Computational model of electrode-induced microenvironmental effects on pH measurements near a cell membrane.

The mechanism of gas transport across cell membranes remains a topic of considerable interest, particularly regarding the extent to which lipids vs. specific membrane proteins provide conduction pathways. Studies of transmembrane (CO2) transport often rely on data collected under controlled conditions, using pH-sensitive microelectrodes at the extracellular surface to record changes due to extracellular CO2 diffusion and reactions. Although recent detailed computational models can predict a qualitatively correct behavior, a mismatch between the dynamical ranges of the predicted and observed pH curves raises the question whether the discrepancy may be due to a bias introduced by the pH electrode itself. More specifically, it is reasonable to ask whether bringing the electrode tip near or in contact with the membrane creates a local microenvironment between the electrode tip and the membrane, so that the measured data refer to the microenvironment rather than to the free surface. Here, we introduce a detailed computational model, designed to address this question. We find that, as long as a zone of free diffusion exists between the tip and the membrane, the microenvironment behaves effectively as the free membrane. However, according to our model, when the tip contacts the membrane, partial quenching of extracellular diffusion by the electrode rim leads to a significant increase in the pH dynamics under the electrode, matching values measured in physiological experiments. The computational schemes for the model predictions are based on semi-discretization by a finite-element method, and an implicit-explicit time integration scheme to capture the different time scales of the system.

[Psychiatric disability and work: assessment of a group of patients examined at the Occupational Medicine Outpatient Department of the Turin University in the period 2000-2012]. / Disabilità psichica e lavoro: la valutazione di un gruppo di pazienti esaminati presso l'Ambulatorio di Medicina del lavoro del Dipartimento dell'Università di Torino nel periodo 2000-2012.

Problems at workplace with psychiatric subjects are increasing and the role of occupational physicians is basic to achieve a suitable job role. The purpose of this study is to assess the main occupational factors and to evaluate the judgement of fitness to work in 1109 patients with psychiatric diseases examined in our outpatients department during the period 2000-2012. These subjects were sent to our service by family doctors or, more frequently, by the companies seeking for judgement of the working residual capacities. The psychiatric diseases were classified according to the DSM IV; for each group considered, we evaluated the production sector, the specific job role, the pharmacological therapy as compared to the final judgement. The most frequent diagnoses were depressive and anxious disorders. The pharmacological therapy does not seem to be related to the final judgement but the small number of subjects defined as unfit to work does not allow a final evaluation. The study suggests the relevance of team work among the different actors of prevention to achieve a successful management of these workers in a specific job role.

Dynamic Bayesian sensitivity analysis of a myocardial metabolic model.

Dynamic compartmentalized metabolic models are identified by a large number of parameters, several of which are either non-physical or extremely difficult to measure. Typically, the available data and prior information is insufficient to fully identify the system. Since the models are used to predict the behavior of unobserved quantities, it is important to understand how sensitive the output of the system is to perturbations in the poorly identifiable parameters. Classically, it is the goal of sensitivity analysis to asses how much the output changes as a function of the parameters. In the case of dynamic models, the output is a function of time and therefore its sensitivity is a time dependent function. If the output is a differentiable function of the parameters, the sensitivity at one time instance can be computed from its partial derivatives with respect to the parameters. The time course of these partial derivatives describes how the sensitivity varies in time. When the model is not uniquely identifiable, or if the solution of the parameter identification problem is known only approximately, we may have not one, but a distribution of possible parameter values. This is always the case when the parameter identification problem is solved in a statistical framework. In that setting, the proper way to perform sensitivity analysis is to not rely on the values of the sensitivity functions corresponding to a single model, but to consider the distributed nature of the sensitivity functions, inherited from the distribution of the vector of the model parameters. In this paper we propose a methodology for analyzing the sensitivity of dynamic metabolic models which takes into account the variability of the sensitivity over time and across a sample. More specifically, we draw a representative sample from the posterior density of the vector of model parameters, viewed as a random variable. To interpret the output of this doubly varying sensitivity analysis, we propose visualization modalities particularly effective at displaying simultaneously variations over time and across a sample. We perform an analysis of the sensitivity of the concentrations of lactate and glycogen in cytosol, and of ATP, ADP, NAD(+) and NADH in cytosol and mitochondria, to the parameters identifying a three compartment model for myocardial metabolism during ischemia.

Statistical analysis of metabolic pathways of brain metabolism at steady state.

The estimation of metabolic fluxes for brain metabolism is important, among other things, to test the validity of different hypotheses which have been proposed in the literature. The metabolic model that we propose considers, in addition to the blood compartment, the cytosol, and mitochondria of both astrocyte and neuron, including detailed metabolic pathways. In this work we use a recently developed methodology to perform a statistical Flux Balance Analysis (FBA) for this model. The methodology recasts the problem in the form of Bayesian statistical inference and therefore can take advantage of qualitative information about brain metabolism for the simultaneous estimation of all reaction fluxes and transport rates at steady state. By a Markov Chain Monte Carlo (MCMC) sampling method, we are able to provide for each reaction flux and transport rate a distribution of possible values. The analysis of the histograms of the reaction fluxes and transport rates provides a very useful tool for assessing the validity of different hypotheses about brain energetics proposed in the literature, and facilitates the design of the pathways network that is in accordance with what is understood of the functioning of the brain. In this work, we focus on the analysis of biochemical pathways within each cell type (astrocyte and neuron) at different levels of neural activity, and we demonstrate how statistical tools can help implement various bounds suggested by experimental data.

[Rare malignant tumors of the thyroid]. / I tumori maligni rari della tiroide.

The incidence of rare malignant tumors of the thyroid is about 4 cases/100,000 people and represent only 1.8% of all the thyroid cancers. When we talk about "rare" tumors, obviously, we do not refer to the most frequent cancers (papillary, follicular), or less frequent tumors (medullary, anaplastic), but to some types of thyroid tumors that have been almost always sporadically observed. Mucoepidermoid carcinoma and squamous carcinoma have been described in the literature. They present occasional papillary formation so that, according to some authors, could be considered as variants of the papillary carcinoma. Teratoma is another rare tumor which in the paediatric age is benign, but its prognosis could be unfavourable because it causes an important respiratory distress, while in the adult it presents a very aggressive clinical course like the anaplastic carcinoma. Lymphoma is the most frequent of the "rare" tumors of the thyroid (1-5% of all the thyroid cancers). It arises often in a setting of a long history of goitre and Hashimoto thyroiditis. Fine-needle aspirate is important to make diagnosis and to start a correct treatment which allows a 5-year survival up to 85% in the favourable cases.

[Modern surgical staging of lung cancer]. / Moderna stadiazione chirurgica del cancro del polmone.

The estimation of the extension of a lung cancer is actually made according to the rules of TNM system. On the basis of the reports of 100 patients who underwent thoracotomy and were staged according to this system after hystological examination of resected specimen (pTNM), the authors consider some not yet clear aspects of this staging. In particular they underline the wide difference between clinical and post-histological staging; the high rate of nodal involvement, if the surgeon always perform a radical excision of the lymph nodes; the further need of accuracy for the data N2 and T3; the role of the anatomo-pathologist for the correct staging pTNM.

[True aneurysms late complications of revascularization operations in the femoropopliteal tract]. / Aneurismi veri: complicanza tardiva degli interventi di rivascolarizzazione nel tratto femoropopliteo.

The Authors report three cases of true aneurysms following arterial reconstructive surgery in the femoropopliteal tract. One time it was an autologous venous graft and two times of an endarterectomized artery. At surgery the suture line was intact; so the differential diagnosis with false aneurysms was made. This complication is very rare (less than 1%). That natural history and the treatment are reviewed.