Spectroscopy along Flerovium Decay Chains: Discovery of

A nuclear spectroscopy experiment was conducted to study α-decay chains stemming from isotopes of flerovium (element Z=114). An upgraded TASISpec decay station was placed behind the gas-filled separator TASCA at the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. The fusion-evaporation reactions ^{48}Ca+^{242}Pu and ^{48}Ca+^{244}Pu provided a total of 32 flerovium-candidate decay chains, of which two and eleven were firmly assigned to ^{286}Fl and ^{288}Fl, respectively. A prompt coincidence between a 9.60(1)-MeV α particle event and a 0.36(1)-MeV conversion electron marked the first observation of an excited state in an even-even isotope of the heaviest man-made elements, namely ^{282}Cn. Spectroscopy of ^{288}Fl decay chains fixed Q_{α}=10.06(1) MeV. In one case, a Q_{α}=9.46(1)-MeV decay from ^{284}Cn into ^{280}Ds was observed, with ^{280}Ds fissioning after only 518 µs. The impact of these findings, aggregated with existing data on decay chains of ^{286,288}Fl, on the size of an anticipated shell gap at proton number Z=114 is discussed in light of predictions from two beyond-mean-field calculations, which take into account triaxial deformation.

Evidence for immunological priming and increased frequency of CD4+ CD25+ cord blood T cells in children born to mothers with type 1 diabetes.

Maternal transmission of islet autoantibodies to children born to mothers with type 1 diabetes (T1D) has been shown to protect from autoantibodies and diabetes development later in life. However, the factors conferring disease protection are poorly understood. The aim of this study was to evaluate comparatively proinflammatory cytokines, autoantibodies and lymphocyte subsets in cord blood (CB) of children born to mothers with either T1D (n = 13), gestational diabetes (GDM) (n = 32) or healthy mothers (n = 81) in relation to transplacental passage of autoantibodies. The results are consistent with early priming of the fetal immune system only in children born to mothers with T1D. Levels of interleukin (IL)-1beta (P = 0.022), tumour necrosis factor (TNF)-alpha (P = 0.002) and IL-8 (P = 0.0012), as well as the frequency of CD4(+) CD25(+) T cells (P < 0.01) were significantly increased, and the increased levels correlated positively with anti-GAD65 autoantibody (GADA) levels. Moreover, CD4(+) CD25(+) T cells of children born to T1D mothers exhibited a more pronounced memory phenotype with increased CCR4 expression and down-regulation of CD62L. These data suggest that early activation of the fetal immune system as a consequence of maternal autoimmunity and transplacental passage of GADA may influence the generation and expansion of fetal regulatory T cells. This might induce an early antigen-specific immunological tolerance that could protect against T1D later in life.

Arsenic trioxide inhibits neuroblastoma growth in vivo and promotes apoptotic cell death in vitro.

Recent clinical studies have shown that inorganic arsenic trioxide (As(2)O(3)) at low concentrations induces complete remission with minimal toxicity in patients with refractory acute promyelocytic leukemia (APL). Preclinical studies suggest that As(2)O(3) induces apoptosis and possibly differentiation in APL cells. Like APL cells, neuroblastoma (NB) cells are thought to be arrested at an early stage of differentiation, and cells of highly malignant tumors fail to undergo spontaneous maturation. Both APL and NB cells can respond with differentiation to retinoic acid (RA) treatment in vitro and probably also in vivo. For that reason we investigated the effect of As(2)O(3) alone and in combination with RA on NB cell lines. In vitro, the number of viable NB cells was reduced at As(2)O(3) concentrations around 1 microM after 72 h exposure. The IC50 in six different cell lines treated for 3 days was in the 1.5 to 5 microM concentration interval, the most sensitive being SK-N-BE(2) cells derived from a chemotherapy resistant tumor. The combined treatment with RA (1 and 3 microM) showed no consistent additional effect with regard to induced cell death. The effect of As(2)O(3) on NB cell number involved As(2)O(3)-induced apoptotic pathways (decreased expression of Bcl-2 and stimulation of caspase-3 activity) with no clear evidence of induced differentiation. The in vivo effect of As(2)O(3) on NB growth was also investigated in nude mice bearing tumors of xenografted NB cells. Although tumor growth was reduced by As(2)O(3) treatment, complete remission was not achieved at the concentrations tested. We suggest that As(2)O(3), in combination with existing treatment modalities, might be a treatment approach for high risk NB patients.

The character of the suspended and dissolved phases in the water cover of the flooded mine tailings at Stekenjokk, northern Sweden.

Studies of the suspended and dissolved phases of the pond water, material collected from sediment traps, and surficial sediments/tailings from the flooded tailings pond at Stekenjokk have been performed. The aim was to characterise the material, to study the seasonal variations and to quantify possible resuspension of the tailings in the pond. The element concentrations in the pond at Stekenjokk seem to be largely controlled by processes controlling the precipitation and dissolution of Mn- and Fe-oxyhydroxides in both the water column and in the surficial tailings. Physiochemical processes such as weathering of silicates on the surrounding mountain slopes or dykes contributes both dissolved elements and detrital particles. The suspended phase consists of detrital silicate material as well as Fe- and Mn-oxyhydroxides. The average heavy metal concentrations are high, e.g. 0.42% Cu, 0.15% Pb and 3.1% Zn, which is probably due to sorption onto Fe- and Mn-oxyhydroxides. The suspended phase is richer in Fe, and particularly Mn, during the winter. The suspended phase resembles the material collected in sediment traps and the material in the surficial sediments. The pond water is well mixed during the ice-free season. The dissolved heavy metal concentrations are generally rather low with, e.g. maximum concentrations of 2.03 micrograms/l Cu, 0.23 microgram/l Pb and 268 micrograms/l Zn during the winter. Higher dissolved concentrations are found below the ice-cover above the sediment surface during the winter, caused by diffusion of elements from the sediment-water interface up into the pond water. Most of the metals occurring in the pond are dissolved and resuspension of tailings is negligible.

Human achaete-scute homologue 1 (HASH-1) is downregulated in differentiating neuroblastoma cells.

The mammalian achaete-scute homologue, MASH-1, is crucial for early development of the sympathetic nervous system and is transiently expressed in sympathetic neuroblasts during embryogenesis. Here we report that the human homologue (HASH-1) was expressed in all analyzed cell lines (6/6) derived from the sympathetic nervous system tumor neuroblastoma. The majority of small-cell lung carcinoma (4/5) cell lines tested expressed HASH-1, while other nonneuronal/non-neuroendocrine cell lines were negative. Induced differentiation of neuroblastoma cells resulted in HASH-1 downregulation. This occurred concomitant with induction of neurite outgrowth and expression of the neuronal marker genes GAP-43 and neuropeptide Y. Constitutive expression of exogenous HASH-1 did not alter the capacity of the neuroblastoma cells to differentiate in response to differentiation-inducing agents. It is concluded that moderate HASH-1 expression does not compromise the capacity of these cells to differentiate.

Early attachment of leucocytes, platelets and fibrinogen in endothelial cell-seeded Dacron venous conduits.

BACKGROUND: There is a need for prosthetic venous conduits in surgery for trauma, cancer and thrombotic disease. Such conduits in use today have a low patency rate, leaving room for much improvement. METHODS: This experimental study investigated the dynamics of the early attachment of radiolabelled platelets, leucocytes and fibrinogen to endothelial cell-seeded Dacron venous conduits in sheep. Grafts were placed as jugular vein interposition grafts, seeded on one side, not seeded on the other, and followed for 4 h. RESULTS: No difference could be demonstrated between the two graft types. Platelets showed an increasing attachment during the whole period, leucocytes an immediate attachment followed by an undulating pattern, and fibrinogen an immediate attachment with a tendency to decrease. Measurements on the vein itself showed a high attachment and, for platelets, an extremely high attachment when measured after the graft in the direction of flow. CONCLUSION: The seeding process did not seem to affect early thrombogenicity. The carefully dissected vein wall showed highly thrombogenic properties, in many ways as high as in the prosthetic graft.

Early attachment of platelets, leukocytes, and fibrinogen in endothelial cell seeded Dacron grafts.

Endothelial cell seeding has been advocated as a method for reducing the thrombogenicity of prosthetic grafts. Principally two different techniques for endothelial cell seeding can be used: immediate seeding of grafts followed by implantation or initial growth and establishment of an endothelial cell-covered surface before subsequent late implantation. This study was designed to determine whether the immediate seeding technique altered thrombogenicity directly after graft implantation. Carotid arteries from 19 sheep were replaced with Dacron interposition grafts; one side was seeded with endothelial cells and the other side was left unseeded. The dynamics of thrombus formation involving radiolabeled platelets, leukocytes, and fibrinogen were studied for 4 hours with flow reduced to 35 ml/min. No difference in platelet uptake (approximately 6-fold increase compared to baseline values) was found between endothelial cell seeded and unseeded grafts. Likewise, there were no differences in leukocyte uptake (approximately 4-fold increase) or fibrinogen uptake (approximately 10- to 15-fold increase) between the two groups. No differences were demonstrated with regard to patency or thrombus weight. In this experimental investigation we were unable to verify any change in the uptake of platelets, white blood cells, or fibrinogen between endothelial cell seeded and unseeded Dacron grafts during the first 4 hours after graft placement. Immediate seeding does not affect the initial thrombogenicity of grafts.

Influence of haemorrhage and blood transfusion on haemostasis. An experimental study in rabbits.

The influence of haemorrhage and blood transfusion on primary haemostasis, coagulation and fibrinolysis was investigated in rabbits. Acute loss of 20% of the blood volume gave a significantly shortened coagulation time (Lee-White method) but no detectable change in fibrinolysis (euglobulin clot lysis time) and primary haemostasis (primary haemostatic plug formation time in transected arterioles in rabbit mesenteric microcirculation). Acute loss of 20% of blood volume followed by blood transfusion resulted in a prolonged coagulation time and also in a prolonged primary haemostatic plug formation time, but no change in fibrinolysis. It could be concluded that the haemorrhage did not affect the platelet-dependent primary haemostasis but resulted in a shortened coagulation time. Blood transfusion seemed to affect adversely both the primary haemostasis and the shortened coagulation time induced by haemorrhage.

The effect of a combined thromboxane receptor- and synthesis-antagonist on platelet, fibrinogen and leucocyte uptake in ePTFE grafts: an experimental study in sheep.

Arterial expanded polytetrafluoroethylene (ePTFE) grafts were interpositioned in the common carotid arteries of 20 adult sheep. This model was used to study the effect of a combined thromboxane receptor- and synthesis-antagonist, Ridogrel (R 68070), on acute graft patency and platelet, fibrinogen and leucocyte uptake. The animals were randomised to treatment (n = 10) or control groups (n = 10). Treatment was given as an intravenous injection with Ridogrel of 8 mg kg body weight-1. The flow in one of the two inserted grafts was restricted to 25 ml min-1. Autologous 111In-labelled platelets, 125I-labelled fibrinogen and 99m-Tc-labelled leucocytes were injected intravenously and the radioactivity over the vessels measured before and after graft insertion using the gamma scintillation technique. After graft insertion the measurements continued for 4 h at two separate points over the proximal and distal anastomosis areas. In the treatment group six out of 10 grafts with restricted flow remained patent compared with nine out of 10 grafts with flow reduction in the control group (N.S.). The median thrombus weights did not differ significantly. There was no difference in the platelet and fibrinogen activities at the proximal anastomosis but distally the animals receiving treatment had a significant reduction during the first 2 h of the experiment. The leucocyte activity in the treatment group compared to the control group did not differ proximally but distally the activity was significantly higher during the last 3 h of the experiment. In the group with unrestricted flow all grafts in both groups remained patent. The thrombus weight was significantly lower in the treatment group compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of a thromboxane receptor antagonist on acute ePTFE arterial graft thrombogenicity--an experimental study in sheep.

ePTFE interposition grafts in the common carotid arteries of 16 adult sheep were used to study the effect of a thromboxane receptor antagonist. Vapiprost (GR 32191, Glaxo research group, London, UK). After insertion of the grafts the sheep were randomised to treatment (n = 8) or control (n = 8). Treatment was given as an intravenous injection with GR 32191 of 1 mg/kg body weight. The flow in one of the two inserted grafts was restricted from normal (190 ml/min) to 25 ml/min. Autologous 111-In labelled platelets and human 125-I labelled fibrinogen were injected intravenously. The radioactivity over each graft was measured for 4 h at two separate points with a gamma scintillation technique. Due to technical complications immediately before the start of the measurements one sheep in each group was excluded from the study. In the treated group three out of seven grafts with restricted flow occluded compared to all seven grafts with a flow reduction in the control group (p less than 0.05). The grafts with unrestricted flow occluded in two of seven in both groups. In the open grafts with unrestricted flow the fibrinogen activity was significantly reduced in the treated group compared to the control group. The platelet activity was not significantly reduced. It is concluded that GR 32191 significantly reduced the fibrinogen uptake as well as graft occlusions of ePTFE grafts in a low flow situation.

Thromboxane A2-receptor blockade and prostacyclin in porcine Escherichia coli shock.

Septic shock was induced by intravenous infusion of live Escherichia coli in pigs to investigate the influences on central hemodynamic, coagulation, and fibrinolytic reactions by a thromboxane A2 (TxA2)-receptor blocker (BM 13.177; n = 6) and a prostacyclin analogue (iloprost or ZK 36,374; n = 7). The early pulmonary vasoconstriction following E coli infusion was attenuated, but not abolished, by BM 13.177. Only minor effects were seen after pretreatment with iloprost. Neither drug had any major effect on the coagulation and fibrinolytic activation. These results confirm that TxA2 is an important, but not the only, mediator of early pulmonary vascular response in porcine septicemia and that neither TxA2 nor prostacyclin is of major importance for the hemostatic reactions in this shock model.

Potentiated thrombolysis in a Chandler system using rtPA and lys-plasminogen.

The effect of glu/lys-plasminogen on rtPA induced thrombolysis was studied in a Chandler model using rabbit blood. Glu/lys-plasminogen in various concentrations was added to the Chandler loop before or after thrombi were formed from 2 ml of rabbit blood containing 125I-labelled rabbit fibrinogen. The thrombolysis was estimated as radioactivity in the supernatant/total radioactivity. Thrombi formed in the presence of extra lys-plasminogen (conc greater than or equal to 0.025 mg/ml blood) lysed spontaneously to a significantly higher extent than thrombi formed in the presence of glu-plasminogen or saline. If the glu/lys-plasminogen was added to a preformed thrombus no thrombolysis occurred. When added together with single-chain rtPA (s.c. rtPA) or two-chain rtPA (t.c.rtPA) the thrombolysis was similar to the one obtained by s.c./t.c.rtPA alone. If on the other hand s.c./t.c.rtPA was added to lys-plasminogen enriched thrombi (greater than 0.01 mg/ml blood) a significantly enhanced thrombolysis as compared to the one achieved by s.c./t.c.rtPA alone was obtained. Based on the observation that lys-plasminogen potentiates the lysis of thrombi in a Chandler model a bolus dose administered preoperatively may enhance spontaneous lysis of thrombi formed during surgery.

Influence of aprotinin, a protease inhibitor, on porcine E. coli shock. Studies on coagulation, fibrinolytic and hemodynamic response.

The effect of a protease inhibitor, aprotinin, on hemostasis (a2M, a2AP, AT III, prothrombin-convertin activity, fibrinogen, fibrinogen monomers and fibrinolytic activity on fibrin plates) was investigated in pigs with septic shock. Anesthetized pigs were given live Escherichia coli i.v. (n = 7), or aprotinin (1,000,000 KIE i.v.) 15 min before live E. coli (n = 6), or Ringer's solution only (sham controls, n = 8). Septic shock developed in all E. coli-infused pigs. Pulmonary vascular resistance increased, platelet and leukocyte counts fell and signs of systemic activation of the coagulation and fibrinolytic systems appeared in the E. coli groups, but aprotinin attenuated the effects on these systems and also on the pulmonary circulation. Five of the six aprotinin-pretreated pigs survived, but none of the seven with septic shock and no pretreatment. Thus the shock induced by infusion of live E. coli and the resultant changes in the coagulation and fibrinolytic systems and in cardiopulmonary hemodynamics were diminished by aprotinin pretreatment.

Arachidonic acid cascade metabolites in porcine E. coli shock. Coagulation, fibrinolytic and hemodynamic response.

Cardiopulmonary hemodynamics and changes in various hemostatic factors (alpha 2M, alpha 2AP, AT III, prothrombin-proconvertin activity, fibrinogen concentration, ethanol gelation test and fibrinolytic activity on fibrin plates) were investigated in pigs during shock induced with live Escherichia coli. Anesthetized pigs were treated with indomethacin or with the combined cyclooxygenase/lipoxygenase inhibitor BW755C before the E. coli infusion or were left untreated as septic controls. Septic shock developed in all of these animals. Pretreatment attenuated the early deterioration of pulmonary circulation but did not modify the coagulation/fibrinolytic activation or the disturbed cardiopulmonary hemodynamics seen in the delayed phase of shock. The arachidonic acid cascade metabolites thus seems to mediate the early, but not the delayed cardiopulmonary reaction and to have minor importance for activation of coagulation and fibrinolysis in E. coli-shocked pigs.

Structural studies of the capsular polysaccharide from Streptococcus pneumoniae types 15B and 15C.

The structures of the capsular polysaccharides (S-15B and S-15C) from Streptococcus pneumoniae types 15B and 15C have been investigated by using n.m.r. spectroscopy, methylation analysis, and various specific degradations. It is concluded that the polysaccharides are composed of pentasaccharide repeating-units having the following structure: (Formula: see text). In this structure, R is H (80%) or CH2CH2N+Me3 (20%). S-15B further contains O-acetyl groups, approximately 0.7 per repeating unit, which have not been located. The capsular polysaccharides S-15F and S-15A, which have been studied previously, are also composed of pentasaccharide repeating-units, containing the same sequence of sugars, but in a linear arrangement.

Pulmonary vascular response to live Escherichia coli: influences of different antiplatelet substances.

The aim of this study was to investigate whether pretreatment with drugs that interfere with platelet functions in different ways could modify the pulmonary vascular response in a porcine septic shock model. Septic shock was induced by i.v. infusion of live Escherichia coli bacteria. Bacteriemic animals were divided into five groups: untreated or pretreated with a thromboxane-A2 synthetase inhibitor (UK 38 485), a serotonin-receptor antagonist (ketanserin), a combination of these two drugs, or a platelet antiaggregating drug (dipyridamole). E. coli induced significant pulmonary hemodynamic and respiratory changes. The pulmonary responses to E. coli infusion were attenuated after pretreatment with UK 38 485 but unaffected by prior administration of ketanserin or dipyridamole. The combined pretreatment did not attenuate the pulmonary hypertension or other pulmonary responses to E. coli more than UK 38 485 alone. Dipyridamole did not alter the pulmonary circulation after bacterial infusion. It was concluded that thromboxane-A2 is an important, but not the only, mediator of the pulmonary vascular response in septic-shocked pigs and that factors such as serotonin and platelet aggregability seem to be of minor, if any, importance for the hemodynamic response.

Coagulation and fibrinolytic reactions in experimental porcine septic shock: pretreatment with different antiplatelet factors.

The aim of this study was to investigate the influence on various hemostatic factors (alpha 2-macroglobulin, antiplasmin, antithrombin III, prothrombin-proconvertin activity, fibrinogen concentration, ethanol gelation test, and fibrinolytic activity on fibrin plates) of bacteremic shock in swine and the influence on these factors of drugs interfering with platelet function. Anesthetized pigs were given live Escherichia coli intravenously (n = 49) or Ringer's solution (n = 7) and were monitored for 3 hours. Pretreatment was given with indomethacin (n = 6), the TxA2 inhibitor UK 38 485 (n = 7), the prostacyclin analogue ZK 36 374 (n = 7), the 5HT antagonist ketanserin (n = 6), or ketanserin combined with UK 38 485 (n = 9) or dipyridamole (n = 8). Septic shock developed in all E. coli animals. There were decreased levels of platelets and leukocytes and activation of the coagulation/fibrinolytic systems by E. coli. Except for a slight attenuating effect on the antithrombin III (ketanserin and dipyridamole) and alpha 2-macroglobulin (ketanserin) decreases, there were no significant effects of the drugs. It is concluded that live E. coli induced several changes within the coagulation and fibrinolytic systems. Only minor effects were seen when different drugs influencing platelet function were given.

The influence of degradable starch microspheres on liver uptake of 5-fluorouracil after hepatic artery injection in the rat.

The effect of degradable starch microspheres (DSM) on the distribution of 5-fluorouracil (5-FU) after hepatic artery injection was studied in normal rats. Carbon-14-labelled 5-FU was injected separately or together with DSM into the hepatic artery. Radioactivity was measured in liver tissue, bile, peripheral blood, and urine. When microspheres were added, the liver uptake of 5-FU was increased; its peak concentration in peripheral blood decreased, as did the early urinary excretion of radioactivity. The addition of degradable starch microspheres to hepatic artery injections of cytostatic drugs might be of value in increasing the drug concentration in tumour tissue and reducing systemic toxicity.

Hepatic artery administration of degradable starch microspheres. I. Effect on energy charge and incorporation of precursors into rat liver nucleic acids.

The effects of hepatic artery administration of degradable starch microspheres on liver energy charge and nucleic acid anabolism were studied in rats. Liver energy charge was evaluated 20 and 60 min after the injection of degradable starch microspheres. As compared to controls the microspheres had no effect on liver energy charge. The incorporation of orotic acid, uracil, and thymidine into liver RNA or DNA was studied 1 h after hepatic artery injection of precursor alone or together with degradable starch microspheres. Orotic acid and uracil incorporation into RNA was studied in normal rats and the DNA incorporation of thymidine in animals with regenerating livers. Orotic acid and thymidine were given in trace amounts. Uracil was given in amounts corresponding to a therapeutic dose of 5-fluorouracil. The addition of microspheres had no effects on the incorporation of the nucleic acid precursors into RNA or DNA. Thus, in the normal liver degradable starch microspheres administered by the hepatic artery had no influence on liver energy charge or RNA anabolism in the liver. Also the microspheres had no negative effects on the DNA anabolism in proliferating liver cells.