Adoption of the governmental affordable medicines programme by ukrainians.

Ensuring that the local population has access to medicines is one of the functions of a modern democratic state and an important element of social policy. The question of the affordability of medicines to the public is extremely important. This is also due to the fact that, unlike in European countries, Ukraine did not have a system of medicines reimbursement. To date, the reimbursement Affordable Medicines Programme has been in effect since April 2017 and is applicable to patients with cardiovascular disease, bronchial asthma, and type II diabetes. In total, 258 medicines are included in the Programme, 64 of which can be obtained free of charge and the others with a small extra payment. The respondents' perceptions of the Programme were conducted through a secondary analysis based on the third wave of the «Health Index. Ukraine» which was held in 2018 by the International Renaissance Foundation, the School of Public Health of the National University of Kyiv Mohyla Academy, and the Kyiv International Institute of Sociology. This study aims to present the results of the research of the attitude of Ukrainians to the government Affordable Medicines Programme and their perception of its implementation. The total number of respondents to this survey totaled more than 10,000 household rep­resentatives. The results of the research indicate a positive assessment of the respondents who participated in the survey «Health Index. Ukraine» (76% in 2018), which is confirmed by other research of the Kyiv International Institute of Sociology (63% in 2019) and by international experts. The results of the survey do not allow us to draw any official conclusions about the impact of the Programme on the health of Ukrainians, but during the interview 60.6% of the respondents said that the Programme «helped improve health»; in addition, positive changes in health were indicated by the most financially vulne­rable categories of the population. It is also noted that 80–82% of prescriptions were reimbursed to Programme participants

Cytomegalovirus induces abnormal chondrogenesis and osteogenesis during embryonic mandibular development

<p>Abstract</p> <p>Background</p> <p>Human clinical studies and mouse models clearly demonstrate that cytomegalovirus (CMV) disrupts normal organ and tissue development. Although CMV is one of the most common causes of major birth defects in humans, little is presently known about the mechanism(s) underlying CMV-induced congenital malformations. Our prior studies have demonstrated that CMV infection of first branchial arch derivatives (salivary glands and teeth) induced severely abnormal phenotypes and that CMV has a particular tropism for neural crest-derived mesenchyme (NCM). Since early embryos are barely susceptible to CMV infection, and the extant evidence suggests that the differentiation program needs to be well underway for embryonic tissues to be susceptible to viral infection and viral-induced pathology, the aim of this study was to determine if first branchial arch NCM cells are susceptible to mCMV infection prior to differentiation of NCM derivatives.</p> <p>Results</p> <p>E11 mouse mandibular processes (MANs) were infected with mouse CMV (mCMV) for up to 16 days <it>in vitr</it>o. mCMV infection of undifferentiated embryonic mouse MANs induced micrognathia consequent to decreased Meckel's cartilage chondrogenesis and mandibular osteogenesis. Specifically, mCMV infection resulted in aberrant stromal cellularity, a smaller, misshapen Meckel's cartilage, and mandibular bone and condylar dysmorphogenesis. Analysis of viral distribution indicates that mCMV primarily infects NCM cells and derivatives. Initial localization studies indicate that mCMV infection changed the cell-specific expression of FN, NF-κB2, RelA, RelB, and Shh and Smad7 proteins.</p> <p>Conclusion</p> <p>Our results indicate that mCMV dysregulation of key signaling pathways in primarily NCM cells and their derivatives severely disrupts mandibular morphogenesis and skeletogenesis. The pathogenesis appears to be centered around the canonical and noncanonical NF-κB pathways, and there is unusual juxtaposition of abnormal stromal cells and surrounding matrix. Moreover, since it is critically important that signaling molecules are expressed in appropriate cell populations during development, the aberrant localization of components of relevant signaling pathways may reveal the pathogenic mechanism underlying mandibular malformations.</p

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity

Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe

A Temporal Gate for Viral Enhancers to Co-opt Toll-Like-Receptor Transcriptional Activation Pathways upon Acute Infection

Viral engagement with macrophages activates Toll-Like-Receptors (TLRs) and viruses must contend with the ensuing inflammatory responses to successfully complete their replication cycle. To date, known counter-strategies involve the use of viral-encoded proteins that often employ mimicry mechanisms to block or redirect the host response to benefit the virus. Whether viral regulatory DNA sequences provide an opportunistic strategy by which viral enhancer elements functionally mimic innate immune enhancers is unknown. Here we find that host innate immune genes and the prototypical viral enhancer of cytomegalovirus (CMV) have comparable expression kinetics, and positively respond to common TLR agonists. In macrophages but not fibroblasts we show that activation of NFκB at immediate-early times of infection is independent of virion-associated protein, M45. We find upon virus infection or transfection of viral genomic DNA the TLR-agonist treatment results in significant enhancement of the virus transcription-replication cycle. In macrophage time-course infection experiments we demonstrate that TLR-agonist stimulation of the viral enhancer and replication cycle is strictly delimited by a temporal gate with a determined half-maximal time for enhancer-activation of 6 h; after which TLR-activation blocks the viral transcription-replication cycle. By performing a systematic siRNA screen of 149 innate immune regulatory factors we identify not only anticipated anti-viral and pro-viral contributions but also new factors involved in the CMV transcription-replication cycle. We identify a central convergent NFκB-SP1-RXR-IRF axis downstream of TLR-signalling. Activation of the RXR component potentiated direct and indirect TLR-induced activation of CMV transcription-replication cycle; whereas chromatin binding experiments using wild-type and enhancer-deletion virus revealed IRF3 and 5 as new pro-viral host transcription factor interactions with the CMV enhancer in macrophages. In a series of pharmacologic, siRNA and genetic loss-of-function experiments we determined that signalling mediated by the TLR-adaptor protein MyD88 plays a vital role for governing the inflammatory activation of the CMV enhancer in macrophages. Downstream TLR-regulated transcription factor binding motif disruption for NFκB, AP1 and CREB/ATF in the CMV enhancer demonstrated the requirement of these inflammatory signal-regulated elements in driving viral gene expression and growth in cells as well as in primary infection of neonatal mice. Thus, this study shows that the prototypical CMV enhancer, in a restricted time-gated manner, co-opts through DNA regulatory mimicry elements, innate-immune transcription factors to drive viral expression and replication in the face of on-going pro-inflammatory antiviral responses in vitro and in vivo and; suggests an unexpected role for inflammation in promoting acute infection and has important future implications for regulating latency

РАННЯ ДІАГНОСТИКА ТА СКРИНІНГ ЯК ОСНОВНІ СКЛАДОВІ СТРАТЕГІЇ ПРОТИДІЇ ОНКОЛОГІЧНИМ ЗАХВОРЮВАННЯМ

Purpose: to analyze current incidence and mortality rates of cancer; a role of early detection or screening in reducing high cancer mortality; and approaches of screening in the world and Ukraine, particularly. Materials and Methods. A bibliosemantic, structural-logical, and comparative analysis and analytical method were used in the research. Results and Discussion. The incidence and mortality from cancer are increasing rapidly worldwide. The causes are complex, but reflect aging and population growth, as well as changes in the prevalence and distribution of major cancer risk factors, some of which are related to socio-economic development. The problem of high mortality from oncological diseases is very acute for all countries of the world, including economically developed ones. Between 30% and 60% of patients are died from cancer because of the late diagnosis. The analysis showed that the strategies for cancer control based on the WHO Resolution on Cancer in Great Britain, France, Poland, and the United States of America include prevention, diagnosis, and screening. It was possible to reduce mortality rate from cancer due to the wide use of the cancer screening system in routine medical practice. There are three mandatory screening tests for breast, cervix, and prostate cancer in Ukraine. However, these screening programs for cancer are currently ineffective. In fact, early diagnosis of cancer still comes from the patient's alertness to changes in health and self-examination for cancer.&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp; Conclusions. According to research released by WHO, millions of deaths due to different types of cancer have been recorded worldwide annually. However, it has been proven that early diagnosis and rational treatment of cancer can reduce incidence or mortality rates. The experience of Western Europe countries and the United States shows that the systematic work in early detection and screening allows reducing cancer incidence and mortality. In Ukraine, there are mandatory screening tests for breast, cervix, and prostate cancer but they have still related to non-systematic and, as a result, are ineffective.Мета: проаналізувати сучасні показники захворюваності та смертності від онкологічних захворювань, роль ранньої діагностики та скринінгу у зниженні показників високої смертності від раку та підходи до скринінгу онкопатологій у світі та Україні. Матеріали і методи. У дослідженні використовувались бібліосемантичний, структурно-логічний та порівняльний аналізи, а також аналітичний метод. Результати дослідження та обговорення. Захворюваність та смертність від онкологічних захворювань зростають дуже швидко в усьому світі. Причини високої захворюваності - складні, але відображають як старіння, так і приріст населення, а також зміни поширеності та розподілу основних факторів ризику онкологічних захворювань, деякі з яких пов'язані із соціально-економічним розвитком. Проблема високої смертності від онкологічних захворювань дуже гостра для всіх країн світу, включаючи економічно розвинені. Від 30% до 60% пацієнтів померли від раку через пізнє діагностування онкопатології. Аналіз показав, що стратегії боротьби з раком у Великобританії, Франції, Польщі та Сполучених Штатах Америки засновані на Резолюції Всесвітньої організації охорони здоров’я щодо профілактики та контролю онкологічних захворювань (2005) і включають профілактику, діагностику та скринінг. Завдяки впровадженню скринінгових програм в рутинну медичну практику країн ЄС та Споглучених Штатів, вдалося знизити рівень смертності від раку. В Україні є три обов’язкові скринінг-тести на рак молочної залози, шийки матки та передміхурової залози. Однак програми скринінгу на ці види раку наразі малоефективні. Насправді, рання діагностика раку все ще випливає з самообстеження та усвідомлення змін у власному здоров’ї потенційного пацієнта, що призводить до пізньої діагностики та важкого перебігу захворювання. Висновки. Згідно з дослідженнями, опублікованими ВООЗ, реєструються мільйони смертей від різних видів раку щорічно у всьому світі. Однак було доведено, що рання діагностика, скринінг та раціональне лікування раку можуть знизити рівні захворюваності та смертності. Досвід країн Західної Європи та США показує, що систематична робота з ранньої діагностики та скринінгу дозволяє зменшити захворюваність та смертність на рак. В Україні існують обов'язкові скринінгові тести на рак молочної залози, шийки матки та передміхурової залози, але вони все ще є несистематичними та, як наслідок, неефективними

Adoption of the Governmental Affordable Medicines Programme by Ukrainians.

Ensuring that the local population has access to medicines is one of the functions of a modern democratic state and an important element of social policy. The question of the affordability of medicines to the public is extremely important. This is also due to the fact that, unlike in European countries, Ukraine did not have a system of medicines reimbursement. To date, the reimbursement Affordable Medicines Programme has been in effect since April 2017 and is applicable to patients with cardiovascular disease, bronchial asthma, and type II diabetes. In total, 258 medicines are included in the Programme, 64 of which can be obtained free of charge and the others with a small extra payment. The respondents' perceptions of the Programme were conducted through a secondary analysis based on the third wave of the «Health Index. Ukraine» which was held in 2018 by the International Renaissance Foundation, the School of Public Health of the National University of Kyiv Mohyla Academy, and the Kyiv International Institute of Sociology. This study aims to present the results of the research of the attitude of Ukrainians to the government Affordable Medicines Programme and their perception of its implementation. The total number of respondents to this survey totaled more than 10,000 household rep­resentatives. The results of the research indicate a positive assessment of the respondents who participated in the survey «Health Index. Ukraine» (76% in 2018), which is confirmed by other research of the Kyiv International Institute of Sociology (63% in 2019) and by International experts. The results of the survey do not allow us to draw any official conclusions about the impact of the Programme on the health of Ukrainians, but during the interview 60.6% of the respondents said that the Programme «helped improve health»; in addition, positive changes in health were indicated by the most financially vulne­rable categories of the population. It is also noted that 80–82% of prescriptions were reimbursed to Programme participants

Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response

Human cytomegalovirus (HCMV) encodes several proteins that can modulate components of the cell cycle machinery. The UL123 gene product, IE1-72, binds the Rb-related, p107 protein and relieves its repression of E2F-responsive promoters; however, it is unable to induce quiescent cells to enter S phase in wild-type (p53(+/+)) cells. IE1-72 also induces p53 accumulation through an unknown mechanism. We present here evidence suggesting that IE1-72 may activate the p53 pathway by increasing the levels of p19(Arf) and by inducing the phosphorylation of p53 at Ser15. Phosphorylation of this residue by IE1-72 expression alone or HCMV infection is found to be dependent on the ataxia-telangiectasia mutated kinase. IE2-86 expression leads to p53 phosphorylation and may contribute to this phenotype in HCMV-infected cells. We also found that IE1-72 promotes p53 nuclear accumulation by abrogating p53 nuclear shuttling. These events result in the stimulation of p53 activity, leading to a p53- and p21-dependent inhibition of cell cycle progression from G(1) to S phase in cells transiently expressing IE1-72. Thus, like many of the small DNA tumor viruses, the first protein expressed upon HCMV infection activates a p53 response by the host cell