Novel Polypyridyl Ruthenium(II) Complexes Containing Oxalamidines as Ligands.

The complexes [Ru(bpy)2(H2TPOA)](PF6)2 ⋅ 4H2O, (1); [Ru(Me-bpy)2(H2TPOA)](PF6)2 ⋅ 2H2O, (2); [Ru(bpy)2(H2TTOA)](PF6)2 ⋅ 2H2O, (3); [Ru(Me-bpy)2(H2TTOA)](PF6)2 ⋅ 2H2O, (4) and {[Ru(bpy)2]2(TPOA)}(PF6)2 ⋅ 2H2O, (5) (where bpy is 2,2´bipyridine; Me-bpy is 4,4´- dimethyl-2,2´-bipyridine; H2TPOA is N, N´, N´´, N´´´- tetraphenyloxalamidine; H2TTOA is N, N´, N´´, N´´´- tetratolyloxalamidine) have been synthesized and characterized by 1H-NMR, FAB-MS, infrared spectroscopy and elemental analysis. The X-ray investigation shows the coordination of the still protonated oxalamidine moiety via the 1,2−diimine unit. The dimeric compound (5) could be separated in its diastereoisomers (5´) and (5´´) by repeated recrystallisation. The diastereomeric forms exhibit different 1H-NMR spectra and slightly shifted electronic spectra. Compared with the model compound [Ru(bpy)3]2+, the absorption maxima of (1)–(5) are shifted to lower energies. The mononuclear complexes show Ru(III/II)- couples at about 0.9 V vs SCE, while for the dinuclear complex two well defined metal based redox couples are observed at 0.45 and 0.65 V indicating substantial interaction between the two metal centres

The Anticancer Peptide TAT-RasGAP317-326 Exerts Broad Antimicrobial Activity.

Antibiotic resistance has become a major health issue. Nosocomial infections and the prevalence of resistant pathogenic bacterial strains are rising steadily. Therefore, there is an urgent need to develop new classes of antibiotics effective on multi-resistant nosocomial pathogenic bacteria. We have previously shown that a cell-permeable peptide derived from the p120 Ras GTPase-activating protein (RasGAP), called TAT-RasGAP317-326, induces cancer cell death, inhibits metastatic progression, and sensitizes tumor cells to various anti-cancer treatments in vitro and in vivo. We here report that TAT-RasGAP317-326 also possesses antimicrobial activity. In vitro, TAT-RasGAP317-326, but not mutated or truncated forms of the peptide, efficiently killed a series of bacteria including Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa. In vivo experiments revealed that TAT-RasGAP317-326 protects mice from lethal E. coli-induced peritonitis if administrated locally at the onset of infection. However, the protective effect was lost when treatment was delayed, likely due to rapid clearance and inadequate biodistribution of the peptide. Peptide modifications might overcome these shortcomings to increase the in vivo efficacy of the compound in the context of the currently limited antimicrobial options

Formation of extracellular traps by circulating neutrophils and monocytes in rheumatoid arthritis patients: a study of new citrullinated autoantigen

Detection of subcellular structures containing typical citrullinated rheumatoid autoantigens in a single compartment presents a special interest, due to importance of anticitrulline autoantibodies for the autoimmune response in RA. Neutrophil and monocyte extracellular traps (NETs and ETs, respectively) may be considered such candidate structures. Our objective was to assess ability of blood neutrophils and monocytes from RA patients to generate NETs and ETs spontaneously and after in vitro induction.32 patients with verified RA and 30 healthy volunteers as controls were included into the study. Circulating neutrophils and monocytes were isolated with one-step density gradient centrifugation using three layers of ficoll-amidotrizoate gradient. Composition of isolated cellular fractions, their viability, and non-specific activation were evaluated microscopically using Trypan Blue exclusion test, as well as Nitro-Blue Tetrazolium test. The NETs were induced by phorbol-12-myristate-13-acetate, and ETs by bacterial LPS. Spontaneous and induced formation of extracellular traps was assessed using fluorescence microscopy. Neutrophil and monocyte fractions contained minute percentages of impurities and low extents of activated and dead cells. Spontaneous NET and ET formation in RA patients was significantly increased comparing to healthy controls. Neutrophils from ACPA-positive RA patients were found to have higher frequency of NET formation, compared to ACPA-negative RA patients. The monocytes did not demonstrate such differences between these subgroups. There were no substantial morphological differences in NETs and ETs patterns between the individuals from both groups. Induced extracellular trap production in RA was significantly higher compared to healthy controls. The level of myeloperoxidase-specific fluorescence in ETs was considerably lower than in NETs. NETs could probably be considered as a source of citrulline autoantigen participating in autoantibody production and stimulation of inflammatory autoimmune responses in RA, whereas ETs may play less important role in this process

Effect of reactive inflammation in osteoarthritis on extracellular traps formation by circulating neutrophils

The results of recent studies demonstrating the presence of pro-inflammatory mediators in osteoarthritis (OA), as well as known similarity of histological signs of inflammation in rheumatoid arthritis (RA) and OA, suggest an important role of NETosis in immune inflammation in OA patients. Our objective was to assess ability of blood neutrophils from ОA patients to generate NETosis spontaneously and after in vitro induction, and impact of reactive synovitis on the dynamics of NETosis indexes. Thirty-one patients with verified OA and 30 healthy volunteers were included into the study. Circulating neutrophils were isolated with one-step density gradient centrifugation using double layers of Iohexol gradient. Subpopulational profile of isolated neutrophil fractions, their viability, and nonspecific activation were evaluated microscopically using Trypan Blue exclusion test, as well as nitro-blue tetrazolium test. NETs were induced by phorbol-12-myristate13-acetate (PMA). Spontaneous and induced formation of NETs was assessed using fluorescence microscopy. The ОA patients were in clinical remission at the time of inclusion in the study. In 23 OA patients, an exacerbation was diagnosed during the study. The neutrophil fractions showed high purity and a high content of viable nonactivated cells. These parameters were comparable in the study groups. Mean percentage of spontaneous NETs in OA patients in remission was significantly increased comparing to healthy controls. Usage of PMA, as inducing agent was accompanied by a significant increase in ability of neutrophils to form NETs. Transition of OA to exacerbation was characterized by further significant increase in spontaneous and PMA-induced NETs. Spontaneous and induced NETs in OA patients at acute stage of the disease are significantly higher than in OA patients in remission state. The growth rate of spontaneous NET formation is 3.74 times higher than the induced NET formation in OA patients upon exacerbation. Statistically significant increase in the ability of peripheral neutrophils to spontaneous and induced formation of extracellular traps was found, depending on the stage of osteoarthritis. The data obtained suggest an opportunity for participation of circulating neutrophils via NETosis in pathogenesis of immune inflammation in OA

Интерстициальное поражение легких при системной склеродермии (обзор литературы и собственное клиническое наблюдение)

Interstitial lesion is one of the most common lung pathologies in patients with systemic scleroderma (SS) In most cases, interstitial lung disease (ILD) is formed during the detailed clinical picture of SS, but it can manifest from interstitial lung disease, which significantly complicates early nosological diagnosis. Patterns of non-specific and common interstitial pneumonia are most often found among the variants of interstitial lung lesion at SS Clinical manifestations of ILD-SS are non-specific and vary significantly between patients from asymptomatic to rapidly progressing respiratory failure. Early diagnosis of subclinical interstitial pulmonary lesion at SS is carried out using high-resolution computed tomography. Active immunosuppressive therapy is required for timely diagnosis of progressive forms of ILD-SS The presented clinical study demonstrates a case of late diagnosis of ILD-SSИнтерстициальное поражение является одним из самых частых вариантов патологии легких у больных системной склеродермией (ССД). В большинстве случаев интерстициальное заболевание легких (ИЗЛ) формируется в период развернутой клинической картины ССД, однако оно может манифестировать с интерстициального поражения легких, что существенно затрудняет раннюю нозологическую диагностику. Среди вариантов интерстициального поражения легких при ССД чаще всего встречаются паттерны неспецифической и обычной интерстициальной пневмонии. Клинические проявления ИЗЛ при ССД неспецифичны и существенно различаются между пациентами от бессимптомных до быстропрогрессирующей дыхательной недостаточности. Ранняя диагностика субклинического интерстициального поражения легких при ССД осуществляется при проведении компьютерной томографии легких высокого разрешения. При своевременной диагностике прогрессирующих форм ИЗЛ при ССД требуется активная иммуносупрессивная терапия. В представленном клиническом наблюдении продемонстрирован случай поздней диагностики ИЗЛ при ССД

Поражение легких при анкилозирующем спондилите

This is a review of published data on pulmonary manifestations of ankylosing spondylitis (AS) and a case report of 49-year old male suffering from AS with pulmonary involvement. Lung lesions are frequent extra-articular manifestations of AS. There are a variety of pulmonary manifestations in AS, including lesions of the lung parenchyma, the pleura, the airways and ventilation disorders due to sclerosis of the costovertebral joints and ankylosis of the thoracic spine. An incidence of the lung injury in AS patients has increased significantly after implementation of high-resolution computed tomography (CT). Pulmonary apical fibro-bullous changes were found in CT scans. These lesions are common targets for Aspergillus infection. In the present case, bilateral upper lobe cavitating pneumonia was diagnosed in the patient after exclusion of pulmonary tuberculosis. The patient repeatedly received prolonged antibiotic therapy. His condition deteriorated with development of chronic bilateral pulmonary cavitary aspergillosis. This clinical case demonstrates insufficient knowledge of physicians and radiologists on pulmonary involvement in AS. This leads to therapeutic mistakes and the late diagnosis of pulmonary disease.Поражение дыхательной системы является одним из самых частых внесуставных проявлений анкилозирующего спондилита (АС). Вовлечение респираторной системы при этом заболевании может сопровождаться поражением трахеобронхиального дерева, легочной паренхимы, плевры, а также вентиляционными расстройствами, обусловленными сращением реберно-позвоночных суставов и анкилозом грудного отдела позвоночника. Частота поражения легких при АС значительно возросла с внедрением в практику компьютерной томографии высокого разрешения (КТВР). Приводятся анализ данных литературных источников по проблеме поражения легких при АС и клиническое наблюдение пациента 49 лет, страдающего АС с легочными проявлениями заболевания. При проведении КТВР органов грудной клетки у пациента выявлены фиброзно-буллезные изменения, преимущественно верхних отделов. Апикальные фиброзно-буллезные изменения нередко становятся мишенью аспергиллезной инфекции. После исключения туберкулеза легких пациенту установлен диагноз двусторонней верхнедолевой деструктивной пневмонии, по поводу чего он неоднократно госпитализировался в терапевтическое отделение и получал антибактериальную терапию с нарастающей отрицательной динамикой и последующим развитием двустороннего хронического полостного аспергиллеза легких. В представленном клиническом случае продемонстрировано, что следствием недостаточной информированности врачей не только о возможных легочных проявлениях при системных заболеваниях соединительной ткани, в частности АС, но и об их потенциальных осложнениях являются неправильная интерпретация проявлений основного заболевания, ошибочная терапия и поздняя диагностика типичного для АС легочного поражения

Search for Primordial Black Holes with SGARFACE

The Short GAmma Ray Front Air Cherenkov Experiment (SGARFACE) uses the Whipple 10 m telescope to search for bursts of $\gamma$ rays. SGARFACE is sensitive to bursts with duration from a few ns to $\sim$20 $\mu$s and with $\gamma$-ray energy above 100 MeV. SGARFACE began operating in March 2003 and has collected 2.2 million events during an exposure time of 2267 hours. A search for bursts of $\gamma$ rays from explosions of primordial black holes (PBH) was carried out. A Hagedorn-type PBH explosion is predicted to be visible within 60 pc of Earth. Background events were caused by cosmic rays and by atmospheric phenomena and their rejection was accomplished to a large extent using the time-resolved images. No unambiguous detection of bursts of $\gamma$ rays could be made as the remaining background events mimic the expected shape and time development of bursts. Upper limits on the PBH explosion rate were derived from the SGARFACE data and are compared to previous and future experiments. We note that a future array of large wide-field air-Cherenkov telescopes equipped with a SGARFACE-like trigger would be able to operate background-free with a 20 to 30 times higher sensitivity for PBH explosions.Comment: 18 pages, 30 figures, accepted by Astroparticle Physics, corrected author list and Section 2.

Restricted dispersal in a sea of gene flow

Howfar domarine larvae disperse in the ocean? Decades of population genetic studies have revealed generally low levels of genetic structure at large spatial scales (hundreds of kilometres). Yet this result, typically based on discrete sampling designs, does not necessarily imply extensive dispersal. Here, we adopt a continuous sampling strategy along 950 km of coast in the northwestern Mediterranean Sea to address this question in four species. In line with expectations, we observe weak genetic structure at a large spatial scale. Nevertheless, our continuous sampling strategy uncovers a pattern of isolation by distance at small spatial scales (few tens of kilometres) in two species. Individual- based simulations indicate that this signal is an expected signature of restricted dispersal. At the other extreme of the connectivity spectrum, two pairs of individuals that are closely related genetically were found more than 290 km apart, indicating long-distance dispersal. Such a combination of restricted dispersal with rare long-distance dispersal events is supported by a high-resolution biophysical model of larval dispersal in the study area, and we posit that it may be common in marine species. Our results bridge population genetic studies with direct dispersal studies and have implications for the design of marine reserve networksVersión del edito