Geometric principles of second messenger dynamics in dendritic spines.

Dendritic spines are small, bulbous protrusions along dendrites in neurons and play a critical role in synaptic transmission. Dendritic spines come in a variety of shapes that depend on their developmental state. Additionally, roughly 14-19% of mature spines have a specialized endoplasmic reticulum called the spine apparatus. How does the shape of a postsynaptic spine and its internal organization affect the spatio-temporal dynamics of short timescale signaling? Answers to this question are central to our understanding the initiation of synaptic transmission, learning, and memory formation. In this work, we investigated the effect of spine and spine apparatus size and shape on the spatio-temporal dynamics of second messengers using mathematical modeling using reaction-diffusion equations in idealized geometries (ellipsoids, spheres, and mushroom-shaped). Our analyses and simulations showed that in the short timescale, spine size and shape coupled with the spine apparatus geometries govern the spatiotemporal dynamics of second messengers. We show that the curvature of the geometries gives rise to pseudo-harmonic functions, which predict the locations of maximum and minimum concentrations along the spine head. Furthermore, we showed that the lifetime of the concentration gradient can be fine-tuned by localization of fluxes on the spine head and varying the relative curvatures and distances between the spine apparatus and the spine head. Thus, we have identified several key geometric determinants of how the spine head and spine apparatus may regulate the short timescale chemical dynamics of small molecules that control synaptic plasticity

Coagulation and skin autoimmunity

Several lines of evidence indicate that the immune system, inflammation, and coagulation are simultaneously activated in autoimmune and immune-mediated skin diseases. Pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha induce the expression of the main initiator of coagulation, i.e., tissue factor. The proteases of coagulation in turn act on protease-activated receptors inducing the expression of various pro-inflammatory cytokines triggering inflammation. The cross-talk among immune system, inflammation, and coagulation amplifies and maintains the activation of all three pathways. This review focuses on three skin disorders as chronic spontaneous urticaria (CSU), angioedema, and bullous pemphigoid (BP), in which the relationships among the three systems have been investigated or their clinical consequences are relevant. Markers of thrombin generation, fibrinolysis, and inflammation have been reported to be increased in the plasma during flares of CSU and angioedema, as well as in the active phase of BP, with the marker levels reverting to normal during remission. The coagulation activation seems to be important only at local level in CSU and angioedema while both at local and systemic levels in BP which is the only condition associated with an increased thrombotic risk. The prothrombotic state in autoimmune skin diseases raises the question of the indication of anticoagulant treatment, particularly in the presence of other cardiovascular risk factors

Validation of the Predictive Model of the European Society of Cardiology for Early Mortality in Acute Pulmonary Embolism

Background \u2003Acute pulmonary embolism (PE) is burdened by high mortality, especially within 30 days from the diagnosis. The development and the validation of predictive models for the risk of early mortality allow to differentiate patients who can undergo home treatment from those who need admission into intensive care units. Methods \u2003To validate the prognostic model for early mortality after PE diagnosis proposed by the European Society of Cardiology (ESC) in 2014, we analyzed data of a cohort of 272 consecutive patients with acute PE, observed in our hospital during a 10-year period. Moreover, we evaluated the additional contribution of D-dimer, measured at PE diagnosis, in improving the prognostic ability of the model. All cases of PE were objectively diagnosed by angiography chest CT scan or perfusion lung scan. Results \u2003The overall mortality rate within 30 days from PE diagnosis was 10% (95% confidence interval [CI]: 6.4-13.5%). According to the ESC prognostic model, the risk of death increased 3.23 times in the intermediate-low-risk category, 5.55 times in the intermediate-high-risk category, and 23.78 times in the high-risk category, as compared with the low-risk category. The receiver operating characteristic analysis showed a good discriminatory power of the model (area under the curve [AUC]\u2009=\u20090.77 [95% CI: 0.67-0.87]), which further increased when D-dimer was added (AUC\u2009=\u20090.85 [95% CI: 0.73-0.96]). Conclusion \u2003This study represents a good validation of the ESC predictive model whose performance can be further improved by adding D-dimer plasma levels measured at PE diagnosis

On the Possibility to Run an Internal Combustion Engine on Acetylene and Alcohol

Abstract It is well known that acetylene is a high flammable and explosive compound. In comparison with commercial liquid fuels, very wide flammability limits and a low Octane Number have relegated the acetylene into the "iperdetonat" fuels category. Thus, it is impossible to run an internal combustion engine on acetylene without a detonation phenomena control system. The current paper deals with a theoretical and experimental analysis of an internal combustion engine running on acetylene and alcohol. A standard 8 kW spark ignition engine with carburettor was modified with electronic injection control system (ECU) and two standard commercial injectors: one for the acetylene and one for the alcohol. The two injectors were installed using a modified engine intake system. The ECU is able to manage two fuels: acetylene and alcohol. Moreover, an optimization method base on Genetic Algorithms and Neural Networks was used to cerate engine parameters map. Thus, Running an ICE on acetylene and alcohol it is possible to achieve acceptable engine performance and very low pollutant emissions

Tocilizumab Effects on Coagulation Factor XIII in Patients with Rheumatoid Arthritis

Introduction: Rheumatoid arthritis (RA) is a chronic systemic auto-immune disease associated with a prothrombotic state. Tocilizumab, an interleukin-6 receptor inhibitor, is highly effective in controlling disease activity and thrombotic risk. Factor XIII (FXIII), involved in thrombotic complications, has been reported to be reduced in RA patients during maintenance treatment with tocilizumab, but no data are available before and after the drug administration. Thus, we investigated the effects of tocilizumab on FXIII, thrombin generation and inflammation in patients with RA na\uefve for the drug. Methods: We studied 15 consecutive adult patients with RA at baseline and 4 weeks after the onset of parenteral administration of tocilizumab, measuring disease activity and plasma levels of C-reactive protein (CRP), FXIII, and prothrombin fragments F1+2 by immunoenzymatic methods. Fifteen healthy subjects, sex-and age-matched with patients, served as normal controls for laboratory measurements. Results: At baseline, patients with established RA had a median DAS28 of 4.8 (3.2\u20138.3) and, compared to healthy controls, had higher plasma levels of CRP (p < 0.0001), FXIII (p = 0.017) and F1+2 (p < 0.0001). Four weeks after starting treatment with tocilizumab, based on the EULAR response criteria, eight patients were classifiable as responders and seven as non-responders. In responders, we observed a statistically significant reduction not only of the values of DAS28 and CRP (p = 0.012 for both), ut also of plasma levels of FXIII (p = 0.05) and F1+2 (p = 0.025). In non-responders, all the studied parameters were unchanged. Conclusion: The decrease of FXIII and F1+2 levels after tocilizumab treatment observed only in those patients who responded to the drug indicates that the effect of tocilizumab on the prothrombotic state is linked to the control of inflammation and disease activity and not to a direct effect of the drug, thus contributing to the reduction of the cardiovascular risk

New insights into the pathogenesis of bullous pemphigoid: 2019 update

There are several lines of evidence indicating that the physiopathological bases of bullous pemphigoid (BP), the most common subepidermal autoimmune bullous disease, are hallmarked by the production of autoantibodies directed against the hemidesmosomal anchoring proteins BP180 and BP230. In contrast to the robustness of the latter assumption, the multifaceted complexity of upstream and downstream mechanisms implied in the pathogenesis of BP remains an area of intense speculation. So far, an imbalance between T regulatory cells and autoreactive T helper (Th) cells has been regarded as the main pathogenic factor triggering the autoimmune response in BP patients. However, the contributory role of signaling pathways fostering the B cell stimulation, such as Toll-like receptor activation, as well as that of ancillary inflammatory mechanisms responsible for blister formation, such as Th17 axis stimulation and the activation of the coagulation cascade, are still a matter of debate. In the same way, the pathomechanisms implied in the loss of dermal-epidermal adhesion secondary to autoantibodies binding are not fully understood. Herein, we review in detail the current concepts and controversies on the complex pathogenesis of BP, shedding light on the most recent theories emerging from the literature