Validation of the time to attain maximal clot amplitude after reaching maximal clot formation velocity parameter as a measure of fibrinolysis using rotational thromboelastometry and its application in the assessment of fibrinolytic resistance in septic patients: a prospective observational study: communication from the ISTH SSC Subcommittee on Fibrinolysis.

BACKGROUND: In sepsis, fibrinolysis resistance correlates with worse outcomes. Practically, rotational thromboelastometry (ROTEM) is used to report residual clot amplitude relative to maximum amplitude at specified times after clot formation clot lysis indices (CLIs). However, healthy individuals can exhibit similar CLIs, thus making it challenging to solely diagnose the low fibrinolytic state. Furthermore, CLI does not include the kinetics of clot formation, which can affect overall fibrinolysis. Therefore, a more nuanced analysis, such as time to attain maximal clot amplitude after reaching maximal clot formation velocity (t-AUCi), is needed to better identify fibrinolysis resistance in sepsis. OBJECTIVES: To evaluate the correlation between the degree of fibrinolytic activation and t-AUCi in healthy or septic individuals. METHODS: Whole blood (n = 60) from septic or healthy donors was analyzed using tissue factor-activated (EXTEM) and nonactivated (NATEM) ROTEM assays. Lysis was initiated with tissue-type plasminogen activator, and CLI and t-AUCi were calculated. Standard coagulation tests and plasma fibrinolysis markers (D-dimer, plasmin-α2-antiplasmin complex, plasminogen activator inhibitor type 1, and plasminogen) were also measured. RESULTS: t-AUCi values decreased with increasing fibrinolytic activity and correlated positively with CLI for different degrees of clot lysis both in EXTEM and NATEM. t-AUCi cutoff value of 1962.0 seconds in EXTEM predicted low fibrinolytic activity with 81.8% sensitivity and 83.7% specificity. In addition, t-AUCi is not influenced by clot retraction. CONCLUSION: Whole-blood point-of-care ROTEM analyses with t-AUCi offers a more rapid and parametric evaluation of fibrinolytic potential compared with CLI, which can be used for a more rapid and accurate diagnosis of fibrinolysis resistance in sepsis.

Effects of drought stress memory on the accumulation of stress-protective compounds in naturally grown pine and spruce.

Forest trees are subjected to multiple stressors during their long lifetime and therefore require effective and finely regulated stress-protective systems. Stressors can induce protective systems either directly or with the involvement of stress memory mechanisms. Stress memory has only begun to be uncovered in model plants and is unexplored in coniferous species. Therefore, we studied the possible role of stress memory in the regulation of the accumulation of stress-protective compounds (heat shock proteins, dehydrins, proline) in the needles of naturally grown Scots pine and Norway spruce trees subjected to the subsequent action of long-term (multiyear) and short-term (seasonal) water shortages. Although the water deficit was relatively mild, it significantly influenced the pattern of expression of stress memory-related heat shock factor (HSF) and SWI/SNF genes, indicating the formation of stress memory in both species. In spruce, dehydrin accumulation was increased by water shortage in a manner compatible with Type II stress memory. The accumulation of HSP40 in spruce needles was positively influenced by long-term water shortage, but this increase was unlikely to be of biological importance due to the concomitant decrease in HSP70, HSP90 and HSP101 accumulation. Finally, proline accumulation was negatively influenced by short-term water deficit in spruce. In pine, no one protective compound accumulated in response to water stress. Taken together, the results indicate that the accumulation of stress-protective compounds was generally independent of stress memory effects both in pine and in spruce.

Mineral Nutrition of Naturally Growing Scots Pine and Norway Spruce under Limited Water Supply.

The deterioration of plant mineral nutrition during drought is a significant factor in the negative influence of drought on plant performance. We aimed to study the effects of seasonal and multiyear water shortages on nutrient supply and demand in Scots pine and Norway spruce. We studied pine and spruce trees naturally grown in the Bryansk region (Russia). The dynamics of several nutrients (K, Ca, Mg, P, Fe, Mn, Zn, and Ca) in wood, needles, and bark of current-year twigs and the dynamics of the available pools of these elements at different soil depths were analysed. To assess the physiological consequences of changes in element concentrations, lipid peroxidation products and photosynthetic pigments were measured in the needles. Water shortage increased the wood concentrations of all elements except for Mn. In pine, this increase was mainly due to seasonal water deficit, whereas in spruce, multiyear differences in water supply were more important. This increased availability of nutrients was not observed in soil-based analyses. In needles, quite similar patterns of changes were found between species, with Mg increasing almost twofold and Fe and Mn decreasing under water shortage, whereas the remainder of the elements did not change much under differing water supplies. Neither the concentrations of photosynthetic pigments nor the contents of lipid peroxidation products correlated with element dynamics in needles. In summary, water shortage increased the availability of all elements except Mn for the plant; however, needle element contents were regulated independently of element availability for plants.

Cirrhotic Cardiomyopathy-A Veiled Threat.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction in patients with liver cirrhosis without preexisting cardiac disease. According to the definition established by the World Congress of Gasteroenterology in 2005, the diagnosis of CCM includes criteria reflecting systolic dysfunction, impaired diastolic relaxation, and electrophysiological disturbances. Because of minimal or even absent clinical symptoms and echocardiographic signs at rest according to the 2005 criteria, CCM diagnosis is often missed or delayed in most clinically stable cirrhotic patients. However, cardiac dysfunction progresses in time and contributes to the pathogenesis of hepatorenal syndrome and increased morbidity and mortality after liver transplantation, surgery, or other invasive procedures in cirrhotic patients. Therefore, a comprehensive cardiovascular assessment using newer techniques for echocardiographic evaluation of systolic and diastolic function, allowing the diagnosis of CCM in the early stage of subclinical cardiovascular dysfunction, should be included in the screening process of liver transplant candidates and patients with cirrhosis in general. The present review aims to summarize the most important pathophysiological aspects of CCM, the usefulness of contemporary cardiovascular imaging techniques and parameters in the diagnosis of CCM, the current therapeutic options, and the importance of early diagnosis of cardiovascular impairment in cirrhotic patients.

Intermittent High-Frequency Percussive Ventilation Therapy in 3 Patients with Severe COVID-19 Pneumonia.

BACKGROUND High-frequency percussive ventilation (HFPV) is a method that combines mechanical ventilation with high-frequency oscillatory ventilation. This report describes 3 cases of patients with severe COVID-19 pneumonia who received intermittent adjunctive treatment with HFPV at a single center without requiring admission to the Intensive Care Unit (ICU). CASE REPORT Case 1 was a 60-year-old woman admitted to the hospital 14 days after the onset of SARS-CoV-2 infection symptoms, and cases 2 and 3 were men aged 65 and 72 years who were admitted to the hospital 10 days after the onset of SARS-CoV-2 infection symptoms. All 3 patients presented with clinical deterioration accompanied by worsening lung lesions on computed tomography (CT) scans after 21 days from the onset of symptoms. SARS-CoV-2 infection was confirmed in all patients by real-time reverse transcription-polymerase chain reaction (RT-PCR) assay from nasal swabs. All 3 patients had impending respiratory failure when non-invasive intermittent HFPV therapy was initiated. After therapy, the patients had significant clinical improvement and visibly decreased lung lesions on followup CT scans performed 4-6 days later. CONCLUSIONS The 3 cases described in this report showed that the use of intermittent adjunctive treatment with HFPV in patients with severe pneumonia due to infection with SARS-CoV-2 improved lung function and may have prevented clinical deterioration. However, recommendations on the use of intermittent HFPV as an adjunctive treatment in COVID-19 pneumonia requires large-scale controlled clinical studies. In the pandemic context, with a shortage of ICU beds, avoiding ICU admission by using adjunctive therapies on the ward is a useful option.

Lidocaine effects on coagulation assessed by whole blood rotational thromboelastometry.

Lidocaine may be beneficial when added in solutions for the preservation of vascular grafts or solid organs as it has anti-inflammatory, endothelial protective, and antithrombotic effects. However, the mechanisms of lidocaine-induced changes in hemostasis were not elucidated until now. The aim of the study was to examine the effect of increasing concentrations of lidocaine on coagulation parameters and blood-clotting kinetics using velocity curves of clot formation assessed by rotational thromboelastometry. Ex-vivo blood coagulation using whole blood from healthy volunteers was studied with rotational thromboelastometry. For each volunteer, four assays were performed: saline control and samples with lidocaine end blood concentrations of 0.3, 0.6, and 0.9%. In this in-vitro study, whole blood from 15 healthy volunteers was used. Lidocaine concentration of 0.3% prolonged the initiation phase of clotting without significant differences in the propagation phase or clot stability and inhibited clot lysis compared with the control group. Higher lidocaine concentrations (0.6 and 0.9%) resulted in prolongation of both initiation and propagation phases and decreased clot firmness compared with the control group. Lysis was significantly increased only in the 0.6% lidocaine group compared with control. Although lidocaine concentration of 0.3% only delays coagulation initiation, the 0.6% concentration inhibits all phases of hemostasis and increases clot lysis compared with control. Higher lidocaine concentration results in very weak clot formation with very low lysis visible on thromboelastometry. More research is needed to explain the effects of lidocaine on clotting kinetics.

Long-term impact of cement plant emissions on the elemental composition of both soils and pine stands and on the formation of Scots pine seeds.

We investigated the long-term impact of the largest Russian cement plant on mesopodzol sandy soils and Scots pine stands. We determined the distributions of the total and available pools of Ca, Mg, K, Na, Mn, Fe, Zn, Ni, Cu, Pb and Cd in the soil profile to a depth of 60 cm (illuvial horizon) as well as the accumulation patterns of these elements in the vegetative and generative organs of Scots pine trees. High Ca accumulation in the impact zone soils was a result of CaO emissions by a cement plant. Also, CaO became the main cause of soil profile alkalization due to neutralization of soil acids and formation of calcium hydroxide or carbonates. Alkalization immobilized substantial amounts of Fe, Mn, Zn and Ni in the soil, reducing their availability. The most prominent effect of long-term cement production was a prominent Mn deficiency in vegetative and generative Scots pine organs due to the exhaustion of the available Mn pool in the illuvial horizon. The miniaturization of cones, a decrease in seed yield and a reduction in seed germinability were observed in the emission impact zones. Pretreatment of Mn-deficient seeds with manganese eliminated Mn deficiency but did not increase seed germination.

Dependence of the evolution of carbon dynamics in the northern permafrost region on the trajectory of climate change.

We conducted a model-based assessment of changes in permafrost area and carbon storage for simulations driven by RCP4.5 and RCP8.5 projections between 2010 and 2299 for the northern permafrost region. All models simulating carbon represented soil with depth, a critical structural feature needed to represent the permafrost carbon-climate feedback, but that is not a universal feature of all climate models. Between 2010 and 2299, simulations indicated losses of permafrost between 3 and 5 million km2 for the RCP4.5 climate and between 6 and 16 million km2 for the RCP8.5 climate. For the RCP4.5 projection, cumulative change in soil carbon varied between 66-Pg C (1015-g carbon) loss to 70-Pg C gain. For the RCP8.5 projection, losses in soil carbon varied between 74 and 652 Pg C (mean loss, 341 Pg C). For the RCP4.5 projection, gains in vegetation carbon were largely responsible for the overall projected net gains in ecosystem carbon by 2299 (8- to 244-Pg C gains). In contrast, for the RCP8.5 projection, gains in vegetation carbon were not great enough to compensate for the losses of carbon projected by four of the five models; changes in ecosystem carbon ranged from a 641-Pg C loss to a 167-Pg C gain (mean, 208-Pg C loss). The models indicate that substantial net losses of ecosystem carbon would not occur until after 2100. This assessment suggests that effective mitigation efforts during the remainder of this century could attenuate the negative consequences of the permafrost carbon-climate feedback.

In-flight performance of the Ozone Monitoring Instrument.

The Dutch-Finnish Ozone Monitoring Instrument (OMI) is an imaging spectrograph flying on NASA's EOS Aura satellite since July 15, 2004. OMI is primarily used to map trace gas concentrations in the Earth's atmosphere, obtaining mid-resolution (0.4-0.6 nm) UV-VIS (264-504 nm) spectra at multiple (30-60) simultaneous fields of view. Assessed via various approaches that include monitoring of radiances from selected ocean, land, ice and cloud areas, as well as measurements of line profiles in the Solar spectra, the instrument shows low optical degradation and high wavelength stability over the mission lifetime. In the regions relatively free from the slowly unraveling 'row anomaly' the OMI irradiances have degraded by 3-8%, while radiances have changed by 1-2%. The long-term wavelength calibration of the instrument remains stable to 0.005-0.020 nm.

Climate change damages to Alaska public infrastructure and the economics of proactive adaptation.

Climate change in the circumpolar region is causing dramatic environmental change that is increasing the vulnerability of infrastructure. We quantified the economic impacts of climate change on Alaska public infrastructure under relatively high and low climate forcing scenarios [representative concentration pathway 8.5 (RCP8.5) and RCP4.5] using an infrastructure model modified to account for unique climate impacts at northern latitudes, including near-surface permafrost thaw. Additionally, we evaluated how proactive adaptation influenced economic impacts on select infrastructure types and developed first-order estimates of potential land losses associated with coastal erosion and lengthening of the coastal ice-free season for 12 communities. Cumulative estimated expenses from climate-related damage to infrastructure without adaptation measures (hereafter damages) from 2015 to 2099 totaled $5.5 billion (2015 dollars, 3% discount) for RCP8.5 and $4.2 billion for RCP4.5, suggesting that reducing greenhouse gas emissions could lessen damages by $1.3 billion this century. The distribution of damages varied across the state, with the largest damages projected for the interior and southcentral Alaska. The largest source of damages was road flooding caused by increased precipitation followed by damages to buildings associated with near-surface permafrost thaw. Smaller damages were observed for airports, railroads, and pipelines. Proactive adaptation reduced total projected cumulative expenditures to $2.9 billion for RCP8.5 and $2.3 billion for RCP4.5. For road flooding, adaptation provided an annual savings of 80-100% across four study eras. For nearly all infrastructure types and time periods evaluated, damages and adaptation costs were larger for RCP8.5 than RCP4.5. Estimated coastal erosion losses were also larger for RCP8.5.

Ion channels of the nuclear membrane of hippocampal neurons.

Rise in Ca(2+) concentration in the nucleus affects gene transcription and has been implicated in neuroprotection, transcription-dependent neuronal plasticity, and pain modulation, but the mechanism of regulation of nuclear Ca(2+) remains poorly understood. The nuclear envelope is a part of the endoplasmic reticulum and may be one of the sources of nuclear Ca(2+) . Here, we studied ion channels in the nuclear membrane of hippocampal neurons using the patch-clamp technique. We have found that the nuclear membrane of CA1 pyramidal and dentate gyrus granule (DG), but not CA3 pyramidal neurons, was enriched in functional inositol 1,4,5-trisphosphate receptors/Ca(2+) -release channels (IP3 Rs) localized mainly in the inner nuclear membrane. A single nuclear ryanodine receptor (RyR) has been detected only in DG granule neurons. Nuclei of the hippocampal neurons also expressed a variety of spontaneously active cation and anion channels specific for each type of neuron. In particular, large-conductance ion channels selective for monovalent cations (LCC) were coexpressed with IP3 Rs. These data suggest that: (1) the nuclear membranes of hippocampal neurons contain distinct sets of ion channels, which are specific for each type of neuron; (2) IP3 Rs, but not RyRs are targeted to the inner nuclear membrane of CA1 pyramidal and DG granule, but they were not found in the nuclear membranes of CA3 pyramidal neurons; (3) the nuclear envelope of these neurons is specialized to release Ca(2+) into the nucleoplasm which may amplify Ca(2+) signals entering the nucleus from the cytoplasm or generate Ca(2+) transients on its own; (4) LCC channels are an integral part the of Ca(2+) -releasing machinery providing a route for counterflow of К(+) and thereby facilitating Ca(2+) movement in and out of the Ca(2+) store.

The large-conductance ion channels in the nuclear envelope of central neurons.

Patch-clamp recording from the nuclear envelope of a variety of cells has revealed the presence of large-conductance ion channels. It has been argued that these channels are the channels of the nuclear pore complex for passive nucleo-cytoplasmic diffusion. Here we studied spontaneously active large-conductance ion channels in the nuclear envelope of cerebellar Purkinje neurons. These channels were selective for small monovalent cations and demonstrated clear voltage dependence. The channels recorded from the outer nuclear membrane were inhibited by positive potentials whereas the channels from the inner nuclear membrane were inhibited by negative potentials in the patch pipette. These data are compatible with the localization of the channels to the nuclear membrane. We conclude that these channels are not a part of the nuclear pore complex but provide a route for exchange of monovalent cations between the perinuclear space and the cytoplasm and the nucleoplasm.

Nuclear Ca2+ signalling in cerebellar Purkinje neurons.

An increase in nuclear Ca(2+) concentration may activate nuclear Ca(2+)-sensitive proteins and thereby regulate gene transcription. Ca(2+) can enter the nucleus from the cytoplasm either through nuclear pores or less certainly by release from the nuclear envelope. Recent studies indicate that the nuclear membrane of cerebellar Purkinje, but not granule neurons, contains multiple inositol 1,4,5-trisphosphate receptors (InsP(3)Rs) localized to the inner nuclear membrane. These data suggest that the nuclear envelope in some neurons is a Ca(2+) store specialized to release Ca(2+) directly into the nucleoplasm and thereby to amplify Ca(2+) signals entering the nucleus from the cytoplasm or to generate nuclear Ca(2+) transients on its own. Here we review current data on the mechanisms of regulation of Ca(2+) in the cell nucleus with particular emphasis on cerebellar Purkinje neurons.

Spontaneously active and InsP3-activated ion channels in cell nuclei from rat cerebellar Purkinje and granule neurones.

Increases in Ca(2+) concentration in the nucleus of neurones modulate gene transcription and may be involved in activity-dependent long-term plasticity, apoptosis, and neurotoxicity. Little is currently known about the regulation of Ca(2+) in the nuclei of neurones. Investigation of neuronal nuclei is hampered by the cellular heterogeneity of the brain where neurones comprise no more than 10% of the cells. The situation is further complicated by large differences in properties of different neurones. Here we report a method for isolating nuclei from identified central neurones. We employed this technique to study nuclei from rat cerebellar Purkinje and granule neurones. Patch-clamp recording from the nuclear membrane of Purkinje neurones revealed numerous large-conductance channels selective for monovalent cations. The nuclear membrane of Purkinje neurones also contained multiple InsP(3)- activated ion channels localized exclusively in the inner nuclear membrane with their receptor loci facing the nucleoplasm. In contrast, the nuclear membrane of granule neurones contained only a small number of mainly anion channels. Nuclear InsP(3) receptors (InsP(3)Rs) were activated by InsP(3) with EC(50) = 0.67 microm and a Hill coefficient of 2.5. Ca(2+) exhibited a biphasic effect on the receptors elevating its activity at low concentrations and inhibiting it at micromolar concentrations. InsP(3) in saturating concentrations did not prevent the inhibitory effect of Ca(2+), but strongly increased InsP(3)R activity at resting Ca(2+) concentrations. These data are the first evidence for the presence of intranuclear sources of Ca(2+) in neurones. Ca(2+) release from the nuclear envelope may amplify Ca(2+) transients penetrating the nucleus from the cytoplasm or generate Ca(2+) transients in the nucleus independently of the cytoplasm.