Searching for Preclinical Models of Acute Decompensated Heart Failure: a Concise Narrative Overview and a Novel Swine Model

Cardiovascular Drugs and Therapy - Available animal models of acute heart failure (AHF) and their limitations are discussed herein. A novel and preclinically relevant porcine model of decompensated...     

The impact of cytogenetic risk on the outcomes of allogeneic hematopoietic cell transplantation in patients with relapsed/refractory acute myeloid leukemia: On behalf of the acute leukemia working party (ALWP) of the European group for blood and marrow transplantation (EBMT)

Karyotypic analysis at time of diagnosis has an important value in determining initial response to treatment, remission duration and overall survival (OS) in acute myeloid leukemia (AML). Less is known about its value before allogeneic hematopoietic cell transplantation (allo‐HCT) in patients transplanted with active disease, either relapsed or primary refractory (Rel‐Ref) AML. We explored the impact of cytogenetic risk (stratification according to MRC‐UK) in 2089 patients with either Ref (n = 972) or Rel AML (n = 1117) transplanted during the period 2000‐2017. Overall, 154 patients had a favorable risk, 1283 had an intermediate risk and 652 had an adverse cytogenetic risk. Median follow‐up was 49 months. Compared to the favorable risk group, intermediate and adverse risk patients were associated with worse leukemia‐free survival and OS and also with a higher incidence of relapse. In a subgroup analysis of patients in the intermediate risk group harboring Fms‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD), this remained an important prognostic factor, being associated with worse outcomes. When analyzing patients according to the intensity of the conditioning regimen, no differences were observed for the main transplant outcomes. In conclusion, in patients diagnosed with AML and transplanted with active disease, karyotype remains an important prognostic factor, allowing splitting patients into different risk groups according to their cytogenetics. Similarly, FLT3‐ITD mutation also remains a negative prognostic factor in this population.     

beta-TCP and beta-TCMP osteoregenerators. New perspectives

The Authors present personal histological findings on a beta-tricalcium phosphate Mg substituted (beta-TCMP) prepared as sintered granules and unsintered powder. A mixture of these materials was used to fill bone cavities or defects in oral surgery. The beta-TCMP represents a biocompatible ceramic material able to accelerate and enhance bone repair of bone defects. It provides a completely biodegradable matrix for new bone growth as well as releasing mineral ions into the tissue during mineralization. Newly formed bone tissue is described in direct contact with residual beta-TCMP granules. No connective tissue layer is present between the new bone and the surface of the alloplastic material.     

Electron microscopic detection and activity of glucosyltransferase B, C, and D in the in situ formed pellicle

Objective

Glucosyltransferases (GTFs) represent a virulence factor of mutans streptococci. The aim of the present in situ study was to investigate the distribution of different GTF-isoforms in the pellicle.

Design

Bovine enamel slabs were fixed on buccal and palatal sites of individual splints worn by five subjects for 30 and 120 min to allow pellicle formation. Pellicle specimens were processed for transmission electron microscopy (TEM) and field emission in-lens scanning electron microscopy (FEI-SEM). Gold-immunolabelling was used for detection of GTF-isoforms B, C and D. Furthermore, glucosyltransferase activity of 3-, 30- and 120-min pellicles was tested via determination of fructose release.

Results

All isoforms of the enzyme were found to be randomly distributed within all layers of the pellicle. In cross-sections (TEM), GTF D was the most abundant isoform. More labelled molecules were detected on buccal sites compared with palatal surfaces, the number of molecules detected increased with time. The amount of GTF B, C and D found on the pellicle surface by FEI-SEM showed no correlation with pellicle formation time or localisation in the oral cavity. Overall, GTF D was detected more frequently on the surface than GTF B and C. All pellicles tested showed GTF-activity.

Conclusion

The study shows for the first time the presence of the GTF-isoforms B, C and D within all layers of the in situ formed pellicle. This emphasises the impact of streptococcal products on the composition of the pellicle and illustrates a mechanism used by bacteria to colonize dental surfaces.     

Defibrotide for Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease Prophylaxis in High-Risk Adult Patients: A Single-Center Experience Study

Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a serious complication after hematopoietic stem cell transplantation (HSCT). SOS/VOD usually occurs within 3 weeks of HSCT, but the 2016 European Society for Blood and Marrow Transplantation diagnosis criteria have been revised to include late forms. Prophylactic use of defibrotide is recommended in the pediatric setting, but its value remains uncertain in the adult population. We report here a single-center series of 63 adult patients considered at high risk for SOS/VOD who received defibrotide prophylaxis in combination with ursodeoxycholic acid between May 2012 and August 2016. The median duration of defibrotide therapy was 23 days. Bleeding occurred in 14 patients (21.5%). Defibrotide prophylaxis was discontinued in 7 patients (10.8%): 4 cases (6.3%) due to bleeding and 3 cases (4.6%) because of the need for antithrombotic therapy. Overall, SOS/VOD occurred in 4 cases (6.3%) within 21 days after HSCT (days 13 and 14) in 2 cases and late-onset SOS/VOD (days 57 and 58) in the other 2 cases. SOS/VOD was moderate in 1 case, very severe in 3 cases, with 2 deaths related to SOS/VOD. Cumulative incidence of grades II to IV acute graft-versus-host disease and transplant-associated thrombotic microangiopathy were 22.2% and 3.2%, respectively. With a median follow-up of 31 months (range, 10.7 to 60.3), the rates of 2-year overall survival, progression-free survival, incidence of relapse, and nonrelapse mortality were 56.5%, 49%, 28.7%, and 22.3%, respectively. In our experience defibrotide prophylaxis is associated with a low incidence of SOS/VOD after allogeneic HSCT in a high-risk adult population with an acceptable safety profile.     

Design,Preparation, and Characterization of Thermoresponsive Hybrid Nanogels Using a Novel Ulvan‐Acrylate Crosslinker as Potential Carriers for Protein Encapsulation

The aim of the present study is the design and development of thermoresponsive nanogels based on ulvan, a sulphated heteropolysaccharide of algal origins with unique biological and chemical properties. Hybrid nanogels are successfully synthesized by means of UV‐initiated radical copolymerization of N‐vinylcaprolactam with an ulvan derivate as a novel crosslinker. In nanogels, the ulvan‐grafted poly(N‐vinylcaprolactam) chains represent the thermoresponsive component. The most promising candidates, selected after a thorough physical–chemical characterization of nanogels in terms of size and responsivity to thermal variation at physiological conditions, are loaded with bovine serum albumin (BSA) as model bioactive compound. The developed nanogels display BAS loading efficiency values similar to those obtained by using synthetic crosslinkers, and thus indicating the suitability of the developed ulvan‐acrylate to act as novel macromolecular crosslinker for thermoresponsive nanogels preparation.     

Expression of the phenotypic abnormality of platelet-type von Willebrand disease in a recombinant glycoprotein Ib alpha fragment.

The platelet GP Ib-IX receptor supports platelet adhesion and activation by binding to vWf in the exposed subendothelial matrix. An abnormal GP Ib-IX complex exists in platelet-type or pseudo-von Willebrand disease and has a characteristic increased affinity for soluble vWf resulting in impaired hemostatic function due to the removal of larger vWf multimers from the circulation. Genetic studies within an afflicted family have demonstrated that the disease is linked to a Gly233-->Val amino acid substitution within the alpha-subunit of the oligomeric GP Ib-IX complex (Miller, J.L., D. Cunningham, V.A. Lyle, and C. L. Finch. 1991. Proc. Natl. Acad. Sci. USA. 88:4761-4765). To evaluate the functional consequences of this mutation, we constructed a recombinant analogue of the alpha-subunit of GP Ib containing Val233. Experiments comparing molecules with either Gly233 or Val233 revealed that the Val substitution generates a molecule with increased affinity for vWf. The recombinant fragment reproduces the functional abnormality of the GP Ib-IX complex in platelet-type von Willebrand disease, thus establishing the molecular basis of the bleeding disorder within this family. Moreover, it becomes apparent that structural elements responsible for the regulation of hemostasis through modulation of vWf affinity for platelets reside within the alpha-subunit of the GP Ib-IX complex.