Abstract
Background
Right heart failure (RHF) represents the final step of distinct diseases, such as pulmonary arterial hypertension (PAH) and pulmonary hypertension (PH) due to heart failure with ...preserved ejection fraction (HFpEF). RHF may be defined by the inability of the heart to maintain a normal cardiac output (CO) or to do so at the expense of high right atrial pressure (RAP), at rest or during exercise.
However, exercise hemodynamic features suggestive of RHF, as well as their determinants, have still not been defined.
Aim
We sought to i. define the limits of normal of RAP increase during exercise; ii. describe the behavior of RAP during exercise in PAH and in PH-HFpEF, and its relation to right heart afterload and preload.
Methods
We retrospectively analyzed data from consecutive patients referred for suspicion of PH, who underwent both a resting and exercise right heart catheterization at two centers with identical methodology. We included patients with PH-HFpEF or PAH. Right heart adaptation to exercise was described either using absolute or CO-normalized RAP increase during exercise (RAP/CO slope), this latter representing the inverse of the Frank-Starling reserve. A control cohort of subjects with normal hemodynamics at rest and during exercise served to define abnormal increase in RAP, i.e. values of RAP and RAP/CO slope > mean ± 2 standard deviation of controls.
Estimated stressed blood volume (eSBV), as a measure of effective preload, was computed using a commercially-available software.
Results
80 patients were included in the analysis, of which 29 were PH-HFpEF, 30 PAH and 21 controls.
HFpEF patients were older than PAH patients and with a higher burden of cardiovascular comorbidities (p<0.05). Sex representation, BMI, and NTproBNP values were similar in the two groups.
Mean pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and total vascular resistance (TPR) were higher in PAH than in PH-HFpEF both at rest and during exercise (p<0.01), in spite of similar CO (Table 1). At rest, eSBV did not differ between HFpEF and PAH, but it was higher in HFpEF at peak exercise.
On average, PH-HFpEF had higher resting and peak RAP than PAH, as well as higher RAP/CO slope (Figure 1).
The upper limit of normal of exercise RAP and of RAP/CO slope, as determined in control subject, was 12 mmHg and 1.55 mmHg/L/min. A higher rate of HFpEF patients, compared with PAH, had a RAP/CO slope and a peak RAP above normal limits (78% and 91% of PH-HFpEF vs 47% and 44% of PAH, respectively, p<0.001).
RAP/CO slope in the whole cohort was associated with eSBV but not with right ventricular afterload measures (PAP, TPR, PVR).
Conclusions
PH-HFpEF display more frequently a steeper increase of RAP during exercise than PAH patients in spite of similar CO, suggesting a more exhausted Frank-Starling reserve. The steep RAP increase during exercise seems to reflect a dysfunctional preload rather than an afterload-mismatch.
Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship.
Agroecological services of cover crops depend mostly on their biomass accumulation, which in turn depends on growing season weather and on nitrogen (N) availability. We hypothesised that cover crop ...growth and weed control can be increased with an early sowing date and under high residual soil inorganic N left after the previous cash crop harvest. This hypothesis was tested in Northern Italy, with a two-year field experiment in two locations with five cover crops, comparing two cover crop sowing dates (beginning of September, SD1, and mid September, SD2), and evaluating the effects of pre-plant soil mineral N addition (N0 and N1). The cover crops, grown between two maize crops, were terminated in March. Weather conditions in both years were drier than normal, reducing on average cover crop growth. In November, cover crop aboveground biomass and N content ranged between 0.5 and 3.3 t DM ha−1 and between 18 and 70 kg N ha−1, respectively, with significantly lower values for SD2 compared to SD1 for most species. In most cases high pre-plant soil mineral N significantly increased cover crop biomass and N content, suggesting that cover crop growth was N-limited. Weed growth was higher in Egyptian clover and hairy vetch (0.7 t DM ha−1 on average) than in white mustard and black oat (0.2 t DM ha−1 on average), due to limited competitive ability of legumes. Cover crop biomass accumulation and weed control were enhanced by early sowing (in particular for legumes) and in conditions of high mineral N residue in the soil (in particular for non-legumes).
•Five cover crops in two years and two sites in Northern Italy were compared.•Cover crop biomass was significantly lower with late than with early sowing date.•Cover crop biomass was significantly higher in white mustard than in other species.•Pre-plant N increased cover crop biomass, suggesting cover crops were N-limited.•Weed growth was higher in legumes than in white mustard and black oat.
•Information on prevalence of dog erythrocyte antigens (DEAs) is important in selection of blood donors.•Corso dogs fulfil common requirements for blood donors: large size, good-tempered, easy to ...handle during blood collection.•There is a high prevalence of DEA 1 and DEA 7-negative dogs in the Corso breed.•The presence of suspected naturally occurring anti-DEA 7 antibodies may be implicated in delayed transfusion reactions.
We sought to determine the prevalence of dog erythrocyte antigen (DEA) 1, 4 and 7 and naturally occurring anti-DEA7 antibodies in Italian Corso dogs. In addition, we correlated DEAs with different epidemiologic variables, compared the prevalence of DEAs against other canine populations and assessed the risk of sensitisation and transfusion reactions (TRs) following unmatched transfusion. Blood samples from 100 Corso dogs were evaluated for DEA 1, 4, 7 and naturally occurring anti-DEA 7 antibodies.
Seventy-one percent of samples were DEA 1-negative, 100% tested DEA 4-positive, and 95% tested DEA 7-negative. Suspected anti-DEA7 antibodies were found in 32% dogs. The DEA 1 and 7-negative phenotypes were significantly more common than in most canine populations. When a previously tested Italian canine population was considered as blood donors for Corso dogs, the risk of DEA 1 sensitisation using DEA 1 untyped blood was 29%, and of acute haemolytic TRs after a second untyped DEA 1-incompatible transfusion was 8%. The potential for delayed TRs between DEA 7-negative Corso dogs with suspected naturally occurring anti-DEA 7 antibodies receiving untyped DEA 7-positive blood was 11%. Conversely, when Corso dogs were blood donors for the same population, the risk of DEA 1 sensitisation was 17% and the risk of an acute haemolytic TR after a second DEA 1-incompatible blood transfusion was 3%. Corso dogs can be suitable blood donors. Additional studies are needed to clarify whether the high prevalence of naturally occurring anti-DEA 7 antibodies in this breed could increase their risk of delayed TRs when they are blood recipients.
In adult rats, status epilepticus (SE) induces cytokine production by glia especially when seizures are associated with neuronal injury. This suggests that cytokines may play a role in ...seizure-induced neuronal damage. As SE-induced injury is age-specific, we used rats of different ages (with distinct susceptibilities to seizure-induced neuronal injury) to elucidate the role of cytokines in this process. Thus, we investigated the activation of microglia and astrocytes, induction of cytokines, and hippocampal neuronal injury 4 and 24 h following kainic acid-induced SE in postnatal day (PN) 9, 15, and 21 rats. At PN9, there was little activation of microglia and astrocytes at any time point studied. Interleukin-1β (IL), tumor necrosis factor-α (TNF), and IL-6 or the naturally occurring IL-1 receptor antagonist (Ra) mRNA expression did not increase. No evidence of cell injury has been detected. At PN15, immunostaining of microglia and astrocytes was enhanced, but only IL-1β mRNA expression was increased. These changes were observed 4 h after SE. Scattered injured neurons in CA3 and subiculum, but not in any other region, were present 24 h following SE. At PN21, immunostaining of microglia and astrocytes and the mRNA expression of all cytokines studied was significantly increased already 4 h after SE. At 24 h, many injured neurons were present in CA1 and CA3 regions and in 40% of rats in other forebrain areas. These data show that (i) the pattern of glia activation and cytokine gene transcription induced by SE is age-dependent and (ii) neuronal injury in the hippocampus occurs only when cytokines are induced and their synthesis precedes the appearance of neuronal damage. Thus, cytokine expression in immature brain is associated specifically with cell injury rather than with seizures
per se, suggesting that proinflammatory cytokines may contribute to the occurence of SE-induced hippocampal damage.
Integrins are associated with tumour cell survival and progression, and their expression has been shown to be increased in tumours. Thus, four novel conjugates of the tripeptide integrin ligand ...Arg-Gly-Asp (RGD) and the cytotoxic agent paclitaxel (cRGD-PTX) were prepared to investigate the potential of the multivalent presentation of the RGD moiety in improving the antitumor efficacy of PTX by tumour targeting. PTX was conjugated to two or four integrin recognizing ligands. The influence of multivalent presentation on in vitro αvβ3-receptor affinity was confirmed. For all the conjugates compared to the previously synthesized monovalent counterparts, an enhancement of the binding strength was observed; this behaviour was more pronounced when considering the tetravalent presented RGD-conjugate. Cell growth inhibition assays on a panel of human tumour cell lines showed remarkable cytotoxic activity for all conjugates with IC50 values in a nanomolar range. Among the four conjugates, the bivalent derivative 3b was selected for in vivo studies in an ovarian carcinoma cell model xenografted in immunodeficient mice. A marked antitumor activity was observed, similar to that of PTX, but with a much more favourable toxicity profile. Overall, the novel cRGD-PTX conjugates disclosed here represent promising candidates for further advancement in the domain of targeted anti-tumour therapy.
A successful realisation of sub-20 nm features on silicon (Si) is becoming the focus of many technological studies, strongly influencing the future performance of modern integrated circuits. Although ...reactive ion etching (RIE), at both micrometric and nanometric scale has already been the target of many studies, a better understanding of the different mechanisms involved at sub-20 nm size etching is still required. In this work, we investigated the influence of the feature size on the etch rate of Si, performed by a cryogenic RIE process through cylinder-forming polystyrene-block-polymethylmethacrylate (PS-b-PMMA) diblock copolymer (DBC) masks with diameter ranging between 19-13 nm. A sensible decrease of the etch depth and etch rate was observed in the mask with the smallest feature size. For all the DBCs under investigation, we determined the process window useful for the correct transfer of the nanometric cylindrical pattern into a Si substrate. A structural and physicochemical investigation of the resulting nanostructured Si is reported in order to delineate the influence of various RIE pattern effects. Feature-size-dependent etch, or RIE-lag, is proved to significantly affect the obtained results.
The Balzi Rossi archaeological complex (comprised of caves, rock shelters, and open-air sites) is a globally significant site for Palaeolithic culture and understanding the transition from ...Neanderthal to Anatomically Modern Human populations in Europe. It also retains some of the earliest evidence of human interactions with their coastal environment. Balzi Rossi has been subject to excavation for over 150 years – traditionally as individual site locations – with most deposits removed when the discipline of archaeology was nascent, and the science not yet developed. The consequence was the unfortunate loss of materials and critically important stratigraphic context. However, valuable information regarding the Palaeolithic population, their coastal environment, and earlier sea-level change, remains in the literature and in museum repositories. In this work we have compiled and reviewed the extensive resources, available largely in French and Italian, to provide a summary and catalogue for each individual site. These ‘Site Summaries’ are available as appendices to this review, which provides a comprehensive synopsis of the history of excavations conducted at Balzi Rossi, a reconstruction of stratigraphy where possible, the evidence of Palaeolithic occupations, the evidence of Pleistocene sea-level fluctuations, and an assessment of the chronological constraint available for both the Palaeolithic populations and sea level. Finally, this synopsis identifies gaps in knowledge and provides comments on pathways for future research, suggesting a consilient approach that can be applied in other archaeological contexts.
•Provides a comprehensive geoarchaeological review of over 150 years of excavations;•Provides the most complete synthesis of human cultural and environmental change yet published;•Confirms evidence of at least three Pleistocene sea-level highstands;•Highlights understanding human-environment interaction requires complete biome approach
Abstract
We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO ...and Advanced Virgo (2019 November 1 15:00 UTC–2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate.
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