Use of Levosimendan as bridge therapy to surgical correction of post-infarction ventricular septal defect: a case report.

OBJECTIVE: Ventricular septal defect (VSD) is an uncommon but frequently fatal complication following acute myocardial infarction. In medically treated patients, mortality rates exceed 90%, while the surgical repair is associated with better outcomes, even though optimal surgical timing is still under debate. CASE REPORT: We present the case of a 78-years-old man with no previous remarkable cardiological history admitted to our Emergency Department with the diagnosis of anterior ST-elevation myocardial infarction and significant reduction of left ventricular ejection fraction. The emergency coronary angiography showed sub-occlusion of the left anterior descending coronary artery, treated with stent implantation. The post-procedural echocardiography unveiled the presence of an apical VSD with a large left-to-right shunt, significant right ventricular overload and dysfunction. An intra-aortic balloon pump (IABP) was positioned and, after Heart Team evaluation, a delayed surgical approach was planned. As a bridge to the intervention Levosimendan infusion was administered, on top of IABP support, and a significant improvement in bi-ventricular function and pressure profiles was obtained. Cardiac surgery was successfully performed 9 days after the admission without periprocedural complications. CONCLUSIONS: This unique case supports the use of Levosimendan as a valid pharmacological strategy for perioperative management of VSD.

Ticagrelor and preconditioning in patients with stable coronary artery disease (TAPER-S): a randomized pilot clinical trial.

BACKGROUND: Ticagrelor is a reversibly binding, direct-acting, oral, P2Y12 antagonist used for the prevention of atherothrombotic events in patients with coronary artery disease (CAD). Ticagrelor blocks adenosine reuptake through the inhibition of equilibrative nucleoside transporter 1 (ENT-1) on erythrocytes and platelets, thereby facilitating adenosine-induced physiological responses such as an increase in coronary blood flow velocity. Meanwhile, adenosine plays an important role in triggering ischemic preconditioning through the activation of the A1 receptor. Therefore, an increase in ticagrelor-enhanced adenosine bioavailability may confer beneficial effects through mechanisms related to preconditioning activation and improvement of coronary microvascular dysfunction. METHODS: To determine whether ticagrelor can trigger ischemic preconditioning and influence microvascular function, we designed this prospective, open-label, pilot study that enrolled patients with stable multivessel CAD requiring staged, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI). Participants will be randomized in 1:1 ratios either to ticagrelor (loading dose (LD) 180 mg, maintenance dose (MD) 90 mg bid) or to clopidogrel (LD 600 mg, MD 75 mg) from 3 to 1 days before the scheduled PCI. The PCI operators will be blinded to the randomization arm. The primary endpoint is the delta (difference) between ST segment elevations (in millimeters, mm) as assessed by intracoronary electrocardiogram (ECG) during the two-step sequential coronary balloon inflation in the culprit vessel. Secondary endpoints are 1) changes in coronary flow reserve (CFR), index of microvascular resistance (IMR), and FFR measured in the culprit vessel and reference vessel at the end of PCI, and 2) angina score during inflations. This study started in 2018 with the aim of enrolling 100 patients. Based on the rate of negative FFR up to 30% and a drop-out rate up to 10%, we expect to detect an absolute difference of 4 mm among the study arms in the mean change of ST elevation following repeated balloon inflations. All study procedures were reviewed and approved by the Ethical Committee of the Catholic University of Sacred Heart. DISCUSSION: Ticagrelor might improve ischemia tolerance and microvascular function compared to clopidogrel, and these effects might translate to better long-term clinical outcomes. TRIAL REGISTRATION: EudraCT No. 2016-004746-28. No. NCT02701140.  TRIAL STATUS: Information provided in this manuscript refers to the definitive version (n. 3.0) of the study protocol, dated 31 October 2017, and includes all protocol amendments. Recruitment started on 18 September 2018 and is currently ongoing. The enrollment is expected to be completed by the end of 2019. TRIAL SPONSOR: Fondazione Policlinico Universitario A. Gemelli - Roma, Polo di Scienze Cardiovascolari e Toraciche, Largo Agostino Gemelli 8, 00168 Rome, Italy.

Seabird colonies as relevant sources of pollutants in Antarctic ecosystems: Part 2 - Persistent Organic Pollutants.

Despite typically not being taken into account (usually in favour of the 'global distillation' process), the input of persistent organic pollutants (POPs) through biological activities can be indeed relevant at the local scale in terrestrial polar environments when seabird colonies are considered. Seabirds can bioaccumulate and biomagnify POPs, gather in large numbers and excrete on land during their reproductive season, thus making them locally as relevant secondary sources of POPs. The first part of this study indicated that these colonies act as so for several essential and non-essential trace elements, and this second part tests the same hypothesis concerning POPs using the very same samples. Lichens (n = 55), mosses (n = 58) and soil (n = 37) were collected from 13 locations in the South Shetlands Archipelago during the austral summers of 2013-14 and 2014-15. They were divided in colony (within the colony itself for soil and within and surrounding the colony for vegetation) and control (at least 150 m away from any colony interference) and analysed for POPs such as organochlorine pesticides, polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers and stable isotopes (C and N). Results showed that colonies act clearly as a secondary source for PCBs and likely for hexachlorobenzene. As in the first part, probable local sources other than the colonies themselves are hypothesised because of high concentrations found in control sites. Again, soil seemed the most adequate matrix for the intended purposes especially because of some particularities in the absorption of animal-derived organic matter by vegetation, pointed out by stable isotope analyses.

Seabird colonies as relevant sources of pollutants in Antarctic ecosystems: Part 1 - Trace elements.

Global distillation is classically pointed as the biggest responsible for contaminant inputs in Polar ecosystems. Mercury (Hg) and other trace elements (TEs) also present natural sources, whereas the biologically mediated input is typically ignored. However, bioaccumulation and biomagnification combined with the fact that seabirds gather in large numbers into large colonies and excrete on land might represent an important local TEs input. A previous work suggested these colonies as sources of not only nutrients, but also organic contaminants. To evaluate a similar hypothesis for TEs, samples of lichen (n = 55), mosses (n = 58) and soil (n = 37) were collected in 13 locations within the South Shetlands Archipelago during the austral summers of 2013-14 and 2014-15. They were divided in: "colony" (within the colony itself for soil and bordering it for vegetation) and "control" (at least 50 m away from colony interference), analysed for TEs (As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, Se, V, and Zn) and stable isotopes (C and N). In most cases, soil seems the best matrix to assess colonies as TEs sources, as it presented more differences between control/colony sites than vegetation. Colonies are clearly local sources of organic matter, Cd, Hg and likely of As, Se and Zn. Conversely, Co, Cr, Ni and Pb come presumably from other sources, natural or anthropogenic. In general, isotopes were more useful for interpreting vegetation data due to fractionation of absorbed animal-derived organic matter. Other local Hg sources could be inferred from high levels in control sites, location and wind patterns.

Mutant FGFR3 associated with SADDAN disease causes cytoskeleton disorganization through PLCγ1/Src-mediated paxillin hyperphosphorylation.

K650M/E substitutions in the Fibroblast growth factor receptor 3 (FGFR3) are associated with Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN) and Thanatophoric Dysplasia type II (TDII), respectively. Both SADDAN and TDII present with affected endochondral ossification marked by impaired chondrocyte functions and growth plate disorganization. In vitro, K650M/E substitutions confer FGFR3 constitutive kinase activity leading to impaired biosynthesis and accumulation of immature receptors in endoplasmic reticulum (ER)/Golgi. From those compartments, both SADDAN-FGFR3 and TDII-FGFR3 receptors engender uncontrolled signalling, activating PLCγ1, signal transducer and activator of transcription 1, 3 and 5 (STAT1/3/5) and ERK1/2 effectors. Here, we investigated the impact of SADDAN-FGFR3 and TDII-FGFR3 signalling on cytoskeletal organization. We report that SADDAN-FGFR3, but not TDII-FGFR3, affects F-actin organization by inducing tyrosine hyperphosphorylation of paxillin, a key regulator of focal adhesions and actin dynamics. Paxillin phosphorylation was upregulated at tyrosine 118, a functional target of Src and FAK kinases. By using Src-deficient cells and a Src kinase inhibitor, we established a role played by Src activation in paxillin hyperphosphorylation. Moreover, we found that SADDAN-FGFR3 induced FAK phosphorylation at tyrosines 576/577, suggesting its involvement as a Src co-activator in paxillin phosphorylation. Interestingly, paxillin hyperphosphorylation by SADDAN-FGFR3 caused paxillin mislocalization and partial co-localization with the mutant receptor. Finally, the SADDAN-FGFR3 double mutant unable to bind PLCγ1 failed to promote paxillin hyperphosphorylation, pointing to PLCγ1 as an early player in mediating paxillin alterations. Overall, our findings contribute to elucidate the molecular mechanism leading to cell dysfunctions caused by SADDAN-FGFR3 signalling.

Persistent organic pollutants in juvenile Magellanic Penguins (Spheniscus magellanicus) in South America.

Magellanic penguins, Spheniscus magellanicus, are the most abundant penguins living in temperate regions of South America and are good indicators of environmental pollution in the region. Persistent organic pollutants (POPs) were detected in the liver of Magellanic penguins found debilitated or dead on the beaches of Brazil (states of Rio de Janeiro, Sao Paulo, Santa Catarina and Rio Grande do Sul) between 2008 and 2012 as well as in Uruguay and Chile in 2011. Polychlorinated biphenyls (PCBs) were more prevalent than organochlorine pesticides (DDTs ∼ HCB ∼ Drins) and polybrominated diphenyl ethers (PBDEs). Among PCBs, penta-, hexa- and hepta-chlorinated congeners were predominant. Concentrations of POPs were similar between the Pacific and Atlantic penguin populations, except for PCBs, which were relatively higher in the Pacific population. During the study years (2008-2012), large variations were found in organochlorine pesticides and PCBs tended to decline. Overall, the southern portion of South America has low concentrations of POPs, with either a constant trend or evidence of decline.

PBDE levels in franciscana dolphin (Pontoporia blainvillei): temporal trend and geographical comparison.

Total PBDE concentrations determined in archived blubber samples from franciscana dolphins (Pontoporia blainvillei) unintentionally captured in the Brazilian coastal region off Rio Grande do Sul State (FMA III) between 1994 and 2004 (n = 73) ranged from 7.9 to 65 ng g(-1) lipid weight in mature males, with an increase over the ten-year period. Total PBDE concentrations in blubber samples collected from the FAM II (n = 41) between 2002 and 2005 were higher (67.8 to 763.7 ng g(-1)lw) than those from FMA III. This is possibly due to the proximity to important industrial development sites in the state of São Paulo. Despite the differences in total concentrations, PBDE profiles were comparable and the PBDE concentrations decreased in the following order BDE 47>BDE99>BDE 100 for both FMA and for males and females as well as adults, juveniles and pups.

Polybrominated diphenyl ethers (PBDES) and polychlorinated biphenyls (PCBS) in mussels and two fish species from the estuary of the Guanabara Bay, Southeastern Brazil.

The present investigation aimed to analyze PBDE and PCB contamination in mussels (Perna perna) and two commercially important fish species, croaker (Micropogonias furnieri) and mullet (Mugil liza), in the Guanabara Bay, the most important Brazilian estuary, by gas chromatography coupled to mass spectrometry, in order to further knowledge regarding these compounds in the southern hemisphere. This is also the first report of PBDE in this mussel species in the Guanabara Bay. Fish were captured in September (dry season, winter) and March (wet season, summer) 2007 and September 2008. Mussels were collected in August (dry season, winter) 2006, in February (wet season, summer) 2007, and in August 2007 (winter). The results show that all samples showed higher PCB contamination when compared to other ecosystems around the world. On the other hand, PBDEs presented lower concentrations in 41 % of the samples. Croakers presented the highest PCB and PBDE levels, with mullet showing intermediary values and mussels, the lowest.

Contaminant concentrations, biochemical and hematological biomarkers in blood of West Indian manatees Trichechus manatus from Brazil.

The West Indian manatee Trichechus manatus is threatened with extinction in Brazil, and this study focused on nondestructive blood samples analyzed for metals, polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), as well as biochemical and hematological biomarkers. Studied manatees were kept at Projeto Peixe-Boi headquarters in Pernambuco State, and at two natural areas in estuaries where they are released to the wild. Manatees kept at the natural estuary in Paraiba State have blood concentrations of Al, Pb, Cd, Sn that are 11, 7, 8 and 23 times greater, respectively, than the concentrations found in blood of animals from the same species in Florida, USA. An inhibition of butyrylcholinesterase in manatees kept at the two reintroduction sites in Alagoas and Paraiba States indicated possible exposure of the animals to cholinesterase inhibitor insecticides. PCBs and OCPs were not detected. Results from this study will help delineate conservation efforts in the region.

PCBs, PBDEs and organochlorine pesticides in crabs Hepatus pudibundus and Callinectes danae from Santos Bay, State of São Paulo, Brazil.

The occurrence of persistent organic pollutants (POPs) as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDE) in crabs Hepatus pudibundus and Callinectesdanae was assessed from two different places inside of the Santos Bay and Moela Island near one of the most economically important metropolitan areas in Southern Brazil. Among POPs analyzed, ∑PCBs (222-923 ng g(-1)lipid weight) and ∑DDTs (154-410 ng g(-1)lw) exhibited the highest concentrations in the crabs. ∑HCHs ranged from 10.3 to 30.9 ng g(-1)lw and were found in all individuals. Other OCPs found in lower concentration was Mirex (7.6-41.6 ng g(-1)lw) and HCB (5.83-16.9 ng g(-1)lw). ∑PBDEs (24.1 ng g(-1)lw) were only found in one male individual from the species C. danae collected near to the submarine sewage of Santos. Male crabs showed higher POP concentrations than female crabs for those two species.

PBDEs in the blubber of marine mammals from coastal areas of São Paulo, Brazil, southwestern Atlantic.

Limited information is available in the literature on the levels of brominated flame retardants in the southern hemisphere. This study presents concentrations of polybrominated diphenyl ethers (PBDEs) in the blubber of small cetaceans from the coast of São Paulo (Brazil), southwestern Atlantic. PBDE levels were highest in Stenella frontalis (770 ng g(-1) lipid) followed by Steno bredanensis (475 ng g(-1) lipid), Sotalia guianensis (65.6 ng g(-1) lipid), Tursiopstruncatus (64.2 ng g(-1) lipid) and Pontoporia blainvillei (60.3 ng g(-1) lipid). In general, continental shelf individuals exhibited higher contamination than inshore animals. This might be related to larger prey items consumed by continental shelf dolphins. The pattern of contamination indicates that Penta-BDE commercial mixtures are a major source of PBDEs to top predators in the southwestern Atlantic. Congeners found in Octa-BDE formulations were not detected in the investigated animals.

Levels of persistent organic pollutants and residual pattern of DDTs in small cetaceans from the coast of São Paulo, Brazil.

The State of São Paulo is the most developed area in Brazil and was impacted by persistent organic pollutants for several decades. This study investigated organochlorines in five species of small cetaceans (Pontoporia blainvillei, Stenella frontalis, Sotalia guianensis, Tursiops truncatus and Steno bredanensis) found dead along the coast of São Paulo between 1997 and 2003. DDTs (15.9 µg g(-1) lipid; mean for all pooled individuals) and PCBs (8.08 µg g(-1)) exhibited the highest concentrations in the animals, reflecting large amounts formerly used in Brazil. Lower levels of mirex (0.149 µg g(-1)), HCB (0.051 µg g(-1)), CHLs (0.008 µg g(-1)) and HCHs (0.007 µg g(-1)) were detected in all species. Residual pattern of DDTs in dolphins suggests that o,p'-DDT is more recalcitrant than p,p'-DDT in the body of the animals and/or the environment. In contrast to p,p'-DDT, residues of o,p'-DDT seem to be preferentially converted into o,p'-DDD rather than o,p'-DDE.

PCBs in the atmosphere of King George Island, Antarctica.

Polychlorinated biphenyls (PCBs) are ubiquitous anthropogenic compounds found even in the polar regions, mainly due to long-range atmospheric transport. In order to assess the occurrence of atmospheric PCBs in the vicinity of the Brazilian Antarctic Research Station (62 degrees 05'S, 58 degrees 23'W), a sampling survey was undertaken in the austral summer of 1995-1996. The concentrations of the PCB congeners in the air ranged from not detected to 33.2 pgm(-3). The lower chlorinated congeners (PCB-101 and below), which are more volatile and subject to long-range transport, predominated in the air samples and represented 66.7% of the total PCB concentrations. Atmospheric levels of PCBs were correlated with meteorological conditions and the highest levels were associated with the passage of the frontal systems coming from South America.

Determination of polychlorinated biphenyls in Antarctic macroalgae Desmarestia sp.

Selected polychlorinated biphenyl (PCB) congeners were measured in Desmarestia sp., an abundant algae in the Antarctica Peninsula and South Shetlands. Samples were collected from various points of Admiralty Bay, King George Island, Antarctic Peninsula, during the 1993-1994 austral summer. Total PCB concentrations ranged from 0.46 to 3.86 ng g(-1) (dry weight). Predominant PCB congeners were 52, 101, 110, 138 and 153. The low levels of PCBs found on all samples and the predominance of low molecular weight congeners indicate that there are no significant local PCBs sources in the area of study.