Ethical considerations in the prehospital treatment of out-of-hospital cardiac arrest: A multi-centre, qualitative study.

Background: Prehospital emergency physicians have to navigate complex decision-making in out-of-hospital cardiac arrest (OHCA) treatment that includes ethical considerations. This study explores Danish prehospital physicians' experiences of ethical issues influencing their decision-making during OHCA.

Methods: We conducted a multisite ethnographic study.

Non-medical factors in prehospital resuscitation decision-making: a mixed-methods systematic review.

Aim: This systematic review explored how non-medical factors influence the prehospital resuscitation providers' decisions whether or not to resuscitate adult patients with cardiac arrest.

Methods: We conducted a mixed-methods systematic review with a narrative synthesis and searched for original quantitative, qualitative, and mixed-methods studies on non-medical factors influencing resuscitation of out-of-hospital cardiac arrest. Mixed-method reviews combine qualitative, quantitative, and mixed-method studies to answer complex multidisciplinary questions.

Documentation of ethically relevant information in out-of-hospital resuscitation is rare: a Danish nationwide observational study of 16,495 out-of-hospital cardiac arrests.

Background: Decision-making in out-of-hospital cardiac arrest should ideally include clinical and ethical factors. Little is known about the extent of ethical considerations and their influence on prehospital resuscitation. We aimed to determine the transparency in medical records regarding decision-making in prehospital resuscitation with a specific focus on ethically relevant information and consideration in resuscitation providers' documentation.

Does the "Morning Morality Effect" Apply to Prehospital Anaesthesiologists? An Investigation into Diurnal Changes in Ethical Behaviour.

The "morning morality effect"-the alleged phenomenon that people are more likely to act in unethical ways in the afternoon when they are tired and have less self-control than in the morning-may well be expected to influence prehospital anaesthesiologist manning mobile emergency care units (MECUs). The working conditions of these units routinely entail fatigue, hunger, sleep deprivation and other physical or emotional conditions that might make prehospital units predisposed to exhibit the "morning morality effect". We investigated whether this is in fact the case by looking at the distribution of patient transports to hospital with and without physician escort late at night at the end of the shift as a surrogate marker for changing thresholds in ethical behaviour.

Termination of prehospital resuscitative efforts: a study of documentation on ethical considerations at the scene.

Background: Discussions on ethical aspects of life-and-death decisions within the hospital are often made in plenary. The prehospital physician, however, may be faced with ethical dilemmas in life-and-death decisions when time-critical decisions to initiate or refrain from resuscitative efforts need to be taken without the possibility to discuss matters with colleagues. Little is known whether these considerations regarding ethical issues in crucial life-and-death decisions are documented prehospitally.

Termination of pre-hospital resuscitation by anaesthesiologists - causes and consequences. A retrospective study.

Aim: Differentiating between a newly deceased patient and the lifeless patient in whom immediate resuscitation is required may be facilitated by a pre-hospital anaesthesiologist. The purpose of our study was to investigate to what extent and why the pre-hospital anaesthesiologist pronounced life extinct in situations where an emergency medical technician (EMT) would have been required to resuscitate.

Methods: All lifeless patients seen pre-hospitally by the anaesthesiologist-manned Mobile Emergency Care Unit in Odense, Denmark, from 2010 to 2014 were retrospectively studied.

Protein expression of TNF-alpha in psoriatic skin is regulated at a posttranscriptional level by MAPK-activated protein kinase 2.

Alterations in specific signal transduction pathways may explain the increased expression of proinflammatory cytokines seen in inflammatory diseases such as psoriasis. We reveal increased TNF-alpha protein expression, but similar TNF-alpha mRNA levels, in lesional compared with nonlesional psoriatic skin, demonstrating for the first time that TNF-alpha expression in lesional psoriatic skin is regulated posttranscriptionally. Increased levels of activated MAPK-activated protein kinase 2 (MK2) together with increased MK2 kinase activity were found in lesional compared with nonlesional psoriatic skin.

25-Hydroxyvitamin D3 1alpha-hydroxylase expression in breast cancer and use of non-1alpha-hydroxylated vitamin D analogue.

Introduction: The cytochrome P450 mitochondrial enzyme 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase) of renal tubule cells hydroxylates the major circulating form of vitamin D (25(OH)D3) to the active systemic hormone 1,25(OH)2D3. Local production of 1,25(OH)2D3 appears to occur also at other sites where 1alpha-hydroxylase is expressed for autocrine/paracrine regulation. To reduce risks of hypercalcemia during treatment with vitamin D, we have previously suggested use of non-1alpha-hydroxylated vitamin D analogues to target tissues where 1alpha-hydroxylase is expressed, including the parathyroid glands in secondary hyperparathyroidism.

Non-anti-coagulant heparin inhibits metastasis but not primary tumor growth.

Experimental and clinical studies indicate that low molecular weight heparins (LMWH) may inhibit cancer and/or metastasis. The purpose of this study was to investigate whether it is possible to design non-anti-coagulant, anti-metastatic compounds based on heparin. The LMWH Tinzaparin and a series of non-anti-coagulant (NAC) heparin derivatives, varying in size from 2,500 to 10,000 Da, were tested for their anti-metastatic activity in an experimental B16F10 metastasis model.

CCAAT/enhancer-binding protein delta: a molecular target of 1,25-dihydroxyvitamin D3 in androgen-responsive prostate cancer LNCaP cells.

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D3, inhibits the proliferation of prostate cancer cells. However, the molecular mechanisms by which 1,25(OH)2D3 inhibits the proliferation of these cells remain to be fully elucidated. In this study, we used microarray technology to identify target genes of 1,25(OH)2D3 in androgen-responsive prostate cancer LNCaP cells.

EB1627: a soluble prodrug of the potent anticancer cyanoguanidine CHS828.

To overcome pharmacokinetic and solubility problems observed in early clinical trials with the potent anticancer compound CHS828, we synthesised a series of prodrugs with improved properties. The best compound obtained was EB1627, with a tetraethyleneglycol moiety attached to the parent drug via a carbonate linkage. This compound was found soluble enough to be given i.

Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines.

Although both the antiapoptotic function of survivin and vitamin D3 (VD3)-mediated cell growth inhibition and apoptosis have been extensively studied, it is not known whether survivin plays a role in VD3 compound-mediated cell growth inhibition and apoptosis induction. Using an isogenic model of MCF-7 breast adenocarcinoma cells (MCF-7E and MCF-7L sublines that are sensitive and resistant to VD3 compounds), we found that VD3 compounds effectively downregulated survivin in VD3-sensitive MCF-7E cells, which was associated with VD3-induced apoptosis. In contrast, VD3 compounds failed to downregulate survivin in VD3-resistant MCF-7L cells, which showed resistant to VD3-induced apoptosis.

The tissue-specific distribution of 3H-seocalcitol (EB 1089) and 3H-calcitriol in rats.

Seocalcitol (EB 1089) is under development for the treatment of hepato-cellular carcinoma (HCC). The tissue distribution of 3H-seocalcitol was investigated in comparison to 3H-calcitriol in rats. Quantitative whole-body autoradiography was used to quantify the tissue distribution.

Anticancer agent CHS 828 suppresses nuclear factor-kappa B activity in cancer cells through downregulation of IKK activity.

CHS 828, a pyridyl cyanoguanidine, has been shown to exert a significant antitumor effect in preclinical tests in vitro and in vivo, and CHS 828 is in phase I/II clinical trials. We have investigated the effect of CHS 828 on the nuclear factor-kappa B (NF-kappa B) because of its well-known role in the control of cell division and apoptosis. CHS 828 is able to inhibit the lipopolysaccharide (LPS)-induced nuclear localization as well as the transcriptional activity of NF-kappa B in human THP-1 leukemia cells.

Vitamin D3 polyunsaturated side-chain analogues (EB1089, GS1590) and the 20-epi-vitamin D3 analogue CB1393 suppress parathyroid hormone secretion and mRNA level in bovine parathyroid cells.

Several vitamin D analogues, with reduced hypercalcemic and hyperphosphatemic toxicity at therapeutic dosages, are in clinical use for prevention and treatment of secondary hyperparathyroidism (HPT) in chronic renal failure. We have performed a first in vitro evaluation of five vitamin D analogues displaying less calcemic activity in normal rats, considerably more antiproliferative ability and higher transcription activation potential than 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), with the future prospects in mind to identify even more effective and less calcemic vitamin D analogues for treatment of HPT. The vitamin D analogues EB1089 and GS1590 have polyunsaturated side-chains, whereas HEP187, MC1598 and CB1393 display altered stereochemistry at carbon 20.

Cytotoxic effect in vivo and in vitro of CHS 828 on human myeloma cell lines.

CHS 828 is a pyridyl cyanoguanidine with promising antitumor activity both in vitro and in vivo, and has previously been found especially active against tumor cells obtained from patients with B cell chronic lymphocytic leukemia. In the present study the cytotoxic effect in vitro of CHS 828 was investigated on a panel of 10 human myeloma cell lines using the fluorometric microculture cytotoxicity assay. CHS 828 induced a concentration-dependent, but variable decrease in tumor cell survival in the cell line panel with inhibitory concentrations 50% (IC50) in the range 0.

Development and characterization of two human tumor sublines expressing high-grade resistance to the cyanoguanidine CHS 828.

The cyanoguanidine CHS 828 has shown promising antitumor properties and is currently in early clinical trials, although the mechanism of action still is largely unknown. In this study, resistant sublines of the histiocytic lymphoma cell line U-937 GTB and the myeloma line RPMI 8226 were developed by culturing under gradually increasing concentrations of CHS 828 until reaching 25 times the parental line EC50s. The new phenotypes demonstrate more than 400-fold resistance to CHS 828 and cross-resistance to six cyanoguanidine analogs, but no resistance to nine standard drugs of different mechanistic classes or to the cytotoxic guanidines m-iodobenzylguanidine and methylglyoxal-bis(guanylhydrazone).

A versatile in vivo chamber angiogenesis assay for measuring anti-angiogenic activity in mice.

We recently described an in vivo angiogenesis assay for rats--an optimized Matrigel plug assay based on subcutaneously implanted chambers with fixed volume and shape. Here we examine the possibility of switching the host animal from rat to mouse, thereby reducing the requirement for test compound an order of magnitude. The chambers consist of a plexiglas ring with a 0.

Synthesis and structure-activity relationship of aminobenzophenones. A novel class of p38 MAP kinase inhibitors with high antiinflammatory activity.

We wish to report the synthesis and structure-activity relationship (SAR) of a series of 4-aminobenzophenones, as a novel compound class with high antiinflammatory activity. Our initial lead, (4-[(2-aminophenyl)amino]phenyl)(phenyl)methanone (3), was systematically optimized and resulted in compounds that potently inhibited the release of the proinflammatory cytokines IL-1beta and TNF-alpha in human peripheral blood mononuclear cells stimulated by LPS. One of the most potent compounds, among others, was (4-[(2-aminophenyl)amino]-2-chlorophenyl)(2-methylphenyl)methanone (45) with IC(50) values of 14 and 6 nM for the inhibition of IL-1beta and TNF-alpha, respectively.

Effects of Seocalcitol (EB1089) on nitrosomethyl urea-induced rat mammary tumors.

Although 1,25-dihydroxyvitamin D3 is a potent cell-differentiating agent, its use in cancer prevention or therapy is precluded because it induces hypercalcemia. Synthetic analogs have been developed which inhibit tumor progression in animal models of breast cancer. One analog, Seocalcitol (EB1089) has been shown to be effective in causing regression of N-methyl-nitrosourea-induced rat mammary tumors.

The combination of a potent vitamin D3 analog, EB 1089, with ionizing radiation reduces tumor growth and induces apoptosis of MCF-7 breast tumor xenografts in nude mice.

Purpose: The purpose of this research was to evaluate theinfluence of the combination of the vitamin D(3) analogue EB 1089 with fractionated radiation on growth and apoptosis of MCF-7 tumor xenografts in athymic mice.

Experimental Design: Four to six-week-old ovariectomized mice were injected s.c.

Ability of potent vitamin D3 analogs to inhibit growth of prostate cancer cells in vivo.

Background: Studies have identified analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], which in vitro are 10- to 3,000-fold more active than 1,25(OH)2D3. We compared in vivo the anti-cancer activity of three potent vitamin D3 analogs and 1,25(OH)2D3 at near to each of their maximal tolerated dose (MTD).

Materials And Methods: Human LNCaP prostate cancer xenografts were grown in nude mice and the animals were treated with intraperitoneal injections of either diluant; 1,25(OH)2D3; 1,25-Dihydroxy-20epi-22-oxa-24,26,27-trisho-mocholecalciferol (KH 1060); 1,25-Dihydroxy-22E,24E-diene-24,26,27-trishomocholecalciferol (EB 1039); and 1,25-Dihydroxy-16-ene-24-oxo-19-norcholecalciferol (RO 26-9114).

Anti-proliferative effects of 20-epi-vitamin-D3 analogue, KH1060 in human neuroblastoma: induction of RAR-beta and p21(Cip1).

We determined the in vitro biological activities of 1 alpha, 25-dihdroxyvitamin D(3) (1,25-D(3)) and its analogue, 20-epi-22-oxa-24a, 26a, 27a-trihomo-1 alpha, 25 (OH)(2) vitamin D(3) (KH1060) in six human neuroblastoma (NB) cell lines (SH-SY5Y, NB69, SK-N-AS, IMR5, CHP-134, NGP). The ability of these compounds to inhibit cell growth and DNA synthesis was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and BrdU incorporation, respectively. The induction of cell death was monitored by caspase-3 activity.

In vivo chamber angiogenesis assay: an optimized Matrigel plug assay for fast assessment of anti-angiogenic activity.

Efficient in vitro and in vivo angiogenesis assays, to assess and compare anti-angiogenic activity are a prerequisite for the discovery and characterization of anti-angiogenic targets. Here we describe an optimized Matrigel plug assay based on subcutaneously implanted chambers and two fast and reproducible measuring techniques. Plexiglas ring/nylon net filter-chambers (0.

Vitamin D3 analogs stimulate hair growth in nude mice.

The active form of vitamin D3 can regulate epidermal keratinization by inducing terminal differentiation; and mice lacking the vitamin D receptor display defects leading to postnatal alopecia. These observations implicate the vitamin D3 pathway in regulation of hair growth. We tested the ability of 1,25 dihydroxyvitamin D3 and its synthetic analogs to stimulate hair growth in biege/nude/xid (BNX) nu/nu (nude) mice exhibiting congenital alopecia.