Immunology of human rickettsial diseases.

Among human rickettsial diseases caused by micro-organisms of the genus Rickettsia (Order Rickettsiales; Family Rickettsiaceae), transmitted to human hosts through arthropod vectors, Mediterranean Spotted Fever, or Boutonneuse Fever, and Rocky Mountain Spotted Fever are considered to be important infectious diseases due to continued prevalence in the developed world, and potentially fatal outcome in severe cases. Proliferation of rickettsiae, at the site of the tick bite, results in focal epidermal and dermal necrosis (tache noire). Rickettsiae then spread via lymphatic vessels to the regional lymph nodes, and, via the bloodstream, to skin, brain, lungs, heart, liver, spleen and kidneys. The pathogen invades and proliferates in the endothelial cells of small vessels, target cells of rickettsial infection, destroying them, and spreading the infection to the endothelia of the vascular tree. The damage of the endothelium, and the subsequent endothelia dysfunction, is followed by the activation of acute phase responses, with alteration in the coagulation and in the cytokine network, together with a transient immune dysregulation, characterized by the reduction in peripheral CD4+ T lymphocytes

Characterization and performance of a toluene-degrading biofilm developed on pumice stones

BACKGROUND: Hydrocarbon-degrading biofilms in the treatment of contaminated groundwaters have received increasing attention due to the role played in the so-called "biobarriers". These are bioremediation systems in which a microbial consortium adherent to a solid support is placed across the flow of a contaminated plume, thus promoting biodegradation of the pollutant. RESULTS: A microbial consortium adherent to pumice granules (biofilm) developed from a toluene-enriched microflora in a mini-scale system, following continuous supply of a mineral medium containing toluene, over a 12-month period. Observation by scanning electron microscopy, together with quantification of the biomass attached to pumice, evidenced the presence of abundant exopolymeric material surrounding the cells in the biofilm. Toluene removal monitored during 12-month operation, reached 99%. Identification of the species, based on comparative 16S ribosomal DNA (rDNA) sequence analysis, revealed that Rhodococcus erythropolis and Pseudomonas marginalis were the predominant bacterial species in the microbial consortium. CONCLUSION: A structurally complex toluene-degrading biofilm, mainly formed by Rhodococcus erythropolis and Pseudomonas marginalis, developed on pumice granules, in a mini-scale apparatus continuously fed with toluene

Simulated microgravity promotes the formation of tridimensional cultures and stimulates pluripotency and a glycolytic metabolism in human hepatic and biliary tree stem/progenitor cells

Many pivotal biological cell processes are affected by gravity. The aim of our study was to evaluate biological and functional effects, differentiation potential and exo-metabolome profile of simulated microgravity (SMG) on human hepatic cell line (HepG2) and human biliary tree stem/progenitor cells (hBTSCs). Both hBTSCs and HepG2 were cultured in a weightless and protected environment SGM produced by the Rotary Cell Culture System (Synthecon) and control condition in normal gravity (NG). Self-replication and differentiation toward mature cells were determined by culturing hBTSCs in Kubota's Medium (KM) and in hormonally defined medium (HDM) tailored for hepatocyte differentiation. The effects on the expression and cell exo-metabolome profiles of SMG versus NG cultures were analyzed. SMG promotes tridimensional (3D) cultures of hBTSCs and HepG2. Significative increase of stemness gene expression (p < 0.05) has been observed in hBTSCs cultured in SMG when compared to NG condition. At the same time, the expression of hepatocyte lineage markers in hBTSCs differentiated by HDM was significantly lower (p < 0.05) in SMG compared to NG, demonstrating an impaired capability of hBTSCs to differentiate in vitro toward mature hepatocytes when cultured in SMG condition. Furthermore, in HepG2 cells the SMG caused a lower (p < 0.05 vs controls) transcription of CYP3A4, a marker of late-stage (i.e. Zone 3) hepatocytes. Exo-metabolome NMR-analysis showed that both cell cultures consumed a higher amount of glucose and lower glutamate in SMG respect to NG (p < 0.05). Moreover, hBTSCs media cultures resulted richer of released fermentation (lactate, acetate) and ketogenesis products (B-hydroxybutyrate) in SGM (p < 0.05) than NG. While, HepG2 cells showed higher consumption of amino acids and release of ketoacids (3-Methyl-2-oxovalerate, 2-oxo-4-methyl-valerate) and formiate with respect to normogravity condition (p < 0.05). Based on our results, SMG could be helpful for developing hBTSCs-derived liver devices. In conclusion, SMG favored the formation of hBTSCs and HepG2 3D cultures and the maintenance of stemness contrasting cell differentiation; these effects being associated with stimulation of glycolytic metabolism. Interestingly, the impact of SMG on stem cell biology should be taken into consideration for workers involved in space medicine programs

A systematic analysis of the memory term in coarse-grained models: The case of the Markovian approximation

The systematic development of coarse-grained (CG) models via the Mori–Zwanzig projector operator formalism requires the explicit description of a deterministic drift term, a dissipative memory term and a random fluctuation term. The memory and fluctuating terms are related by the fluctuation–dissipation relation and are more challenging to sample and describe than the drift term due to complex dependence on space and time. This work proposes a rational basis for a Markovian data-driven approach to approximating the memory and fluctuating terms. We assumed a functional form for the memory kernel and under broad regularity hypothesis, we derived bounds for the error committed in replacing the original term with an approximation obtained by its asymptotic expansions. These error bounds depend on the characteristic time scale of the atomistic model, representing the decay of the autocorrelation function of the fluctuating force; and the characteristic time scale of the CG model, representing the decay of the autocorrelation function of the momenta of the beads. Using appropriate parameters to describe these time scales, we provide a quantitative meaning to the observation that the Markovian approximation improves as they separate. We then proceed to show how the leading-order term of such expansion can be identified with the Markovian approximation usually considered in the CG theory. We also show that, while the error of the approximation involving time can be controlled, the Markovian term usually considered in CG simulations may exhibit significant spatial variation. It follows that assuming a spatially constant memory term is an uncontrolled approximation which should be carefully checked. We complement our analysis with an application to the estimation of the memory in the CG model of a one-dimensional Lennard–Jones chain with different masses and interactions, showing that even for such a simple case, a non-negligible spatial dependence for the memory term exists

Synthesis, characterization and DNA interactions of [Pt3(TPymT)Cl3], the trinuclear platinum(II) complex of the TPymT ligand

The triplatinum complex of the 2,4,6-Tris(2-pyrimidyl)-1,3,5-triazine ligand, Pt3TPymT hereafter, has been prepared and characterized for the first time. NMR studies point out that the three platinum(II) centers possess an identical coordination environment. The interactions of Pt3TPymT with DNA were explored in comparison to the free ligand. Specifically, fluorescence, mass spectrometry, viscometry and melting measurements were carried out. In contrast to expectations, the obtained data reveal that no intercalative binding takes place; we propose that binding of Pt3TPymT to DNA mainly occurs through external/groove binding

Relationship Between Human Leucocyte Antigen Class I and Class II and Chronic Idiopathic Urticaria Associated With Aspirin and/or NSAIDs Hypersensitivity

Background. HLA genes play a role in the predisposition of several diseases. The aim was to analyze the prevalence of HLA class I phenotypes and HLA-DRB1* genotype in patients with CIU associated with ASA and NSAIDs hypersensitivity (AICU). Methods. 69 patients with AICU, and 200 healthy subjects. Results. Subjects with HLA-B44 and HLA-Cw5 antigens were more represented in patients with AICU than in control group. Subjects with HLA-A11, HLA-B13, HLACw4, and HLA-Cw7 antigen were more represented in control group than in patients with AICU. Multiple logistic regression demonstrated an association of HLA-Cw4 and HLA-Cw7 with a lower risk of AICU, whereas carriers of HLA-B44 phenotype had a higher risk of AICU. No differences were found between patients and controls as regards to HLA-DRB1* genotype. Conclusions. We observed an association between some HLA class-I antigens and AICU. To the best of our knowledge this is the first description of such association

[Budget impact analysis of idarucizumab for the management of patients treated with dabigatran in emergency / urgent situations in Italy]

BACKGROUND: Each drug therapy with an anticoagulant effect may require, in emergency conditions, a rapid and specific strategy for a prompt restoration of coagulation. Dabigatran is the first-in-class of the so-called new oral anticoagulants (NAO), that have been made available in recent years in addition to traditionally-used vitamin K antagonists (VKA). Idarucizumab is a monoclonal antibody that binds to dabigatran, neutralizing its anticoagulant effect.OBJECTIVE: To assess the economic effect of idarucizumab in patients treated with dabigatran when the rapid reversal of its anticoagulant effect is required.METHODS: The analysis was carried over through the development of a budget impact model specifically adapted to the context of Italian care. The analysis was conducted along a time horizon of five years. The target population was defined by those patients on dabigatran treatment presenting uncontrolled and life-threatening bleedings (gastro-intestinal, intracranial or other) or requiring emergency surgery or urgent procedures. The estimation of healthcare resources (i.e. diagnostic procedures, medications, and other in-hospital services) needed for the management of uncontrolled bleeding and emergency surgery in patients treated with dabigatran was obtained from a panel of five Italian Clinical Experts. Unit costs were derived from current prices and tariffs.RESULTS: The total cost of management with the current therapeutic modalities ranged from € 16.5 million in year 1 to € 20.1 million in year 5. In the scenario with idarucizumab the total cost ranged from € 15.4 million in year 1 to € 18.7 million in year 5. The adoption of idarucizumab resulted in a cumulative 5-year savings of 6.5 million euro corresponding to 7.1% of the total expense.CONCLUSION: Idarucizumab for the management of patients treated with dabigatran in emergency / urgent situations has the potential for substantial savings, compared to treatments currently available. This preliminary assessment will require further confirmatory evidence when the product will become available in Italian healthcare setting.[Article in Italian

From Smart Apes to Human Brain Boxes. A Uniquely Derived Brain Shape in Late Hominins Clade

Modern humans have larger and more globular brains when compared to other primates. Such anatomical features are further reflected in the possession of a moderately asymmetrical brain with the two hemispheres apparently rotated counterclockwise and slid anteroposteriorly on one another, in what is traditionally described as the Yakovlevian torque. Developmental disturbance in human brain asymmetry, or lack thereof, has been linked to several cognitive disorders including schizophrenia and depression. More importantly, the presence of the Yakovlevian torque is often advocated as the exterior manifestation of our unparalleled cognitive abilities. Consequently, studies of brain size and asymmetry in our own lineage indirectly address the question of what, and when, made us humans, trying to trace the emergence of brain asymmetry and expansion of cortical areas back in our Homo antecedents. Here, we tackle this same issue by studying the evolution of human brain size, shape, and asymmetry on a phylogenetic tree including 19 apes and Homo species, inclusive of our fellow ancestors. We found that a significant positive shift in the rate of brain shape evolution pertains to the clade including modern humans, Neanderthals, and Homo heidelbergensis. Although the Yakovlevian torque is well evident in these species and levels of brain asymmetry are correlated to changes in brain shape, further early Homo species possess the torque. Even though a strong allometric component is present in hominoid brain shape variability, this component seems unrelated to asymmetry and to the rate shift we recorded. These results suggest that changes in brain size and asymmetry were not the sole factors behind the fast evolution of brain shape in the most recent Homo species. The emergence of handedness and early manifestations of cultural modernity in the archeological record nicely coincide with the same three species sharing the largest and most rapidly evolving brains among all hominoids