Added value of the DIC score and of D-dimer to predict outcome after successfully resuscitated out-of-hospital cardiac arrest.

BACKGROUND: Recent Korean data suggest a high prevalence of overt disseminated intravascular coagulation (DIC) and a good predictive performance of the ISTH DIC score in successfully resuscitated out-of-hospital cardiac arrest. OBJECTIVES: We hypothesised that in a European cohort of resuscitated out-of-hospital cardiac arrest patients the prevalence of DIC is substantially lower. Furthermore, the determination of D-dimer levels at admission, but not the DIC score, could improve mortality prediction above traditional predictors. PATIENTS/METHODS: Data were extracted from a prospective cardiac arrest registry including patients admitted between 2006 and 2015, who achieved return of spontaneous circulation and had parameters for DIC score calculation available. The primary outcome was the prevalence of overt DIC at admission. Secondary outcomes included the association of overt DIC with 30-day mortality and the contribution of the DIC score and D-dimer levels to 30-day mortality prediction using logistic regression. Three stepwise models were evaluated by receiver-operating-characteristic analysis. RESULTS: Out of 1179 patients 388 were included in the study. Overt DIC was present in 8% of patients and associated with substantial 30-day mortality (83% vs. 39%). The AUC for model 1, including traditional mortality predictors, was 0.83. The inclusion of D-dimer levels significantly improved prognostication above traditional predictors (model 3, AUC 0.89), whereas the inclusion of the DIC Score had no effect on mortality prediction (model 2, AUC 0.83). CONCLUSION: Overt DIC was rare in a European cohort of out-of-hospital cardiac arrest patients. D-dimer levels improved 30-day mortality prediction and provided added value to assess early mortality risk after successful resuscitation.

Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 ± 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Emergency extracorporeal life support and ongoing resuscitation: a retrospective comparison for refractory out-of-hospital cardiac arrest.

BACKGROUND: In refractory cardiac arrest, with cardiopulmonary resuscitation (CPR) for more than 30 min, chances of survival are small. Extracorporeal cardiopulmonary resuscitation (ECPR) is an option for certain patients with cardiac arrest. The aim of this study was to evaluate characteristics of patients selected for ECPR. METHODS: Anonymised data of adult patients suffering refractory cardiac arrest, transported with ongoing CPR to an ED of a tertiary care centre between 2002 and 2012 were analysed. Outcome measure was the selection for ECPR. Secondary outcome was 180 days survival in good neurological condition. RESULTS: Overall, 239 patients fulfilled the inclusion criteria. ECPR was initiated in seven patients. Patients treated with ECPR were younger (46 vs 60 years; p=0.04), had shorter intervals before CPR was started (0 vs 1 min; p=0.013), faster admissions at the ED (38 vs 56 min; p=0.31) and lower blood glucose levels on admission (14 vs 21 mmol/L; p=0.018). Survival to discharge in good neurological condition was achieved in 14 (6%) of all patients. One patient in the ECPR group survived in excellent neurological condition. Age was independently associated with the selection for ECPR (OR 0.07; 95% CI 0.01 to 0.85; p=0.037). CONCLUSIONS: Emergency extracorporeal life support was used for a highly selected group of patients in refractory cardiac arrest. Several parameters were associated with the decision, but only age was independently associated with the selection for ECPR. The patient selection resulting in a survival of one patient out of seven treated seems reasonable. Randomised controlled trials evaluating the age limit as selection criteria are urgently needed to confirm these findings.

Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)-a subtype of Hodgkin lymphoma (HL)-is characterized by a low content of tumor cells, the lymphocyte predominant (LP) cells. Transformation into diffuse large B-cell lymphoma (DLBCL) occurs in about 10% of patients. We performed whole-genome mutation analysis of the DLBCL components from two composite lymphomas consisting of clonally related NLPHL and DLBCL as a means to identify candidate tumor suppressor genes and oncogenes in NLPHL. The analysis of LP cells for selected mutations of the DLBCL revealed that most mutations are also present in the LP cells, indicating a close relationship between the two components. The analysis of 62 selected genes in NLPHL by targeted ultra-deep sequencing revealed three novel highly recurrently mutated genes (each mutated in ~50% of cases), that is, DUSP2, SGK1 and JUNB. SGK1 was expressed in the LP cells of primary NLPHL cases and in the NLPHL cell line DEV. Administration of an SGK1 inhibitor induced apoptosis in the NLPHL cell line DEV and the DLBCL cell line Farage, suggesting a pathogenetic role of SGK1 in the LP and DLBCL cells. In summary, the present study identifies SGK1, DUSP2 and JUNB as novel key players in the pathogenesis of NLPHL.

Abscisic Acid increases terrestrial plant cell resistance to hydrostatic pressure.

Cells of the terrestrial plant species bromegrass (Bromus inermis L.) are not naturally adapted to withstand the hydrostatic pressures encountered in aquatic environments. However, after treatment with the natural plant growth hormone abscisic acid (75 micromolar), bromegrass cells survived a hydrostatic pressure of 101.3 megapascals, approximating the limits of ocean depth (10,860 m). The increased resistance to hydrostatic pressure from 1 to 7 days of abscisic acid treatment paralleled the induced elevation of cell tolerance to freezing stress.

Water Content during Abscisic Acid Induced Freezing Tolerance in Bromegrass Cells.

Changes in water content and dry weight were determined in control cells and those induced to cold harden in response to abscisic acid (ABA) treatment (7.5 x 10(-5) molar). Bromegrass (Bromus inermis Leyss cv Manchar) cells grown in suspension culture at room temperature (23 degrees C) for 7 days acclimated to -28 degrees C (LT(50)) when treated with ABA, or to -5 degrees C when untreated. ABA significantly reduced cell growth rates at 5 and 7 days after treatment. Growth reduction was due to a decrease in cell number rather than cell size. When the cell water content was expressed as percent water (percent H(2)O) or as grams water per gram dry weight (gram H(2)O/gram dry weight [g DW]), the water content of hardy, ABA-treated cells decreased from 85% to 77% or from 6.4 to 3.3 g H(2)O/g DW in 7 days. Control cell water content remained static at approximately 87% and 7.5 g H(2)O/g DW. However, cell water content, expressed as milligrams water per million cells (milligram H(2)O/10(6) cells), did not differ in ABA-treated or control cells. The dry matter content of ABA-treated cells, expressed as milligram DW/10(6) cells increased to 3.3 milligram/10(6) cells in 7 days, whereas the dry weight of the control cells remained between 1.4 to 2.1 milligrams/10(6) cells. The osmotic potential of ABA-treated cells decreased by the fifth day while that of control cells increased significantly and then decreased by day 7. Elevated osmotic potentials were not associated with increased ion uptake. In contrast to much published literature, these results suggest that cell water content does not decrease in ABA-treated cells during the induction of freezing tolerance, rather the dry matter mass per cell increased. Cell water content may be more accurately expressed as a function of cell number when accompanying changes to dry cell matter occur.

Freezing of water in red-osier dogwood stems in relation to cold hardiness.

Studies of stem water in red-osier dogwood (Cornus stolonifera Michx.) using nuclear magnetic resonance spectroscopy indicated that most freezing occurs at temperatures above -30 C in cold-hardy and tender stems. Hardy and tender stems had about the same amount of unfrozen water at -40 C (0.28 gram of water per gram dry weight). When hardy stems were slowly cooled below -20 C, the temperature below which little additional freezing occurs, they survived direct immersion in liquid N(2) (-196 C). Fully hardy samples not slowly precooled to at least -15 C did not survive direct immersion in liquid N(2). The results support the hypothesis that cooling rate is an unimportant factor in tissue survival at and below temperatures where there is little freezable water.

Environmental and Seasonal Factors Affecting the Frost-induced Stage of Cold Acclimation in Cornus stolonifera Michx.

Stem tissues of red-osier dogwood (Cornus stolonifera Michx.) acclimated from -3 C to -40 or -50 C in 8 to 10 weeks under a short photoperiod (9 hours) and controlled temperature conditions. During the summer months plants did not acclimate as well as at other times. The sequence of day/night temperature regimes which induced maximum acclimation was 20/15 C for 5 to 6 weeks; 15/5 C for 2 to 3 weeks; 15/5 C plus 1 hour of frost per day for 1 week. The duration of exposure to each temperature regime influenced the rate and intensity of frost-induced acclimation. Less than 5 weeks of warm temperature preconditioning at 20/15 C reduced subsequent frost-induced acclimation. The inductive influence of frost on cold acclimation was additive over 5 days of repeated exposure, but its effects after the first exposure(s) were not immediate-requiring 1 to 4 days of 15/5 C following the frost treatments for the expression of the frost-induced acclimation to be manifest. There was a 75% increase in rRNA following 3 days of frost exposure and plants in an O(2)-free atmosphere during frost exposure failed to acclimate. The results suggest that seasonal acclimation behavior was due to endogenous rhythms rather than developmental stage, and that the frost-induced phase of acclimation involves aerobic metabolic processes.

Endogenous ethylene and abscisic Acid relative to phytogerontology.

Endogenous production of ethylene and endogenous levels of abscisic acid were measured from Hibiscus rosa-sinensis L. abscission zone explants at six stages of development: tight bud, open flower, closed flower, petal abscission, calyx abscission, and peduncle abscission.Explants acropetal and basipetal to the abscission zone produced less ethylene than the abscission zone explants. Ethylene production increased with time both prior to and during abscission, reaching a peak in the later stages of senescence after abscission was complete.Bound abscisic acid was greatest in segments acropetal to the abscission zone at the closed flower stage. Free abscisic acid was double that of bound abscisic acid in the tight bud stage with the basipetal level exceeding that of the acropetal level until flower closure. Acropetal-free abscisic acid began to rise at petal abscission increasing sharply to a peak at calyx abscission. Both free and bound abscisic acid were greatly reduced at peduncle abscission. A relationship of ethylene and abscisic acid to abscission and senescence appears to exist.

Water Permeability and Cold Hardiness of Cortex Cells in Cornus stolonifera Michx.-A Preliminary Report.

The relationship of freezing resistance to water permeability of cortex cells was studied in stems of red osier dogwood (Cornus stolonifera Michx.). Permeability was estimated by determining the diffusion flux of tritiated water from cortex slices previously equilibrated in tritiated water. Energy of activation and diffusion time comparisons of tritiated water flux from living cortex slices and slices killed by immersion in liquid N(2) verified that intact membranes of uninjured cortex cells limited water flux.Water permeability of living phloem and cortical parenchyma cells increased during the initial (photoperiodically induced) phase of cold acclimation. This accompanied an increase in hardiness from -3 to -12 C. Little if any further increase in permeability was noted during subsequent acclimation to below -65 C.Permeability measurements on nonhardy cortex samples yielded consistent results, but measurements on samples from hardy twigs were often difficult to reproduce. This unexplained variability precludes specific conclusions, but the tritiated water diffusion flux technique may provide an alternative to traditional plasmolytic techniques in studying water permeability in woody plant tissues.

Supercooling in overwintering azalea flower buds.

Differential thermal analysis and nuclear magnetic resonance spectroscopy experiments on whole flower buds and excised floral primordia of azalea (Rhododendron kosterianum, Schneid.) proved that supercooling is the mode of freezing resistance (avoidance) of azalea flower primordia. Increase in the linewidth of nuclear magnetic resonance spectra for water upon thawing supports the view that injury to the primordia occurs at the moment of freezing. Nonliving primordia freeze at the same temperatures as living primordia, indicating that morphological features of primordial tissues are a key factor in freezing avoidance of dormant azalea flower primordia. Differential thermal analyses was used to study the relationship of cooling rate to the freezing points of floral primordia in whole flower buds. At a cooling rate of 8.5 C per hour, primordia in whole buds froze at about the same subfreezing temperatures as did excised primordia cooled at 37 C per hour. At more rapid cooling rates primordia in intact buds froze at higher temperatures.

Effects of Red and Far Red Light on the Initiation of Cold Acclimation in Cornus stolonifera Michx.

Red and far red light distinctly influence the initial phytochrome-mediated phase of cold acclimation in red-osier dogwood (Cornus stolonifera). Under controlled conditions, short days and end-of-day far red light exposure after long days promote growth cessation, cold acclimation, and subsequent cold hardening of dogwood stems in response to low temperature. Nuclear magnetic resonance absorption spectra of the water in internode stem sections imply that the short day-induced phase of cold acclimation involves a change in tissue hydration, at least in part, due to a substantial reduction in bulk phase water as a result of senescence and loss of water from the pith. Seasonal responses to light and an attempt to induce early acclimation under natural conditions with end-of-day far red light are discussed.

Short term increases in the cold tolerance of red osier dogwood stems induced by application of cysteine.

Bark tissues of Cornus stolonifera stems, treated with cysteine at 24 hours after treatment, survived exposure to -11 C (the tissue temperature) with little or no injury. An initiation of increase in the cold tolerance was usually observed when plants were treated with cysteine at 12 hours after treatment. Neither plants at 36 or 48 hours after treatment nor plants 12 hours before treatment had shown increases in the cold tolerance. They were killed below -5 C, which was the survival temperature of untreated control plants. Two weeks or more of short day induction before cysteine application were required for a significant effect of short term 5 C increase in the cold tolerance.

The mechanism of freezing injury in xylem of winter apple twigs.

In acclimated winter twigs of Haralson apple (Pyrus Malus L.), a lag in temperature during cooling at a constant rate was observed at about -41 C by differential thermal analysis. The temperature at which this low temperature exotherm occurred was essentially unaffected by the cooling rate. During thawing there was no lag in temperature (endotherm) near the temperature at which the low temperature exotherm occurred, but upon subsequent refreezing the exotherm reappeared at a somewhat higher temperature when twigs were rewarmed to at least -5 C before refreezing. These observations indicate that a small fraction of water may remain unfrozen to as low as -42 C after freezing of the bulk water in stems. The low temperature exotherm was not present in twigs freeze-dried to a water content below 8.5% (per unit fresh weight), but it reappeared when twigs were rehydrated to 20% water. When freeze-dried twigs were ground to a fine powder prior to rehydration, no exotherm was observed. Previous work has shown that the low temperature exotherm arises from xylem and pith tissues, and that injury to living cells in these tissues invariably occurs only when twigs are cooled below, but not above the temperature of the low temperature exotherm. This study revealed that the low temperature exotherm resulted from the freezing of a water fraction, that the freezing of this water was independent of the freezing of the bulk water, that the exotherm was associated with some gross structural feature but not the viability of the tissue, and that injury to living cells in the xylem and pith was closely and perhaps causally related to the initial freezing of this water.

Freezing injury in potato leaves.

Time-temperature profiles of freezing leaves from frost-resistant (Solanum acaule Bitt.) and frost-susceptible (Solanum tuberosum L. subsp. tuberosum Hawkes) types of potatoes did not reveal any major differences. The pattern of change in resistance of leaves to low voltage, low frequency current during freezing was different in the frost-resistant and susceptible leaves. In tissue sections from both types of leaves, cells freeze extracellularly at cooling velocities lower than 5 C per minute. Cells from leaves of resistant plants showed a higher osmotic pressure but not a higher water permeability than those from susceptible plants. The extent of injury caused by even very slow freezing was greater than that caused by equivalent isopiestic desiccation, particularly in susceptible leaves. The higher osmotic pressure in cells of leaves from resistant plants can account for the greater desiccation resistance but not for the frost resistance observed.

Influence of decenylsuccinic Acid on water permeability of plant cells.

Decenylsuccinic acid altered permeability to water of epidermal cells of bulb scales of Allium cepa and of the leaf midrib of Rhoeo discolor. Water permeability, as determined by deplasmolysis time measurements, was related to the dose of undissociated decenylsuccinic acid (mm undissociated decenylsuccinic acid x minute). No relationship was found between permeability and total dose of decenylsuccinic acid, or dose of dissociated decenylsuccinic acid, suggesting that the undissociated molecule was the active factor in permeability changes and injury.At doses which did not damage cells (0.0008 to 0.6 [mm of the undissociated molecule x minute]) decenylsuccinic acid decreased water permeability. At higher doses (e.g., 4 to 8 [mm x minute]) injury to cells was common and decenylsuccinic acid increased permeability. Doses above the 10 to 20 (mm x minute) range were generally lethal. The plasmolysis form of uninjured cells was altered and protoplasmic swelling occasionally was observed. The dose-dependent reversal of water permeability changes (decreased to increased permeability) may reflect decenylsuccinic acid-induced changes in membrane structure. Reported effects of decenylsuccinic acid on temperature dependence of permeability and frost resistance were not verified.

Nucleic Acid and protein changes in relation to cold acclimation and freezing injury of korean boxwood leaves.

Quantitative and qualitative differences in nucleic acids of Korean boxwood (Buxus microphylla var. Koreana) leaves were determined by methylated albumin kieselguhr chromatography at different levels of cold hardiness. During cold acclimation there was an increase in RNA, mainly ribosomal RNA, with little or no change in DNA. The increase in ribosomal RNA was closely paralleled by an increase in water soluble and membrane bound proteins. As cold hardiness increased, ribonuclease activity declined.Exposure of hardy boxwood plants to warm temperatures resulted in a rapid loss in cold resistance and a rapid synthesis of nucleic acids as judged by (32)P incorporation.Following a killing frost to Korean boxwood leaves, there was a rapid decrease in all nucleic acid fractions which was attributed to nuclease activity. Within 5 hours there was no measurable soluble RNA and ribosomal RNA. Tenaciously bound RNA was somewhat more persistent.