Six-month therapy of CGRP monoclonal antibodies in real-world clinical practice: an interim analysis of efficacy and safety data

Introduction. Migraine is one of the most common disabling neurological disorders. Recently developed monoclonal antibodies to calcitonin gene-related peptide (CGRP) or its receptor are the first targeted medication for preventive therapy of both episodic and chronic migraine. They have been thoroughly investigated in clinical trials; however, there is little data from real-world clinical practice available to date. The aim of this study is to assess the efficacy and safety of 6 months of treatment with erenumab in real-world clinical practice and investigate the effect of the drug on the patients’ sensitivity to medicines for migraine headaches relief and patient satisfaction after treatment.Materials and methods. Our observational cohort prospective study included patients in our Headache Clinic prescribed monoclonal antibodies blocking the  CGRP-receptor  – erenumab. During the  investigation, we evaluated the  previous preventive therapy and its efficacy, the number of days with migraine per month, adverse events occurring during the erenumab treatment, depression and anxiety (HADS), migraine disability (MIDAS), the presence of allodynia (ACS-12) and improved response to acute therapy after treatment. A total of 42 patients participated in the study: 6 men, 36 women, the average age was 43.9 ± 12.2. Of them, 38 patients (90%) had chronic migraine. Thirty-two patients (76%) had previously been prescribed preventive therapy, which proved ineffective, and 10 patients (24%) had not once received any type of migraine prevention.Results. Among our patients, we identified 11 patients with resistant migraine and one patient with refractory migraine. During the study, two patients dropped out due to adverse events (constipation). Thirty patients continued the administration of erenumab 70 mg for at least six months. The average number of migraine days per month before treatment was 22.8, and after six months of treatment, it dropped to 7.3. Twenty-nine patients (72.5%) also noted that the response to acute headache treatment improved after the therapy.Conclusion. The results of our study are consistent with the international experience of using erenumab and confirm its effectiveness for migraine preventive therapy, including difficult-to-treat migraine cases. However, further studies with more participants and evaluation of predictors of successful monoclonal antibody therapy are still needed

Overview of mathematical approaches used to model bacterial chemotaxis II: bacterial populations

We review the application of mathematical modeling to understanding the behavior of populations of chemotactic bacteria. The application of continuum mathematical models, in particular generalized Keller–Segel models, is discussed along with attempts to incorporate the microscale (individual) behavior on the macroscale, modeling the interaction between different species of bacteria, the interaction of bacteria with their environment, and methods used to obtain experimentally verified parameter values. We allude briefly to the role of modeling pattern formation in understanding collective behavior within bacterial populations. Various aspects of each model are discussed and areas for possible future research are postulated

Aromatic Amino Acids: Phenylalanine and Tyrosine in Patients with Hypertension and Coronary Artery Disease

Aim. To evaluate changes in the profile of aromatic amino acids (AAA) in patients with cardiovascular diseases (CVD): hypertension and coronary artery disease (CАD) in comparison with healthy study participants.Material and methods. One hundred and thirty-one participants were included in the study: 58 participants were included in the hypertension group, 46 in the CАD group, and 27 participants without signs of CVD in the control group. We used ultrahigh-performance liquid chromatography in combination with a triple quadrupole analyzer to measure plasma AAA: phenylalanine and tyrosine (Phe, Tyr) in all study participants. The association of AAA with biochemical blood test parameters, echocardiography (EchoCG) parameters, blood pressure level and clinical characteristics was analyzed.Results. A statistically significant difference in the level of concentration of Phe and Tyr was revealed (p=0,002 and p=0,024, respectively), comparing the three groups. Post-hoc analysis showed differences in the circulating level of both amino acids in patients with CAD vs the control group (Phe p=0,008 and Tyr p=0,020). Also a statistically significant difference in the level of Phe of the hypertension and CАD groups (p=0,017) was found. A negative correlation of low-density lipoproteins (LDL) with the level of Phe (r=-0,685, p<0,05) and Tyr (r=-0,583, p<0,05), as well as the level of Phe with total cholesterol (r=-0,461, p<0,05) was found in the group without CVD. In the hypertension group, only a weak positive correlation was found between very low-density lipoproteins and AAA levels (Phe r=0,326 and Tyr r=0,365, p<0,05), while in patients with CAD, the level of Phe and Tyr was negative correlated with high-density lipoprotein (r=-0,378 and r=-0,543, respectively, p<0,05), and the level of Tyr with LDL (r=0,349, p<0,05). When isolating the group with proven atherosclerosis of peripheral and/or coronary arteries, a statistically significant difference was revealed between the group of patients with CVD and clinical and instrumental signs of atherosclerosis and the group of patients with CVD without proven atherosclerosis in Phe level (p=0,019).Conclusion. Concentrations of AAA were higher in patients with CVD, comparing with the control group. At the same time, an increase of the Phe level was associated with the presence of peripheral or coronary atherosclerosis. The revealed correlations of AAA with EchoCG parameters and lipid spectrum parameters require further study to understand the involvement of AAA in pathogenesis of CVD and its potential role as treatment target

ОСНОВНЫЕ ПОКАЗАТЕЛИ МЕДИЦИНСКОЙ ПОМОЩИ ОНКОЛОГИЧЕСКИМ БОЛЬНЫМ В АМУРСКОЙ ОБЛАСТИ

Materials of the research was accepted in the Russian accounting and reporting documents of cial cancer statistics. The article presents the main indicators of medical care for cancer patients in the Amur region, where the 2014 3012 registered new cases of malignant neoplasms, which is 8.9 % more than in the previous year (2013 year – 27.67). Under medical supervision were 15997 patients, i.e. 2 % of the population. Of these, a 45.5 % male and 54.5% female. The maximum number of cases was in the age group 50–69 years. Fewer patients with I–II stages of the process, but it was more of patients with advanced forms of cancer pathology. The number of patients identi ed during preventive examinations amounted to 593 (2013 – 513). Mortality remained at the same level – 120.3 (2013 year – 129.5), whereas the incidence for the last 5 years has increased from 221.7 to in 2010 to 249.9 in 2014 (per 100 000 population). Mortality in the rst year from the time of diagnosis has decreased to 28.4 % (2013 year – 29.4 %). The proportion of patients registered for 5 years or more is 54.5 %. In the cities and districts of the region signi cantly reduced the number of oncologists (2012 year – 22; 2014 year – 13). In 2014 registered 20 cases of malignant neoplasms in children. Data on spatial features of the cancer disease are the basis for the analysis of cancer epidemiology in a speci c region and is aimed primarily at the prevention of this disease. Материалами исследования являлись общепринятые в России учетно-отчетные документы официальной онкологической статистики. Приведены основные показатели оказания медицинской помощи онкологическим больным в Амурской области, где в 2014 г. зарегистрировано 3 012 новых случаев злокачественных новообразований, что на 8,9 % больше, чем в предыдущем году (в 2013 г. – 2 767). Под диспансерным наблюдением находились 15 997 пациентов, т.е. 2 % населения области. Из них мужчин – 45,5 %, женщин – 54,5 %. Максимальное число заболевших приходилось на возрастную группу 50–69 лет. Уменьшилось количество больных с I–II стадиями процесса, но больше стало пациентов с запущенными формами онкопатологии. Количество больных, выявленных при профилактических осмотрах, – 593 (в 2013 г. – 513). Смертность снизилась в сравнении с прежним уровнем – 120,31 0/0000 (в 2013 г. – 129,5 0/0000), тогда как заболеваемость за последние 5 лет выросла с 221,74 0/0000 в 2010 г. до 249,91 0/0000 в 2014 г. Летальность на первом году с момента установления диагноза снизилась до 28,4 % (в 2013 г. – 29,4 %). Удельный вес больных, состоявших на учете 5 и более лет, – 54,5 %. В 2014 году зарегистрировано 20 случаев злокачественных новообразований у детей. Данные о территориальных особенностях онкологической патологии являются основой для анализа эпидемиологии рака в конкретном регионе.

Viral infections during pregnancy - optimization of therapy

The article presents the results of a clinical study of a comparative assessment of the therapeutic efficacy, safety and tolerability of the drug Panavir, a solution for intravenous administration of 0.04 mg / ml with the preparations of the basic complex therapy of IVI in pregnant women in the II and III trimesters. The study revealed that the inclusion of the drug "Panavir" in the complex therapy of viral infections during pregnancy effectively reduces the risk of developing amnionitis, placenta and infection of the fetus; is safe for both the mother and the fetus and is not accompanied by side effects and undesirable phenomena.В статье представлены результаты клинического исследования сравнительной оценки лечебной эффективности, безопасности и переносимости препарата «Панавир», раствора для внутривенного введения 0,04 мг/мл с препаратами базовой комплексной терапии ВУИ у беременных во II и III триместрах. В результате исследования выявлено, что включение препарата «Панавир» в комплексную терапию вирусных инфекций во время беременности эффективно снижает риск развития амнионита, плацентита и инфицирование плода; безопасно как для матери, так и для плода и не сопровождается побочными эффектами и нежелательными явлениями

Noisy-threshold control of cell death

<p>Abstract</p> <p>Background</p> <p>Cellular responses to death-promoting stimuli typically proceed through a differentiated multistage process, involving a lag phase, extensive death, and potential adaptation. Deregulation of this chain of events is at the root of many diseases. Improper adaptation is particularly important because it allows cell sub-populations to survive even in the continuous presence of death conditions, which results, among others, in the eventual failure of many targeted anticancer therapies.</p> <p>Results</p> <p>Here, I show that these typical responses arise naturally from the interplay of intracellular variability with a threshold-based control mechanism that detects cellular changes in addition to just the cellular state itself. Implementation of this mechanism in a quantitative model for T-cell apoptosis, a prototypical example of programmed cell death, captures with exceptional accuracy experimental observations for different expression levels of the oncogene Bcl-x_Land directly links adaptation with noise in an ATP threshold below which cells die.</p> <p>Conclusions</p> <p>These results indicate that oncogenes like Bcl-x_L, besides regulating absolute death values, can have a novel role as active controllers of cell-cell variability and the extent of adaptation.</p

Phenotypic Variation and Bistable Switching in Bacteria

Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.

On the Origin and Characteristics of Noise-Induced Lévy Walks of E. Coli

Lévy walks as a random search strategy have recently attracted a lot of attention, and have been described in many animal species. However, very little is known about one of the most important issues, namely how Lévy walks are generated by biological organisms. We study a model of the chemotaxis signaling pathway of E. coli, and demonstrate that stochastic fluctuations and the specific design of the signaling pathway in concert enable the generation of Lévy walks. We show that Lévy walks result from the superposition of an ensemble of exponential distributions, which occurs due to the shifts in the internal enzyme concentrations following the stochastic fluctuations. With our approach we derive the power-law analytically from a model of the chemotaxis signaling pathway, and obtain a power-law exponent , which coincides with experimental results. This work provides a means to confirm Lévy walks as natural phenomenon by providing understanding on the process through which they emerge. Furthermore, our results give novel insights into the design aspects of biological systems that are capable of translating additive noise on the microscopic scale into beneficial macroscopic behavior

Noise Filtering Strategies of Adaptive Signaling Networks: The Case of E. Coli Chemotaxis

Two distinct mechanisms for filtering noise in an input signal are identified in a class of adaptive sensory networks. We find that the high frequency noise is filtered by the output degradation process through time-averaging; while the low frequency noise is damped by adaptation through negative feedback. Both filtering processes themselves introduce intrinsic noises, which are found to be unfiltered and can thus amount to a significant internal noise floor even without signaling. These results are applied to E. coli chemotaxis. We show unambiguously that the molecular mechanism for the Berg-Purcell time-averaging scheme is the dephosphorylation of the response regulator CheY-P, not the receptor adaptation process as previously suggested. The high frequency noise due to the stochastic ligand binding-unbinding events and the random ligand molecule diffusion is averaged by the CheY-P dephosphorylation process to a negligible level in E.coli. We identify a previously unstudied noise source caused by the random motion of the cell in a ligand gradient. We show that this random walk induced signal noise has a divergent low frequency component, which is only rendered finite by the receptor adaptation process. For gradients within the E. coli sensing range, this dominant external noise can be comparable to the significant intrinsic noise in the system. The dependence of the response and its fluctuations on the key time scales of the system are studied systematically. We show that the chemotaxis pathway may have evolved to optimize gradient sensing, strong response, and noise control in different time scalesComment: 15 pages, 4 figure

Stochastic dynamics and mean field approach in a system of three interacting species

The spatio-temporal dynamics of three interacting species, two preys and one predator, in the presence of two different kinds of noise sources is studied. To describe the spatial distributions of the species we use a model based on Lotka-Volterra equations. A correlated dichotomous noise acts on \beta, the interaction parameter between the two preys, and a multiplicative white noise affects directly the dynamics of each one of the three species. We study the time behaviour of the three species in single site for different values of the multiplicative noise intensity, finding noise-induced oscillations of the three species densities with an anticorrelated behaviour of the two preys. Afterwards, by considering a spatially extended system formed by a two-dimensional lattice with N sites and applying a mean field approach, we get the corresponding moment equations in Gaussian approximation. Within this formalism we obtain the time behaviour of the first and second order moments for different values of multiplicative noise intensity, with \beta(t) subject to the same dichotomous noise source. Finally, we compare our results with those obtained by using a coupled map lattice model, consisting of a time discrete version of the Lotka-Volterra equations.Comment: 21 pages, 7 figures. Submitted to Centr. Eur. J. Phy