Electrophysiological properties of the propafenone-analogue GE 68 (1-[3-(phenylethyl)-2-benzofuryl]-2-(propylamino)-ethanol) in isolated preparations and ventricular myocytes of guinea-pig hearts

GE 68 ((Rac.)-1-[3-(Phenylethyl)-2-benzofuryl]-2-(propylamino)-ethanol hydrochloride) is structurally related to propafenone, and exerts negative inotropic and negative chronotropic effects similar to the parent drug, but lacks any β-adrenoceptor blocking activity contrary to propafenone. Thus, the electrophysiological effects of GE 68 were studied in papillary muscles, left atria, Purkinje fibres, sinoatrial nodes and ventricular myocytes of the guinea-pig heart with the intracellular microelectrode technique and the patch-clamp technique in the cell-attached mode. The decrease of the maximum upstroke velocity (V˙_max) by GE 68 (1 to 10 μM) was use- and frequency-dependent. V˙_max recovered from the use-dependent block with a time constant of 4.1 ± 0.6 s. In papillary muscles and Purkinje fibres action potential duration was shortened, while it was prolonged in left atria and sinoatrial nodes. Half-maximal steady-state inactivation of the sodium channels was shifted to more negative membrane potentials (control: –91.5 ± 0.8 mV, 10 μM GE 68: –97.9 ± 2.5 mV). The peak of the current-voltage relationship and the reversal potential were not changed by GE 68. The amplitude of the unitary current remained unaltered, while open state probability was decreased. The most striking effect of GE 68 was an increase of the number of sweeps without single channel openings (1 μM: 2 fold, 10 μM: 6 fold). GE 68 also caused a decrease of the mean open times, and an increase of the mean closed times in unmodified and pronase-modified sodium channels. Besides the lack of β-adrenoceptor blocking activity, data present a faster recovery from the use-dependent block by GE 68 and a lower affinity to inactivated sodium channels compared to the reference drug propafenone, as well as differences in the effect on single channel kinetics. Received: 25 July 1996 / Accepted: 14 October 1996     

Characteristics of human neural stem cells In Vitro and after transplantation into rat brain

We studied the effect of culturing conditions on the fate of human neural stem cells after transplantation into rat brain. Human neural stem cells cultured in the presence of mitogens without LIF migrated along the ependyma and cerebral vessels of recipients, but to a great extent degenerated by the 20th day after transplantation. Neural stem cells cultured with LIF migrated, apart from the above mentioned pathways, in the cortex and hippocampus, well survived; proliferating cells were retained 30 days after transplantation.__________This revised version was published online in July 2005 with the addition of the issue title and article categoryTranslated from Kletochnye Tekhnologii v Biologii i Meditsine, Vol. 1, No. 1, pp. 13–19, January, 2005     

Placental protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm pre-eclampsia and HELLP syndrome

Placental protein 13 (PP13) is a galectin expressed by the syncytiotrophoblast. Women who subsequently develop preterm pre-eclampsia have low first trimester maternal serum PP13 concentrations. This study revealed that third trimester maternal serum PP13 concentration increased with gestational age in normal pregnancies (p < 0.0001), and it was significantly higher in women presenting with preterm pre-eclampsia (p = 0.02) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (p = 0.01) than in preterm controls. Conversely, placental PP13 mRNA (p = 0.03) and protein, as well as cytoplasmic PP13 staining of the syncytiotrophoblast (p < 0.05) was decreased in these pathological pregnancies compared to controls. No differences in placental expression and serum concentrations of PP13 were found at term between patients with pre-eclampsia and control women. In contrast, the immunoreactivity of the syncytiotrophoblast microvillous membrane was stronger in both term and preterm pre-eclampsia and HELLP syndrome than in controls. Moreover, large syncytial cytoplasm protrusions, membrane blebs and shed microparticles strongly stained for PP13 in pre-eclampsia and HELLP syndrome. In conclusion, parallel to its decreased placental expression, an augmented membrane shedding of PP13 contributes to the increased third trimester maternal serum PP13 concentrations in women with preterm pre-eclampsia and HELLP syndrome.     

Characteristics of Suture Materials Used in Oral Surgery: Systematic Review

BackgroundThe aim of this review was to evaluate the most used suture materials with regards to their inflammatory response, their bacterial adhesion, and their physical properties when used to close oral wounds.MethodsFour databases (PubMed, Scopus, Dentistry & Oral Sciences, and OVID) were searched to retrieve relevant studies from January 1, 2000, to January 31, 2020.ResultsOut of the 269 articles, only 13 studies were selected as they were relevant and met the systematic review's protocol. These studies showed that almost all suture materials studies (catgut, polyglycolic acid [PGA] sutures, nylon, expanded polytetrafluoroethylene, and silk sutures) caused bacterial adherence and tissue reaction. In nylon and chromic catgut, the number of bacteria accumulated was lowest. Silk and nylon were found to be more impacted than catgut and PGA in terms of physical characteristics such as tensile strength. PGA, on the other hand, was said to be the most susceptible to knot unwinding.ConclusionsFollowing an oral surgical operation, all sutures revealed varied degrees of irritation and microbial accumulation. Nonresorbable monofilament synthetic sutures, however, exhibited less tissue response and less microbial accumulation.     

Transplantation of Cultured Human Neural Progenitor Cells into Rat Brain: Migration and Differentiation

We studied the fate in vitro cultured human stem/progenitor cells after transplantation into rat brain. The cells from human fetuses at 8-12 weeks' gestation were cultured in vitro for 14 days and transplanted into the brain of 10-day-old and adult rats. Microscopic examination showed that human stem/progenitor cells migrated into various regions of rat brain. Immunohistochemical assay demonstrated that some cells differentiated into astrocytes and neurons, while others retained the embryonic phenotype.     

Nilotinib alone or in combination with selumetinib is a drug candidate for neurofibromatosis type 2

Loss of the tumor suppressor merlin is a cause of frequent tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas, which occur spontaneously or as part of neurofibromatosis type 2 (NF2). Because there is medical need for drug therapies for these tumors, our aim is to find therapeutic targets. We have studied the pathobiology of schwannomas, because they are the most common merlin-deficient tumors and are a model for all merlin-deficient tumors. With use of a human schwannoma in vitro model, we previously described strong overexpression/activation of platelet-derived growth factor receptor-β (PDGFR-β) leading to strong, long-lasting activation of extracellular-signal-regulated kinase (ERK1/2) and AKT and increased schwannoma growth, which we successfully inhibited using the PDGFR/Raf inhibitor sorafenib. However, the benign character of schwannomas may require long-term treatment; thus, drug tolerability is an issue. With the use of Western blotting, proliferation assays, viability assays, and a primary human schwannoma cell in vitro model, we tested the PDGFR/c-KIT inhibitors imatinib (Glivec(;) Novartis) and nilotinib (Tasigna(;) Novartis). Imatinib and nilotinib inhibited PDGF-DD-mediated ERK1/2 activation, basal and PDGF-DD-mediated activation of PDGFR-β and AKT, and schwannoma proliferation. Nilotinib is more potent than imatinib, exerting its maximal inhibitory effect at concentrations lower than steady-state trough plasma levels. In addition, nilotinib combined with the MEK1/2 inhibitor selumetinib (AZD6244) at low concentrations displayed stronger efficiency toward tumor growth inhibition, compared with nilotinib alone. We suggest that therapy with nilotinib or combinational therapy that simultaneously inhibits PDGFR and the downstream Raf/MEK1/2/ERK1/2 pathway could represent an effective treatment for schwannomas and other merlin-deficient tumors.     

Increased vulnerability to ischemia/reperfusion-induced ventricular tachyarrhythmias by pre-ischemic inhibition of nitric oxide synthase in isolated rat hearts.

INTRODUCTION: The relationship between vulnerability to reperfusion-induced ventricular tachyarrhythmias, such as ventricular tachycardia (VT) and fibrillation (VF), and the endogenous activity of nitric oxide synthase (NOS) has not been well documented. The objective of the present study was to clarify whether the vulnerability to reperfusion-induced VT/VF changes with preishemic, sustained inhibition of NOS. METHODS: The experiments were performed using Langendorff-perfused isolated rat hearts, in which left ventricular pressure (LVP) and left ventricular cardiomyograms (LVCMGs) were measured. RESULTS: A pre-ischemic, sustained inhibition of NOS resulted in an increased vulnerability to reperfusion-induced VT/VF, and the increase was markedly attenuated by co-treatment with L-arginine or by post-ischemic treatment with 2,4-diamino-6-hydroxypyrimidine (DAHP), an inhibitor of tetrahydrobiopterin (BH(4)) synthesis. We then tried to elucidate whether nitric oxide (NO) and superoxide were produced during reperfusion, and ATP-sensitive potassium channels (K(ATP)), especially mitochondrial ATP-sensitive potassium channels (mitoK(ATP)), are involved in the increased vulnerability. Post-ischemic inhibition of NOS and treatment with a NO scavenger attenuated the increased vulnerability to reperfusion-induced VT/VF, but post-ischemic treatment with a superoxide scavenger did not. In addition, post-ischemic treatment with S-nitroso-N-acetyl-DL-penicillamine (SNAP), a NO donor, or with diazoxide, a selective opener of mitoK(ATP), increased the VT/VF duration during reperfusion. The increased vulnerability to VT/VF was attenuated by the treatment with a selective mitoK(ATP) blocker. CONCLUSION: The results suggest that a pre-ischemic, sustained inhibition of NOS increases the vulnerability to reperfusion-induced VT/VF, and the NO-mitoK(ATP) pathway is one of the possible factors contributing to the increased vulnerability to VT/VF.     

Characterization of a series of monoclonal antibodies against human T cells

A set of 6 monoclonal antibodies is characterized reacting only with human T-cells but not with B lymphocytes. The antibody BL-T1 binds to the E receptor, being there on all mature T cells and on the majority of thymocytes. All respectively the majority of peripheral T cells but only subpopulations of thymocytes are recognized by the monoclonals BL-T2, BL-T3, BL-T4 and BL-T5. For identification and quantification of mature human T cells especially the antibody BL-T2 is suitable. The antigen recognized by BL-E1 is missing on peripheral B lymphocytes but expressed not only on T cells but also on erythrocytes, monocytes and a fraction of granulocytes. The monoclonals discussed are compared with the monoclonals for identification of leucocyte differentiation antigens (cluster of differentiation) characterized on the 1st Int. Workshop on Human Leucocyte Differentiation Antigens (Paris, 1982).