Peculiarities of ion homeostasis in neurons containing calcium-permeable AMPA receptors.

Glutamate excitotoxicity accompanies numerous brain pathologies, including traumatic brain injury, ischemic stroke, and epilepsy. Disturbances of the ion homeostasis, mitochondria dysfunction, and further cell death are considered the main detrimental consequences of excitotoxicity. It is well known that neurons demonstrate different vulnerability to pathological exposures. In this regard, neurons containing calcium-permeable AMPA receptors (CP-AMPARs) may show higher susceptibility to excitotoxicity due to an additional pathway of Ca2+ influx. Here, we demonstrate that neurons containing CP-AMPARs are characterized by the higher amplitude of the glutamate-induced elevation of intracellular Ca2+ concentration ([Ca2+]i) and slower restoration of [Ca2+]i level compared to non-CP-AMPA neurons. Moreover, we have found that NASPM, an antagonist of CP-AMPARs, significantly decreases the amplitude of the [Ca2+]i elevation induced by glutamate or selective AMPARs agonist, 5-fluorowillardiine. In contrast, the antagonists of NMDARs or KARs affect insignificantly. We have also described some peculiarities of Na+, K+, and H+ intracellular dynamics in neurons containing CP-AMPARs. In particular, the amplitude of [Na+]i elevation was lower compared to non-CP-AMPA neurons, whereas the amplitude of [K+]i decrease was higher. We have shown the significant inverse correlation between [K+]i and [Ca2+]i and between intracellular pH and [Na+]i in CP-AMPARs-containing and non-CP-AMPA neurons upon glutamate excitotoxicity. Our data indicate that CP-AMPARs-mediated Ca2+ influx and slow removal of Ca2+ from the cytosol may underlie the vulnerability of the CP-AMPARs-containing neurons to glutamate excitotoxicity. Further studies of the mechanisms mediating the disturbances in ion homeostasis are crucial for developing new approaches for protecting these neurons at brain pathologies.

A discrete choice experiment to elicit preferences for a chronic disease screening programme in Queensland, Australia.

OBJECTIVE: Patient-centred care, increasingly highlighted in healthcare strategies, necessitates understanding public preferences for healthcare service attributes. We aimed to understand the preferences of the Australian population regarding the attributes of chronic disease screening programmes. STUDY DESIGN: The preferences were elicited using the discrete choice experiment (DCE) methodology. METHODS: A DCE was administered to a sample of the Australian general population. Respondents were asked to make choices, each offering two hypothetical screening scenarios defined by screening conduct, quality and accuracy of the test results, cost to the patient, wait time and source of information. Data were analysed using a panel mixed multinomial logit model. RESULTS: A strong preference for highly accurate screening tests and nurse-led screenings at local health clinics was evident. They expressed disutility for waiting time and out-of-pocket costs but were indifferent about the source of information. Their preference for a nurse-led programme was highlighted by the fact that they were willing to pay $81 and $88 to get a nurse-led programme when they were offered a general practitioner-led and a specialist-led programme, respectively. Furthermore, they were willing to pay $32 to reduce a week of waiting time and $205 for a 95% accurate test compared to a 75% accurate test. Preferences remained consistent irrespective of the respondent's place of residence. CONCLUSIONS: Our findings highlight the importance of diagnostic test accuracy and nurse-led service delivery in chronic disease screening programmes. These insights could guide the development of patient-centric services by enhancing test accuracy, reducing waiting times and promoting nurse-led care models.

Rising hospital admissions for alcohol-related cirrhosis and the impact of sex and comorbidity - a data linkage study.

OBJECTIVES: International studies have shown shifting demographic data and rising hospitalizations for alcohol-related cirrhosis (ARC), with a paucity of data from Australia. We examined hospitalizations, mortality and demographic data for people admitted with ARC over the last decade in Queensland, Australia. STUDY DESIGN: Data linkage study. METHODS: A retrospective analysis of adults hospitalized with ARC during 2008-2019 was performed using state-wide admissions data. International Classification of Diseases, 10th revision, codes identified admissions with the principal diagnosis of ARC based on validated algorithms. Comorbidity was assessed using the Charlson Comorbidity Index. RESULTS: A total of 7152 individuals had 24,342 hospital admissions with ARC (16,388 were for ARC). There was a predominance of males (72.6%) and age ≥50 years (80.4%) at index admission. Females were admitted at a significantly younger age than men (59% of women and 43% of men were aged <60 years, P < 0.001). Comorbidities were common, with 45.1% of people having at least one comorbidity. More than half (54.6%) of the patients died over the study period (median follow-up time was 5.1 years; interquartile range 2.4-8.6). Women had significantly lower mortality, with 47.6% (95% confidence interval [CI] 45.0-50.2) probability of 5-year survival, compared with 40.1% (95% CI 38.5-41.6) in men. In multivariable analysis, this was attributable to significantly lower age and comorbidity burden in women. Significantly lower survival was seen in people with higher comorbidity burden. Overall, the number of admissions for ARC increased 2.2-fold from 869 admissions in 2008 to 1932 in 2019. CONCLUSIONS: Hospital admissions for ARC have risen substantially in the last decade. Females were admitted at a younger age, with fewer comorbidities and had lower mortality compared with males. The association between greater comorbidity burden and higher mortality has important clinical implications, as comorbidity-directed interventions may reduce mortality.

A novel approach for vital visualization and studying of neurons containing Ca2+ -permeable AMPA receptors.

Calcium-permeable AMPA receptors (CP-AMPARs) play a pivotal role in brain functioning in health and disease. They are involved in synaptic plasticity, synaptogenesis, and neuronal circuits development. However, the functions of neurons expressing CP-AMPARs and their role in the modulation of network activity remain elusive since reliable and accurate visualization methods are absent. Here we developed an approach allowing the vital identification of neurons containing CP-AMPARs. The proposed method relies on evaluating Ca2+ influx in neurons during activation of AMPARs in the presence of NMDAR and KAR antagonists, and blockers of voltage-gated Ca2+ channels. Using this method, we studied the properties of CP-AMPARs-containing neurons. We showed that the overwhelming majority of neurons containing CP-AMPARs are GABAergic, and they are distinguished by higher amplitudes of the calcium responses to applications of the agonists. Furthermore, about 30% of CP-AMPARs-containing neurons demonstrate the presence of GluK1-containing KARs. Although CP-AMPARs-containing neurons are characterized by more significant Ca2+ influx during the activation of AMPARs than other neurons, AMPAR-mediated Na+ influx is similar in these two groups. We revealed that neurons containing CP-AMPARs demonstrate weak GABA(A)R-mediated inhibition because of the low percentage of GABAergic synapses on the soma of these cells. However, our data show that weak GABA(A)R-mediated inhibition is inherent to all GABAergic neurons in the culture and cannot be considered a unique feature of CP-AMPARs-containing neurons. We believe that the suggested approach will help to understand the role of CP-AMPARs in the mammalian nervous system in more detail.

Carrageenans and Their Oligosaccharides from Red Seaweeds Ahnfeltiopsis flabelliformis and Mastocarpus pacificus (Phyllophoraceae) and Their Antiproliferative Activity.

Comparative structural analysis of gelling polysaccharides from A. flabelliformis and M. pacificus belonging to Phyllophoraceae and the effect of their structural features and molecular weight on human colon cancer cell lines (HT-29, DLD-1, HCT-116) was carried out. According to chemical analysis, IR and NMR spectroscopies, M. pacificus produces kappa/iota-carrageenan with a predominance of kappa units and minor amounts of mu and/or nu units, while the polysaccharide from A. flabelliformis is iota/kappa-carrageenan (predominance of iota units) and contains negligible amounts of beta- and nu-carrageenans. Iota/kappa- (Afg-OS) and kappa/iota-oligosaccharides (Mp-OS) were obtained from the original polysaccharides through mild acid hydrolysis. The content of more sulfated iota units in Afg-OS (iota/kappa 7:1) was higher than in Mp-OS (1.0:1.8). The poly- and oligosaccharides up to 1 mg/mL did not show a cytotoxic effect on all tested cell lines. Polysaccharides showed an antiproliferative effect only at 1 mg/mL. Oligosaccharides had a more pronounced effect on HT-29 and HCT-116 cells than the original polymers, while HCT-116 cells were slightly more sensitive to their action. Kappa/iota-oligosaccharides exhibit a greater antiproliferative effect and more strongly decrease the number of colonies forming in HCT-116 cells. At the same time, iota/kappa-oligosaccharides inhibit cell migration more strongly. Kappa/iota-oligosaccharides induce apoptosis in the SubG0 and G2/M phases, while iota/kappa-oligosaccharides in the SubG0 phase.

Of the Mechanisms of Paroxysmal Depolarization Shifts: Generation and Maintenance of Bicuculline-Induced Paroxysmal Activity in Rat Hippocampal Cell Cultures.

Abnormal depolarization of neuronal membranes called paroxysmal depolarization shift (PDS) represents a cellular correlate of interictal spikes. The mechanisms underlying the generation of PDSs or PDS clusters remain obscure. This study aimed to investigate the role of ionotropic glutamate receptors (iGluRs) in the generation of PDS and dependence of the PDS pattern on neuronal membrane potential. We have shown that significant depolarization or hyperpolarization (by more than ±50 mV) of a single neuron does not change the number of individual PDSs in the cluster, indicating the involvement of an external stimulus in PDS induction. Based on this data, we have suggested reliable protocols for stimulating single PDS or PDS clusters. Furthermore, we have found that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are necessary for PDS generation since AMPAR antagonist NBQX completely suppresses bicuculline-induced paroxysmal activity. In turn, antagonists of NMDA (N-methyl-D-aspartate) and kainate receptors (D-AP5 and UBP310, respectively) caused a decrease in the amplitude of the first action potential in PDSs and in the amplitude of the oscillations of intracellular Ca2+ concentration occurring alongside the PDS cluster generation. The effects of the NMDAR (NMDA receptor) and KAR (kainate receptor) antagonists indicate that these receptors are involved only in the modulation of paroxysmal activity. We have also shown that agonists of some Gi-coupled receptors, such as A1 adenosine (A1Rs) or cannabinoid receptors (CBRs) (N6-cyclohexyladenosine and WIN 55,212-2, respectively), completely suppressed PDS generation, while the A1R agonist even prevented it. We hypothesized that the dynamics of extracellular glutamate concentration govern paroxysmal activity. Fine-tuning of neuronal activity via action on Gi-coupled receptors or iGluRs paves the way for the development of new approaches for epilepsy pharmacotherapy.

Apoptosis Genes as a Key to Identification of Inverse Comorbidity of Huntington's Disease and Cancer.

Cancer and neurodegenerative disorders present overwhelming challenges for healthcare worldwide. Epidemiological studies showed a decrease in cancer rates in patients with neurodegenerative disorders, including the Huntington disease (HD). Apoptosis is one of the most important processes for both cancer and neurodegeneration. We suggest that genes closely connected with apoptosis and associated with HD may affect carcinogenesis. We applied reconstruction and analysis of gene networks associated with HD and apoptosis and identified potentially important genes for inverse comorbidity of cancer and HD. The top 10 high-priority candidate genes included APOE, PSEN1, INS, IL6, SQSTM1, SP1, HTT, LEP, HSPA4, and BDNF. Functional analysis of these genes was carried out using gene ontology and KEGG pathways. By exploring genome-wide association study results, we identified genes associated with neurodegenerative and oncological disorders, as well as their endophenotypes and risk factors. We used publicly available datasets of HD and breast and prostate cancers to analyze the expression of the identified genes. Functional modules of these genes were characterized according to disease-specific tissues. This integrative approach revealed that these genes predominantly exert similar functions in different tissues. Apoptosis along with lipid metabolism dysregulation and cell homeostasis maintenance in the response to environmental stimulus and drugs are likely key processes in inverse comorbidity of cancer in patients with HD. Overall, the identified genes represent the promising targets for studying molecular relations of cancer and HD.

Energetic Polymer Possessing Furazan, 1,2,3-Triazole, and Nitramine Subunits.

A [3 + 2] cycloaddition reaction using dialkyne and diazide comonomers, both bearing explosophoric groups, to synthesize energetic polymers containing furazan and 1,2,3-triazole ring as well as nitramine group in the polymer chain have been described. The developed solvent- and catalyst-free approach is methodologically simple and effective, the comonomers used are easily available, and the resulting polymer does not need any purification. All this makes it a promising tool for the synthesis of energetic polymers. The protocol was utilized to generate multigram quantities of the target polymer, which has been comprehensively investigated. The resulting polymer was fully characterized by spectral and physico-chemical methods. Compatibility with energetic plasticizers, thermochemical characteristics, and combustion features indicate the prospects of this polymer as a binder base for energetic materials. The polymer of this study surpasses the benchmark energetic polymer, nitrocellulose (NC), in a number of properties.

New approach to soil management focusing on soil health and air quality: one earth one life (critical review).

Soil plays a key role in ecosphere and air quality regulation. Obsolete environmental technologies lead to soil quality loss, air, water, and land systems pollution. Pedosphere and plants are intertwined with the air quality. Ionized O2 is capable to intensify atmosphere turbulence, providing particulate matter (PM2.5) coalescence and dry deposition. Addressing environmental quality, a Biogeosystem Technique (BGT*) heuristic transcendental (nonstandard and not direct imitation of nature) methodology has been developed. A BGT* main focus is an enrichment of Earth's biogeochemical cycles through land use and air cleaning. An intra-soil processing, which provides the soil multilevel architecture, is one of the BGT* ingredients. A next BGT* implementation is intra-soil pulse continuously discrete watering for optimal soil water regime and freshwater saving up to 10-20 times. The BGT* comprises intra-soil dispersed environmentally safe recycling of the PM sediments, heavy metals (HMs) and other pollutants, controlling biofilm-mediated microbial community interactions in the soil. This provides abundant biogeochemical cycle formation and better functioning of the humic substances, biological preparation, and microbial biofilms as a soil-biological starter, ensuring priority plants and trees nutrition, growth and resistance to phytopathogens. A higher underground and aboveground soil biological product increases a reversible C biological sequestration from the atmosphere. An additional light O2 ions photosynthetic production ensures a PM2.5 and PM0.1 coalescence and strengthens an intra-soil transformation of PM sediments into nutrients and improves atmosphere quality. The BGT* provides PM and HMs intra-soil passivation, increases soil biological productivity, stabilizes a climate system of the earth and promotes a green circular economy.

Reduced QED with Few Planes and Fermion Gap Generation.

The formalism of reduced quantum electrodynamics is generalized to the case of heterostructures composed of a few atomically thick layers, and the corresponding effective (2+1)-dimensional gauge theory is formulated. This dimensionally reduced theory describes charged fermions confined to N planes and contains N vector fields with Maxwell's action modified by non-local form factors whose explicit form is determined. Taking into account the polarization function, the explicit formulae for the screened electromagnetic interaction are presented in the case of two and three layers. For a heterostructure with two atomically thick layers and charged fermions described by the massless Dirac equation, the dynamical gap generation of the excitonic type is studied. It is found that additional screening due to the second layer increases the value of the critical coupling constant for the gap generation compared to that in graphene.

Investigation of the Antioxidant Properties of the Quaternized Chitosan Modified with a Gallic Acid Residue Using Peroxidase that Produces Reactive Oxygen Species.

Chitosan modified with a (2-hydroxy-3-trimethylammonium) propyl group and gallic acid residue, or quaternized chitosan with gallic acid (QCG), was synthesized. Antioxidant properties of the produced QCG have been investigated. Peroxidase in combination with NADH and salicyl hydroxamate (SHAM) caused consumption of oxygen and production of H2O2 in aqueous solution as a result of O2 reduction in the peroxidase-oxidase reactions. The rates of O2 consumption and H2O2 generation were reduced in the presence of QCG. The antioxidant propyl gallate (PG) and superoxide dismutase (SOD) had the same effect, but not the quaternized chitosan (QC) without gallic acid. The effect of chitosan derivatives on the production of reactive oxygen species (ROS) in the cells of pea leaf epidermis and on the cell death detected by the destruction of cell nuclei, was investigated. QCG, QC, and SOD had no effect, while PG decreased the rate of ROS generation in the cells of the epidermis, which was induced by NADH with SHAM or by menadione. QCG and QC prevented destruction of the guard cell nuclei in the pea leaf epidermis that was caused by NADH with SHAM or by KCN. SOD had no effect on the destruction of nuclei, while the effect of PG depended on the inducer of the cell death. Suppression of the destruction of guard cell nuclei by chitosan derivatives was associated not with their antioxidant effect, but with the disruption of the plasma membrane of the cells. The results obtained have shown that QCG exhibits antioxidant properties in solutions, but does not prevent generation of ROS in the plant cells. The mechanism of antioxidant effect of QCG is similar to that of PG and SOD.

Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease.

An increasing number of the population all around the world suffer from age-associated neurodegenerative diseases including Parkinson's disease (PD). This disorder presents different signs of genetic, epigenetic and environmental origin, and molecular, cellular and intracellular dysfunction. At the molecular level, α-synuclein (αSyn) was identified as the principal molecule constituting the Lewy bodies (LB). The gut microbiota participates in the pathogenesis of PD and may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The most important pathogenetic link is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species (ROS). In this review, genetic, epigenetic and environmental factors that cause these disorders and their cause-and-effect relationships are considered. As a constituent of environmental factors, the example of organophosphates (OPs) is also reviewed. The role of endothelial damage in the pathogenesis of PD is discussed, and a 'triple hit hypothesis' is proposed as a modification of Braak's dual hit one. In the absence of effective therapies for neurodegenerative diseases, more and more evidence is emerging about the positive impact of nutritional structure and healthy lifestyle on the state of blood vessels and the risk of developing these diseases.

Antiherpetic Activity of Carrageenan Complex with Echinochrome A and Its Liposomal Form.

Herpes simplex virus (HSV) infections, the incidence of which is still widespread throughout the world, are actualizing the search and development of new, more effective antiherpetic drugs. The development of multifunctional drug delivery systems, including liposome-based ones, has become a relevant and attractive concept in nanotechnology. The ability of complexes of κ- and Σ-carrageenans (CRGs)-sulfated polysaccharides of red algae, with echinochrome A (Ech), as well as the liposomal form of the Σ-CRG/Ech complex-to inhibit different stages of HSV-1 infection in Vero cells was studied. By quantum chemical calculations, it was shown that CRG forms stable complexes with Ech. We have shown that complexes of κ-CRG/Ech and Σ-CRG/Ech exhibit highest virucidal activity with a selectivity index (SI) of 270 and 350, respectively, and inhibition of virus-cell interaction (SI of 83 and 32, respectively). The liposomal form of the Σ-CRG/Ech complex after virus adsorption and penetration to cells effectively reduced the HSV-1 plaque formation. The virus-inhibiting activity of the liposomal form of the Σ-CRG/Ech complex was three times higher than that of the Σ-CRG/Ech complex itself. Obtaining CRGs/Ech complexes and their liposomal forms can become the basis of a successful strategy for the development of promising antiherpetic drugs.

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

Extracellular vesicles (EV) derived from stem cells have become an effective complement to the use in cell therapy of stem cells themselves, which has led to an explosion of research into the mechanisms of vesicle formation and their action. There is evidence demonstrating the presence of mitochondrial components in EV, but a definitive conclusion about whether EV contains fully functional mitochondria has not yet been made. In this study, two EV fractions derived from mesenchymal stromal stem cells (MSC) and separated by their size were examined. Flow cytometry revealed the presence of mitochondrial lipid components capable of interacting with mitochondrial dyes MitoTracker Green and 10-nonylacridine orange; however, the EV response to the probe for mitochondrial membrane potential was negative. Detailed analysis revealed components from all mitochondria compartments, including house-keeping mitochondria proteins and DNA as well as energy-related proteins such as membrane-localized proteins of complexes I, IV, and V, and soluble proteins from the Krebs cycle. When assessing the functional activity of mitochondria, high variability in oxygen consumption was noted, which was only partially attributed to mitochondrial respiratory activity. Our findings demonstrate that the EV contain all parts of mitochondria; however, their independent functionality inside EV has not been confirmed, which may be due either to the absence of necessary cofactors and/or the EV formation process and, probably the methodology of obtaining EV.

Energetic [1,2,5]oxadiazolo [2,3-a]pyrimidin-8-ium Perchlorates: Synthesis and Characterization.

A convenient method to access the above perchlorates has been developed, based on the cyclocondensation of 3-aminofurazans with 1,3-diketones in the presence of HClO4. All compounds were fully characterized by multinuclear NMR spectroscopy and X-ray crystal structure determinations. Initial safety testing (impact and friction sensitivity) and thermal stability measurements (DSC/DTA) were also carried out. Energetic performance was calculated by using the PILEM code based on calculated enthalpies of formation and experimental densities at r.t. These salts exhibit excellent burn rates and combustion behavior and are promising ingredients for energetic materials.

Promising Oxygen- and Nitrogen-Rich Azidonitramino Ether Plasticizers for Energetic Materials.

A simple, mild and general method has been developed for the preparation of alkyl nitramines bearing a halogenoalkoxylic moiety. From these reactive halogen intermediates, a few azidoalkoxyl alkyl nitramines have been produced as energetic plasticizers. This simple protocol allows azidonitramino ether plasticizers to be obtained from available precursors in high yields, as it is safe and viable for large-scale operations. The resulting products have been fully characterized by spectral methods, and their impact sensitivity, thermal transformations and burning properties were determined, thus allowing complete comparison to the analogues including other combinations of structural units. Such characterization of these new plasticizers illustrates the extent to which the nature and position of the functional units can be used to tune the above properties of these nitramines. All azidonitramino ethers are liquid with excellent energetic performance and are promising candidates for new environmentally friendly energetic materials.

Intra-soil waste recycling provides safety of environment.

Amelioration and remediation technology was developed for phosphogypsum utilization in Haplic Chernozem of South-European facies (Rostov Region). The technology comprises phosphogypsum dispersed application into the soil layer of 20-45 cm during intra-soil milling. In the model experiment, the phosphogypsum doses 0 (control), 10, 20, and 40 t ha-1 were studied. The Cd thermodynamic forms in soil solution were calculated via the developed mathematical chemical-thermodynamic model and program ION-3. The form of ion in soil solution (or water extract) was considered accounting the calcium-carbonate equilibrium (CCE) and association of ion pairs CaCO30; CaSO40, MgCO30, MgSO40, CaHCO3+, MgHCO3+, NaCO3-, NaSO4-, CaOH+, MgOH+. For calculation of the equilibrium of microelements concentration in soil solution ion including heavy metals (HMs), the coefficient of microelement association kas was proposed. According to calculations, Cd2+ ion in soil solution was mostly bounded to associates CdOH+, partly to associates CdCO30 and CdHCO3+. The calculated kas of Cd was 1.24 units in the control option of experiment and decreased to 0.95 units at phosphogypsum dose 40 t ha-1. The ratio of "active [Cd2+] to total Cd" reduced from 33.5% in control option to 28.0% in the option of phosphogypsum dose 40 t ha-1. The biogeochemical barrier for penetration of HMs from soil to plant roots was high after application of phosphogypsum. According to calculation by ION-3, the standard soil environmental limitations overestimate the toxicity of Cd in soil solution. New decision for intra-soil milling and simultaneous application of phosphogypsum was developed to provide the environmentally safe waste recycling.

In vivo diagnosis of skin cancer with a portable Raman spectroscopic device.

In this study, we performed in vivo diagnosis of skin cancer based on implementation of a portable low-cost spectroscopy setup combining analysis of Raman and autofluorescence spectra in the near-infrared region (800-915 nm). We studied 617 cases of skin neoplasms (615 patients, 70 melanomas, 122 basal cell carcinomas, 12 squamous cell carcinomas and 413 benign tumors) in vivo with a portable setup. The studies considered the patients examined by GPs in local clinics and directed to a specialized Oncology Dispensary with suspected skin cancer. Each sample was histologically examined after excisional biopsy. The spectra were classified with a projection on latent structures and discriminant analysis. To check the classification models stability, a 10-fold cross-validation was performed. We obtained ROC AUCs of 0.75 (0.71-0.79; 95% CI), 0.69 (0.63-0.76; 95% CI) and 0.81 (0.74-0.87; 95% CI) for classification of a) malignant and benign tumors, b) melanomas and pigmented tumors and c) melanomas and seborrhoeic keratosis, respectively. The positive and negative predictive values ranged from 20% to 52% and from 73% to 99%, respectively. The biopsy ratio varied from 0.92:1 to 4.08:1 (at sensitivity levels from 90% to 99%). The accuracy of automatic analysis with the proposed system is higher than the accuracy of GPs and trainees, and is comparable or less to the accuracy of trained dermatologists. The proposed approach may be combined with other optical techniques of skin lesion analysis, such as dermoscopy- and spectroscopy-based computer-assisted diagnosis systems to increase accuracy of neoplasms classification.

Editor's Choice - A Cost Effectiveness Analysis of Outpatient versus Inpatient Hospitalisation for Lower Extremity Arterial Disease Endovascular Revascularisation in France: A Randomised Controlled Trial.

OBJECTIVE: The AMBUVASC trial evaluated the cost effectiveness of outpatient vs. inpatient hospitalisation for endovascular repair of lower extremity arterial disease (LEAD). METHODS: AMBUVASC was a national multicentre, prospective, randomised controlled trial conducted in nine public and two private French centres. The primary endpoint was the incremental cost effectiveness ratio (ICER), defined by cost per quality adjusted life year (QALY). Analysis was conducted from a societal perspective, excluding indirect costs, and considering a one month time horizon. RESULTS: From 16 February 2016 to 29 May 2017, 160 patients were randomised (80 per group). A modified intention to treat analysis was performed with 153 patients (outpatient hospitalisation: n = 76; inpatient hospitalisation: n = 77). The patients mainly presented intermittent claudication (outpatient arm: 97%; inpatient arm: 92%). Rates of peri-operative complications were 20% (15 events) and 18% (14 events) for the outpatient and inpatient arms respectively (p = .81). Overall costs (difference: €187.83; 95% confidence interval [CI] -275.68-651.34) and QALYs (difference: 0.00277; 95% CI -0.00237 - 0.00791) were higher for outpatients due to more re-admissions than the inpatient arm. The mean ICER was €67 741 per QALY gained for the base case analysis with missing data imputed using multiple imputation by predictive mean matching. The outpatient procedure was not cost effective for a willingness to pay of €50 000 per QALY and the probability of being cost effective was only 59% for a €100 000/QALY threshold. CONCLUSION: Outpatient hospitalisation is not cost effective compared with inpatient hospitalisation for endovascular repair of patients with claudication at a €50 000/QALY threshold.

Catalytic antibodies in the bone marrow and other organs of Th mice during spontaneous development of experimental autoimmune encephalomyelitis associated with cell differentiation.

Exact mechanisms of autoimmune disease development are still yet unknown. However, it is known that the development of autoimmune diseases is associated with defects in the immune system, namely, the violation of the bone marrow hematopoietic stem cells (HSCs) differentiation profiles. Different characteristics of autoimmune reaction development in experimental autoimmune encephalomyelitis (EAE) prone Th mice characterizing T-lymphocytes response were analyzed using standard approaches. Profiles of several HSCs differentiation of bone marrow (BFU-E, CFU-E, CFU-GM, CFU-GEMM, T- and B-lymphocytes) of Th male and female mice during spontaneous development of EAE were noticeably different. Patterns of total lymphocytes, B- and T-cells proliferation in several different organs (bone marrow, blood, spleen, thymus, and lymph nodes) were also remarkably different. In addition, there were in time noticeable differences in their changes for some organs of male and female mice. Characters of changes in the profiles of CD4 and CD8 cells proliferation in some organs not always coincide with those for total T lymphocytes. The changes in the differentiation profiles of HSCs and the level of lymphocytes proliferation in the bone marrow and other organs were associated with the increase in the concentration of antibodies against DNA, myelin basic protein, and myelin oligodendrocyte glycoprotein, and catalytic antibodies hydrolyzing these substrates. Despite some differences in changes in the analyzed parameters, in general, the spontaneous development of EAE in male and female mice occurs to some extent in a comparable way.