Синдром такоцубо после протезирования митрального клапана (клинический случай)

The article describes the case of Takotsubo syndrome, which arose in a 71-year-old female patient after a mitral heart valve replacement , performed due to its severe (3rd degree) insufficiency of non-rheumatic genesis. This pathology is quite rare. Questions of its etiology and pathogenesis remain controversial. A special feature of this case is the development of reversible left ventricular dysfunction in the early postoperative period after mitral valve replacement. The reduction of the left ventricular ejection fraction to 25% with hyperkinesia of its basal parts with subsequent recovery of the ejection fraction to 56% 3 weeks after the onset of the disease was observed. There were also electrocardiographic changes simulating acute circular myocardial infarction with the absence of hemodynamically significant lesions of the coronary arteries. The patient had risk factors for this syndrome (age, female gender, stress situation, surgical intervention, administration of dobutamine and fluoroquinolones). For the reasons given above, the presence of Takotsubo syndrome was suspected. This case demonstrates the possibility of developing takotsubo syndrome after cardiosurgical interventions and defibrillation.В статье представлен случай синдрома такоцубо, резвившегося у 71-летней пациентки после протезирования митрального клапана сердца, выполненного в связи с его выраженной (3-я степень) недостаточностью неревматического генеза. Данная нозология является редко встречающейся. В литературе имеются единичные разрозненные сообщения о синдроме такоцубо после кардиохирургических вмешательств и электроимпульсной терапии. Вопросы этиологии и патогенеза остаются дискутабельными. Особенностью данного случая является развитие обратимой дисфункции левого желудочка в раннем послеоперационном периоде после протезирования митрального клапана – снижение фракции выброса левого желудочка до 25% с гиперкинезией его базальных отделов с ее последующим восстановлением до 56% через 3 нед после дебюта заболевания. Также имели место электрокардиографические изменения, имитирующие острый циркулярный инфаркт миокарда, при отсутствии гемодинамически значимых поражений коронарных артерий. У пациентки были выявлены факторы риска развития данного синдрома (возраст, женский пол, стрессовая ситуация, хирургическое вмешательство, дефибрилляция, применение добутамина и фторхинолонов). На основании перечисленного было заподозрено наличие синдрома такоцубо. Данный случай демонстрирует возможность развития синдрома такоцубо после кардиохирургических вмешательств и дефибрилляции

Inorganic Polyphosphate Modulates TRPM8 Channels

Polyphosphate (polyP) is an inorganic polymer built of tens to hundreds of phosphates, linked by high-energy phosphoanhydride bonds. PolyP forms complexes and modulates activities of many proteins including ion channels. Here we investigated the role of polyP in the function of the transient receptor potential melastatin 8 (TRPM8) channel. Using whole-cell patch-clamp and fluorescent calcium measurements we demonstrate that enzymatic breakdown of polyP by exopolyphosphatase (scPPX1) inhibits channel activity in human embryonic kidney and F-11 neuronal cells expressing TRPM8. We demonstrate that the TRPM8 channel protein is associated with polyP. Furthermore, addition of scPPX1 altered the voltage-dependence and blocked the activity of the purified TRPM8 channels reconstituted into planar lipid bilayers, where the activity of the channel was initiated by cold and menthol in the presence of phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2). The biochemical analysis of the TRPM8 protein also uncovered the presence of poly-(R)-3-hydroxybutyrate (PHB), which is frequently associated with polyP. We conclude that the TRPM8 protein forms a stable complex with polyP and its presence is essential for normal channel activity

Inorganic polyphosphate as an energy source in tumorigenesis

Indexación ScopusCancer cells have high demands for energy to maintain their exceedingly proliferative growth. However, the mechanism of energy expenditure in cancer is not well understood. We hypothesize that cancer cells might utilize energy-rich inorganic polyphosphate (polyP), as energetic reserve. PolyP is comprised of orthophosphates linked by phosphoanhydride bonds, as in ATP. Here, we show that polyP is highly abundant in several types of cancer cells, including brain tumor-initiating cells (BTICs), i.e., stem-like cells derived from a mouse brain tumor model that we have previously described. The polymer is avidly consumed during starvation of the BTICs. Depletion of ATP by inhibiting glycolysis and mitochondrial ATP-synthase (OXPHOS) further decreases the levels of polyP and alters morphology of the cells. Moreover, enzymatic hydrolysis of the polymer impairs the viability of cancer cells and significantly deprives ATP stores. These results suggest that polyP might be utilized as a source of phosphate energy in cancer. While the role of polyP as an energy source is established for bacteria, this finding is the first demonstration that polyP may play a similar role in the metabolism of cancer cells. Copyright: © 2020 Boyineni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.https://www.oncotarget.com/article/27838/text

Multidimensional Conservation Laws: Overview, Problems, and Perspective

Some of recent important developments are overviewed, several longstanding open problems are discussed, and a perspective is presented for the mathematical theory of multidimensional conservation laws. Some basic features and phenomena of multidimensional hyperbolic conservation laws are revealed, and some samples of multidimensional systems/models and related important problems are presented and analyzed with emphasis on the prototypes that have been solved or may be expected to be solved rigorously at least for some cases. In particular, multidimensional steady supersonic problems and transonic problems, shock reflection-diffraction problems, and related effective nonlinear approaches are analyzed. A theory of divergence-measure vector fields and related analytical frameworks for the analysis of entropy solutions are discussed.Comment: 43 pages, 3 figure

Water-Soluble Fullerene (C60) Derivatives as Nonviral Gene-Delivery Vectors

A new class of water-soluble C60 transfecting agents has been prepared using Hirsch-Bingel chemistry and assessed for their ability to act as gene-delivery vectors in vitro. In an effort to elucidate the relationship between the hydrophobicity of the fullerene core, the hydrophilicity of the water-solubilizing groups, and the overall charge state of the C60 vectors in gene delivery and expression, several different C60 derivatives were synthesized to yield either positively charged, negatively charged, or neutral chemical functionalities under physiological conditions. These fullerene derivatives were then tested for their ability to transfect cells grown in culture with DNA carrying the green fluorescent protein (GFP) reporter gene. Statistically significant expression of GFP was observed for all forms of the C60 derivatives when used as DNA vectors and compared to the ability of naked DNA alone to transfect cells. However, efficient in vitro transfection was only achieved with the two positively charged C60 derivatives, namely, an octa-amino derivatized C60 and a dodeca-amino derivatized C60 vector. All C60 vectors showed an increase in toxicity in a dose-dependent manner. Increased levels of cellular toxicity were observed for positively charged C60 vectors relative to the negatively charged and neutral vectors. Structural analyses using dynamic light scattering and optical microscopy offered further insights into possible correlations between the various derivatized C60 compounds, the C60 vector/DNA complexes, their physical attributes (aggregation, charge) and their transfection efficiencies. Recently, similar Gd@C60-based compounds have demonstrated potential as advanced contrast agents for magnetic resonance imaging (MRI). Thus, the successful demonstration of intracellular DNA uptake, intracellular transport, and gene expression from DNA using C60 vectors suggests the possibility of developing analogous Gd@C60-based vectors to serve simultaneously as both therapeutic and diagnostic agents

How β-Lactam Antibiotics Enter Bacteria: A Dialogue with the Porins

BACKGROUND:Multi-drug resistant (MDR) infections have become a major concern in hospitals worldwide. This study investigates membrane translocation, which is the first step required for drug action on internal bacterial targets. beta-lactams, a major antibiotic class, use porins to pass through the outer membrane barrier of Gram-negative bacteria. Clinical reports have linked the MDR phenotype to altered membrane permeability including porin modification and efflux pump expression. METHODOLOGY/PRINCIPAL FINDINGS: Here influx of beta-lactams through the major Enterobacter aerogenes porin Omp36 is characterized. Conductance measurements through a single Omp36 trimer reconstituted into a planar lipid bilayer allowed us to count the passage of single beta-lactam molecules. Statistical analysis of each transport event yielded the kinetic parameters of antibiotic travel through Omp36 and distinguishable translocation properties of beta-lactams were quantified for ertapenem and cefepime. Expression of Omp36 in an otherwise porin-null bacterial strain is shown to confer increases in the killing rate of these antibiotics and in the corresponding bacterial susceptibility. CONCLUSIONS/SIGNIFICANCE: We propose the idea of a molecular "passport" that allows rapid transport of substrates through porins. Deciphering antibiotic translocation provides new insights for the design of novel drugs that may be highly effective at passing through the porin constriction zone. Such data may hold the key for the next generation of antibiotics capable of rapid intracellular accumulation to circumvent the further development MDR infections

Transcriptional Portrait of Actinobacillus pleuropneumoniae during Acute Disease - Potential Strategies for Survival and Persistence in the Host

BACKGROUND: Gene expression profiles of bacteria in their natural hosts can provide novel insight into the host-pathogen interactions and molecular determinants of bacterial infections. In the present study, the transcriptional profile of the porcine lung pathogen Actinobacillus pleuropneumoniae was monitored during the acute phase of infection in its natural host. METHODOLOGY/PRINCIPAL FINDINGS: Bacterial expression profiles of A. pleuropneumoniae isolated from lung lesions of 25 infected pigs were compared in samples taken 6, 12, 24 and 48 hours post experimental challenge. Within 6 hours, focal, fibrino hemorrhagic lesions could be observed in the pig lungs, indicating that A. pleuropneumoniae had managed to establish itself successfully in the host. We identified 237 differentially regulated genes likely to encode functions required by the bacteria for colonization and survival in the host. This group was dominated by genes involved in various aspects of energy metabolism, especially anaerobic respiration and carbohydrate metabolism. Remodeling of the bacterial envelope and modifications of posttranslational processing of proteins also appeared to be of importance during early infection. The results suggested that A. pleuropneumoniae is using various strategies to increase its fitness, such as applying Na+ pumps as an alternative way of gaining energy. Furthermore, the transcriptional data provided potential clues as to how A. pleuropneumoniae is able to circumvent host immune factors and survive within the hostile environment of host macrophages. This persistence within macrophages may be related to urease activity, mobilization of various stress responses and active evasion of the host defenses by cell surface sialylation. CONCLUSIONS/SIGNIFICANCE: The data presented here highlight the importance of metabolic adjustments to host conditions as virulence factors of infecting microorganisms and help to provide insight into the mechanisms behind the efficient colonization and persistence of A. pleuropneumoniae during acute disease

Takotsubo syndrome after mitral valve replacement and defibrillation

The article describes the case of Takotsubo syndrome, which arose in a 71-year-old female patient after a mitral heart valve replacement , performed due to its severe (3rd degree) insufficiency of non-rheumatic genesis. This pathology is quite rare. Questions of its etiology and pathogenesis remain controversial. A special feature of this case is the development of reversible left ventricular dysfunction in the early postoperative period after mitral valve replacement. The reduction of the left ventricular ejection fraction to 25% with hyperkinesia of its basal parts with subsequent recovery of the ejection fraction to 56% 3 weeks after the onset of the disease was observed. There were also electrocardiographic changes simulating acute circular myocardial infarction with the absence of hemodynamically significant lesions of the coronary arteries. The patient had risk factors for this syndrome (age, female gender, stress situation, surgical intervention, administration of dobutamine and fluoroquinolones). For the reasons given above, the presence of Takotsubo syndrome was suspected. This case demonstrates the possibility of developing takotsubo syndrome after cardiosurgical interventions and defibrillation

Pore Characteristics of Nontypeable Haemophilus influenzae Outer Membrane Protein P5 in Planar Lipid Bilayers

The structure of outer membrane protein P5 of NTHi, a homolog of Escherichia coli OmpA, was investigated by observing its pore characteristics in planar lipid bilayers. Recombinant NTHi P5 was overexpressed in E. coli and purified using ionic detergent, LDS-P5, or nonionic detergent, OG-P5. LDS-P5 and OG-P5 could not be distinguished by their migration on SDS-PAGE gels; however, when incorporated into planar bilayers of DPhPC between symmetric aqueous solutions of 1 M KCl at 22°C, LDS-P5 formed narrow pores (58 ± 6 pS) with low open probability, whereas OG-P5 formed large pores (1.1 ± 0.1 nS) with high open probability (0.99). LDS-P5 narrow pores were gradually and irreversibly transformed into large pores, indistinguishable from those formed by OG-P5, at temperatures ≥40°C; the process took 4–6 h at 40°C or 35–45 min at 42°C. Large pores were stable to changes in temperatures; however, large pores were rapidly converted to narrow pores when exposed to LDS at room temperatures, indicating acute sensitivity of this conformer to ionic detergent. These studies suggest that narrow pores are partially denatured forms and support the premise that the native conformation of NTHi P5 is that of a large monomeric pore

Haemophilus influenzae Outer Membrane Protein P5 Is Associated with Inorganic Polyphosphate and Polyhydroxybutyrate

Outer membrane protein P5 of nontypeable (acapsulate) Haemophilus influenzae (NTHi P5) forms large pores in planar lipid bilayers between symmetric solutions that unpredictably display a nonzero reversal potential. Moreover, NTHi P5 has a high theoretical isoelectric point, calculated as 9.58, which is not in agreement with the experimental isoelectric point, determined as 6.3–6.8, or with its preference for cations, disproportionately strong at one side. These anomalous results intimate that NTHi P5 is associated with a polyanion. Chemical and immunological analyses revealed the presence of inorganic polyphosphate (polyP), and the amphiphilic, solvating polyester, poly-(R)-3-hydroxybutyrate, frequently associated with polyP. A sharp reduction in cation selectivity was observed after addition of Saccharomyces cerevisiae exopolyphosphatase X to the bilayer, providing functional evidence for the involvement of polyP in selectivity. The results suggest that NTHi P5 associates with polyP and poly-(R)-3-hydroxybutyrate to create large, cation-selective pores in the outer membrane of H. influenzae