming growth factor beta1, as well as alpha-smooth muscle actin, in the neointima. The immunohistochemical score for cyclic guanosine monophosphate was higher in the treated neointima (4.80 +/- 0.76 vs 2.84 +/- 0.40 in the control group, P < .05), and increased plasma cyclic guanosine monophosphate levels were found by means of enzyme immunoassay as well (84.65 +/- 12.77 pmol/mL vs 43.50 +/- 3.30 pmol/mL in the control group, P < .05). CONCLUSIONS: Treatment with vardenafil can be considered a new possibility to prevent neointimal hyperplasia after endarterectomy

Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure

Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure.BackgroundPatients with acute renal failure (ARF) have high morbidity and mortality rates, particularly if they have serious comorbid conditions. Several studies indicate that in rats with ARF caused by ischemia or certain nephrotoxins, insulin-like growth factor-I (IGF-I) enhances the recovery of renal function and suppresses protein catabolism.MethodsOur objective was to determine whether injections of recombinant human IGF-I (rhIGF-I) would enhance the recovery of renal function and is safe in patients with ARF. The study was designed as a randomized, double-blind, placebo-controlled trial in intensive care units in 20 teaching hospitals. Seventy-two patients with ARF were randomized to receive rhIGF-I (35 patients) or placebo (37 patients). The most common causes of ARF in the rhIGF-I and placebo groups were, respectively, sepsis (37 and 35% of patients) and hypotension or hemodynamic shock (42 and 27% of patients). At baseline, the mean (± sd) APACHE II scores in the rhIGF-I and placebo-treated groups were 24 ± 5 and 25 ± 8, respectively. In the rhIGF-I and placebo groups, the mean (median) urine volume and urinary iothalamate clearances (glomerular filtration rate) were 1116 ± 1037 (887) and 1402 ± 1183 (1430)ml/24hr and 6.4 ± 5.9 (4.3) and 8.7 ± 7.2 (4.4)ml/min and did not differ between the two groups. Patients were injected subcutaneously every 12hours with rhIGF-I, 100 μg/kg desirable body weight, or placebo for up to 14days. Injections were started within six days of the onset of ARF. The primary end-point was a change in glomerular filtration rate from baseline. Other end points included changes from baseline in urine volume, creatinine clearance and serum urea, creatinine, albumin and transferrin, frequency of hemodialysis or ultrafiltration, and mortality rate.ResultsDuring the treatment period, which averaged 10.7 ± 4.1 and 10.6 ± 4.5days in the rhIGF-I and placebo groups, there were no differences in the changes from baseline values of the glomerular filtration rate, creatinine clearance, daily urine volume, or serum urea nitrogen, creatinine, albumin or transferrin. In patients who did not receive renal replacement therapy, there was also no significant difference in serum creatinine and urea between the two groups. Twenty patients in the rhIGF-I group and 17 placebo-treated patients underwent dialysis or ultrafiltration. Twelve rhIGF-I–treated patients and 12 placebo-treated patients died during the 28days after the onset of treatment.ConclusionsrhIGF-I does not accelerate the recovery of renal function in ARF patients with substantial comorbidity

“CAN YOU GIVE ME ANOTHER WORD FOR HYPERBARIC?”: IMPROVING SPEECH TRANSLATION USING TARGETED CLARIFICATION QUESTIONS

We present a novel approach for improving communication success between users of speech-to-speech translation systems by automatically detecting errors in the output of automatic speech recognition (ASR) and statistical machine translation (SMT) systems. Our approach initiates system-driven targeted clarification about errorful regions in user input and repairs them given user responses. Our system has been evaluated by unbiased subjects in live mode, and results show improved success of communication between users of the system. Index Terms — Speech translation, error detection, error correction, spoken dialog systems. 1