[Low adherence to treatment is a weak link in the problems of ulcerative colitis].

AIM: To determine factors of adherence to treatment in patients with ulcerative colitis (UC). MATERIALS AND METHODS: The study was performed in the department of treatment of inflammatory bowel diseases in Loginov Moscow Clinical Scientific Center from 2019 till 2021 years by surveying 1089 patients with UC. This analysis revealed patients with high adherence (HAP) and low adherence to treatment (LAP). RESULTS: In the survey analysis was determined, that there were more low-adherence patients, than high-adherence patients [596 (59.6%) and 404 (40.4%), respectively, (p0.001)]. In the group of HAP (100%) were 297 women (73.5%) and 107 (26.5%) men (p0.001). Also in this group prevailed patients with duration of disease more 5 years 305 (75.5%) and extraintestinal manifestations 261 (64.6%); p0.001. In the group of LAP (100%) were more patients younger 44 years, with bad habits and who did not follow diet (p0.001). The rate of UC reccurence more than 1 time per year was higher in LAP group 430 (72.1%), versus 137 (33.9%) patients in HAP (p0.001). The frequency of surgical procedures in UC patients was significantly higher in LAP 12 (2.0%) in comparison with 2 (0.5%) in HAP group (p0.001). CONCLUSION: In our study was determined, that among UC patients, examined in the department of inflammatory bowel diseases, 60% patients had low adherence to treatment. High adherence to the treatment is statistically significantly associated with female gender, family accommodation, non-working patients, extraintestinal manifestations, additional medical maintenance. Low adherence to the treatment is associated with steroids, male gender, age less than 44 year, bad habits (smoking, alcohol consumption), higher education, complicated UC and frequency of reccurences.

Advancing Biomarker Development Through Convergent Engagement: Summary Report of the 2nd International Danube Symposium on Biomarker Development, Molecular Imaging and Applied Diagnostics; March 14-16, 2018; Vienna, Austria.

Here, we report on the outcome of the 2nd International Danube Symposium on advanced biomarker development that was held in Vienna, Austria, in early 2018. During the meeting, cross-speciality participants assessed critical aspects of non-invasive, quantitative biomarker development in view of the need to expand our understanding of disease mechanisms and the definition of appropriate strategies both for molecular diagnostics and personalised therapies. More specifically, panelists addressed the main topics, including the current status of disease characterisation by means of non-invasive imaging, histopathology and liquid biopsies as well as strategies of gaining new understanding of disease formation, modulation and plasticity to large-scale molecular imaging as well as integrative multi-platform approaches. Highlights of the 2018 meeting included dedicated sessions on non-invasive disease characterisation, development of disease and therapeutic tailored biomarkers, standardisation and quality measures in biospecimens, new therapeutic approaches and socio-economic challenges of biomarker developments. The scientific programme was accompanied by a roundtable discussion on identification and implementation of sustainable strategies to address the educational needs in the rapidly evolving field of molecular diagnostics. The central theme that emanated from the 2nd Donau Symposium was the importance of the conceptualisation and implementation of a convergent approach towards a disease characterisation beyond lesion-counting "lumpology" for a cost-effective and patient-centric diagnosis, therapy planning, guidance and monitoring. This involves a judicious choice of diagnostic means, the adoption of clinical decision support systems and, above all, a new way of communication involving all stakeholders across modalities and specialities. Moreover, complex diseases require a comprehensive diagnosis by converging parameters from different disciplines, which will finally yield to a precise therapeutic guidance and outcome prediction. While it is attractive to focus on technical advances alone, it is important to develop a patient-centric approach, thus asking "What can we do with our expertise to help patients?"

Rapid effects of oestrogen on synaptic plasticity: interactions with actin and its signalling proteins.

Oestrogen rapidly enhances fast excitatory postsynaptic potentials, facilitates long-term potentiation (LTP) and increases spine numbers. Each effect likely contributes to the influence of the steroid on cognition and memory. In the present review, we first describe a model for the substrates of LTP that includes an outline of the synaptic events occurring during induction, expression and consolidation. Briefly, critical signalling pathways involving the small GTPases RhoA and Rac/Cdc42 are activated by theta burst-induced calcium influx and initiate actin filament assembly via phosphorylation (inactivation) of cofilin. Reorganisation of the actin cytoskeleton changes spine and synapse morphology, resulting in increased concentrations of AMPA receptors at stimulated contacts. We then use the synaptic model to develop a specific hypothesis about how oestrogen affects both baseline transmission and plasticity. Brief infusions of 17ß-oestradiol (E2 ) reversibly stimulate the RhoA, cofilin phosphorylation and actin polymerisation cascade of the LTP machinery; blocking this eliminates the effects of the steroid on transmission. We accordingly propose that E2 induces a weak form of LTP and thereby increases synaptic responses, a hypothesis that also accounts for how it markedly enhances theta burst induced potentiation. Although the effects of E2 on the cytoskeleton could be a result of the direct activation of small GTPases by oestrogen receptors on the synaptic membrane, the hormone also activates tropomyosin-related kinase B receptors for brain-derived neurotrophic factor, a neurotrophin that engages the RhoA-cofilin sequence and promotes LTP. The latter observations raise the possibility that E2 produces its effects on synaptic physiology via transactivation of neighbouring receptors that have prominent roles in the management of spine actin, synaptic physiology and plasticity.

Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton.

Estrogen's acute, facilitatory effects on glutamatergic transmission and long-term potentiation (LTP) provide a potential explanation for the steroid's considerable influence on behavior. Recent work has identified mechanisms underlying these synaptic actions. Brief infusion of 17ß-estradiol (E2) into adult male rat hippocampal slices triggers actin polymerization within dendritic spines via a signaling cascade beginning with the GTPase RhoA and ending with inactivation of the filament-severing protein cofilin. Blocking this sequence, or actin polymerization itself, eliminates E2's effects on synaptic physiology. Notably, the theta burst stimulation used to induce LTP activates the same signaling pathway as E2 plus events that stabilize the reorganization of the sub-synaptic cytoskeleton. These observations suggest that E2 elicits a partial form of LTP, resulting in an increase of fast excitatory postsynaptic potentials (EPSPs) and a reduction in the threshold for lasting synaptic changes. While E2's effects on the cytoskeleton could be direct, results described here indicate that the hormone activates synaptic tropomyosin-related kinase B (TrkB) receptors for brain-derived neurotrophic factor (BDNF), a releasable neurotrophin that stimulates the RhoA to cofilin pathway. It is therefore possible that E2 acts via transactivation of neighboring receptors to modify the composition and structure of excitatory contacts. Finally, there is the question of whether a loss of acute synaptic actions contributes to the memory problems associated with estrogen depletion. Initial tests found that ovariectomy in middle-aged rats disrupts RhoA signaling, actin polymerization, and LTP consolidation. Acute applications of E2 reversed these defects, a result consistent with the idea that disturbances to actin management are one cause of behavioral effects that emerge with reductions in steroid levels.

Loss of the Reelin-signaling pathway differentially disrupts heat, mechanical and chemical nociceptive processing.

The Reelin-signaling pathway regulates neuronal positioning during embryonic development. Reelin, the extracellular matrix protein missing in reeler mutants, is secreted by neurons in laminae I, II and V, binds to Vldl and Apoer2 receptors on nearby neurons, and tyrosine phosphorylates the adaptor protein Disabled-1 (Dab1), which activates downstream signaling. We previously reported that reeler and dab1 mutants had significantly reduced mechanical and increased heat nociception. Here we extend our analysis to chemical, visceral, and cold pain and importantly, used Fos expression to relate positioning errors in mutant mouse dorsal horn to changes in neuronal activity. We found that noxious mechanical stimulation-induced Fos expression is reduced in reeler and dab1 laminae I-II, compared to wild-type mice. Additionally, mutants had fewer Fos-immunoreactive neurons in the lateral-reticulated area of the deep dorsal horn than wild-type mice, a finding that correlates with a 50% reduction and subsequent mispositioning of the large Dab1-positive cells in the mutant lateral-reticulated area. Furthermore, several of these Dab1 cells expressed Fos in wild-type mice but rarely in reeler mutants. By contrast, paralleling the behavioral observations, noxious heat stimulation evoked significantly greater Fos expression in laminae I-II of reeler and dab1 mutants. We then used the formalin test to show that chemical nociception is reduced in reeler and dab1 mutants and that there is a corresponding decrease in formalin-induced Fos expression. Finally, neither visceral pain nor cold-pain sensitivity differed between wild-type and mutant mice. As differences in the nociceptor distribution within reeler and dab1 mutant dorsal horn were not detected, these differential effects observed on distinct pain modalities suggest that dorsal horn circuits are organized along modality-specific lines.