Crystalloid resuscitation in trauma patients: deleterious effect of 5L or more in the first 24h.

BACKGROUND: Over-aggressive intravenous fluid therapy with crystalloids has adverse effects in trauma patients. We assessed the role of large-volume (≥5l) administration of crystalloids within 24h of injury as an independent risk-factor for mortality, in-hospital complications, and prolonged mechanical ventilation. METHODS: A retrospective cohort analysis of adult trauma patients admitted to a level 1-trauma center between December 2011 and December 2012. Patient demographics, clinical and laboratory values, and total resuscitation fluid administered within the first 24h of injury were obtained. Outcomes included mortality, in-hospital complications and ventilator-days. Multivariable logistic regression and Poisson regression analyses were performed to investigate any association between the administration of ≥5L crystalloids with the aforementioned outcomes while controlling for selected clinical variables. RESULTS: A total of 970 patients were included in the analysis. 264 (27%) received ≥5L of crystalloids in the first 24h of injury. 118 (12%) had in-hospital complications and 337 (35%) required mechanical ventilation. The median age was 46 years (interquartile range (IQR) 27-65) years and 73% (n = 708) were males. The median injury severity score (ISS) was 17 (IQR 9-25). Overall mortality rate was 7% (n = 67). Multivariable logistic regression analysis showed several variables independently associated with mortality (p < 0.05), including resuscitation with ≥5L crystalloid in the first 24h (adjusted odds ratio (aOR) 2.55), older age (aOR 1.03), higher ISS (aOR 1.09), and lower temperature (aOR 0.68). The variables independently associated with in-hospital complications (p < 0.05) were older age, longer ICU stay, and platelet transfusion within 24h of the injury. Need for mechanical ventilation was more common in patients who received ≥5L crystalloids (RR 2.31) had higher ISS (RR 1.02), developed in-hospital complications (RR 1.91) and had lower presenting temperature (RR 0.87). CONCLUSION: Large-volume crystalloid resuscitation is associated with increased mortality and longer time ventilated, but not with in-hospital complications such as pneumonia and sepsis. Based on this data, we recommend judicious use of crystalloids in the resuscitation of trauma patients.

Background dose-rates to reference animals and plants arising from exposure to naturally occurring radionuclides in aquatic environments.

In order to put dose-rates derived in environmental impact assessments into context, the International Commission on Radiological Protection (ICRP) has recommended the structuring of effects data according to background exposure levels. The ICRP has also recommended a suite of reference animals and plants (RAPs), including seven aquatic organisms, for use within their developing framework. In light of these propositions, the objective of this work was to collate information on activity concentrations of naturally occurring primordial radionuclides for marine and freshwater ecosystems and apply appropriate dosimetry models to derive absorbed dose-rates. Although coverage of activity concentration data is comprehensive for sediment and water, few, or in some cases no, data were found for some RAPs, e.g. for frogs (Ranidae) and freshwater grasses (Poaceae) for most radionuclides. The activity concentrations for individual radionuclides in both organisms and their habitat often exhibit standard deviations that are substantially greater than arithmetic mean values, reflecting large variability in activity concentrations. To take account of variability a probabilistic approach was adopted. The dominating radionuclides contributing to exposure in the RAPs are (40)K, (210)Po and (226)Ra. The mean unweighted and weighted dose-rates for aquatic RAPs are in the ranges 0.07-0.39 microGy h(-1) and 0.37-1.9 microGy h(-1) respectively.

Extent and severity of coronary disease and mortality in patients with end-stage renal failure evaluated for renal transplantation.

The purpose of this study is to explore the relationship between coronary artery disease (CAD), transplantation status and subsequent mortality in end-stage renal disease (ESRD) patients undergoing evaluation for renal transplantation. Two hundred fifty-three ESRD patients at high risk for CAD underwent coronary angiography as part of a renal transplant evaluation. The cohort was divided into three groups: Group 1 (n = 127) had no vessels with >or=50% stenosis, Group 2 (n = 56) had one vessel with >or=50% stenosis and Group 3 (n = 70) had two or more vessels with >or=50% stenosis. Long-term survival was determined; median follow-up was 3.3 years. The baseline characteristics were similar except for older age and higher proportion of diabetes mellitus, dyslipidemia and peripheral vascular disease in Groups 2 and 3 patients as compared to Group 1. Survival was worse in Group 3 compared to Group 1 (p < 0.0001). Each of the three subgroups had better survival with renal transplantation than those who did not undergo transplantation (p < 0.0001). Although the degree of CAD is related to subsequent mortality, transplantation is associated with better survival regardless of the extent and severity of CAD. Thus, the presence of CAD should not exclude ESRD patients from consideration for this therapy.

Assessment of the in vitro efficacy of the novel antimicrobial peptide CECT7121 against human Gram-positive bacteria from serious infections refractory to treatment.

BACKGROUND: Resistant Gram-positive bacteria are causing increasing concern in clinical practice. This work investigated the efficacy of AP-CECT7121 (an antimicrobial peptide isolated from an environmental strain of Enterococcus faecalis CECT7121) against various pathogenic Gram-positive bacteria. METHODS: Strains were isolated from intensive care unit patients unresponsive to standard antibiotic treatments. Inhibitory activity of AP-CECT7121 was assessed using the agar-well diffusion method. The most resistant isolates from each species screened (Enterococcus faecium, Enterococcus faecalis,Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Clostridium perfringens and Clostridium difficile) were further examined in time-killing curve studies. RESULTS: These bactericidal kinetic experiments demonstrated a rapid killing effect with no viable bacteria being detected within 30 and 90 min for enterococcal and streptococcal strains and 180 min for community-acquired methicillin-resistant S. aureus and C. perfringens: viable counts for C. difficile were threefold decreased after 90 min. CONCLUSIONS: AP-CECT7121 may provide a novel strategy for treating potentially fatal clinical infections in hospitalized patients.

In vitro efficacy of the novel peptide CECT7121 against bacteria isolated from mastitic dairy cattle.

AIMS: To evaluate the in vitro bactericidal activity of the novel antimicrobial peptide (AP) CECT7121 against Gram-positive bacteria from mastitic dairy cattle. METHODS AND RESULTS: A total of 15 Staphylococcus aureus, 10 Streptococcus dysgalactiae, 7 Strep. uberis, 1 Strep. agalactiae strains were isolated from 33 different mastitic dairy cattle, sourced from two dairies in Tandil-Argentina. Isolates from each of the bacterial species screened which developed the lowest inhibition zones in response to the peptide, were further evaluated in a series of time-killing curve studies. No survivors were detected in whole strains (from the three Streptococcal species isolated) within 120 min of incubation in presence of the peptide. The Staph. aureus isolates were less sensitive but, nevertheless, a drop in viable counts to below the detection limit was achieved for all the test strains by the final postincubation sampling point at 180 min. CONCLUSIONS: The study demonstrated the in vitro efficacy of the AP-CECT7121 against a variety strains of Gram positives isolated from mastitic dairy cattle. SIGNIFICANCE AND IMPACT OF THE STUDY: There is urgent global interest in the development of natural alternatives for the control and prevention of mastitis. Confirmation of the in vitro activity of the novel AP-CECT7121 against Gram-positive isolates encourages further research.

Noble gases confirm plume-related mantle degassing beneath Southern Africa.

Southern Africa is characterised by unusually elevated topography and abnormal heat flow. This can be explained by thermal perturbation of the mantle, but the origin of this is unclear. Geophysics has not detected a thermal anomaly in the upper mantle and there is no geochemical evidence of an asthenosphere mantle contribution to the Cenozoic volcanic record of the region. Here we show that natural CO2 seeps along the Ntlakwe-Bongwan fault within KwaZulu-Natal, South Africa, have C-He isotope systematics that support an origin from degassing mantle melts. Neon isotopes indicate that the melts originate from a deep mantle source that is similar to the mantle plume beneath Réunion, rather than the convecting upper mantle or sub-continental lithosphere. This confirms the existence of the Quathlamba mantle plume and importantly provides the first evidence in support of upwelling deep mantle beneath Southern Africa, helping to explain the regions elevation and abnormal heat flow.

Characterization of a galectin-like activity from the parasitic nematode, Haemonchus contortus, which modulates ovine eosinophil migration in vitro.

The development of eosinophilia is a characteristic feature of helminth infection, although the exact nature of the interaction between eosinophils and parasites remains to be fully defined. Previously, it has been reported that Haemonchus contortus and other nematodes produce eosinophil-specific chemoattractants. This paper describes studies aimed at isolating and identifying the factor(s) responsible. Initial studies showed that soluble extracts of infective larvae (L3) of H. contortus provoked a chemokinetic, rather than chemotactic, response in ovine bone marrow eosinophils in vitro. This activity was inhibited by lactose to a markedly greater extent than sucrose suggesting a galectin-like identity. Lactose affinity chromatography of soluble H. contortus extracts resulted in the isolation a specific bound fraction which retained biological activity. SDS-PAGE gel electrophoresis indicated a single Coomassie-stained band at between 31 and 41kDa. Subsequent, mass spectrometric analysis confirmed that the bound fraction contained a mixture of nematode galectins. The results confirm that H. contortus larvae produce several galectin-like proteins, at least one of which demonstrates eosinophil chemokinetic activity in vitro. The possibility of the parasite-derived factor mimicking the mammalian galectin-9, a known eosinophil chemokine, is discussed.

Background exposure rates of terrestrial wildlife in England and Wales.

It has been suggested that, when assessing radiation impacts on non-human biota, estimated dose rates due to anthropogenically released radionuclides should be put in context by comparison to dose rates from natural background radiation. In order to make these comparisons, we need data on the activity concentrations of naturally occurring radionuclides in environmental media and organisms of interest. This paper presents the results of a study to determine the exposure of terrestrial organisms in England and Wales to naturally occurring radionuclides, specifically (40)K, (238)U series and (232)Th series radionuclides. Whole-body activity concentrations for the reference animals and plants (RAPs) as proposed by the ICRP have been collated from literature review, data archives and a targeted sampling campaign. Data specifically for the proposed RAP are sparse. Soil activity concentrations have been derived from an extensive geochemical survey of the UK. Unweighted and weighted absorbed dose rates were estimated using the ERICA Tool. Mean total weighted whole-body absorbed dose rates estimated for the selected terrestrial organisms was in the range 6.9 x 10(-2) to 6.1 x 10(-1) microGy h(-1).

Stimulation of the in vitro migration of ovine eosinophils by factors derived from the sheep scab mite, Psoroptes ovis.

The ectoparasitic astigmatid mite Psoroptes ovis causes sheep scab, a highly contagious, severe allergic dermatitis associated with damage to the fleece and hide, loss of condition and occasional mortality. The scab lesion is characterized by a massive infiltration of eosinophils that begins very rapidly after infection. This paper reports the finding that mite-derived factors directly enhance the migration of ovine eosinophils in vitro. Significant (p < 0.01) and dose-dependent (r = 0.972 +/- 0.018 (SD)) activity was initially identified in whole mite extracts, by comparison with medium controls in an assay based on modified Boyden chambers and ovine bone marrow target cells. Similar pro-migratory activity (p < 0.005; r = 0.928 +/- 0.069 (SD)) was detected in washes containing mite excretory/secretory material. By direct comparison with migration ratios (n = 3) for defined chemotactic (rmeotaxin = 3.430 +/- 0.360 (SD)) and chemokinetic (rminterleukin-5 = 0.982 +/- 0.112 (SD)) stimuli it was determined that the activity in both mite extracts (0.992 +/- 0.038 (SD)) and mite washes (0.969 +/- 0.071 (SD)) was chemokinetic. Subsequent experiments (n = 3) in which live mites were incorporated directly into the in vitro assay system indicated that they produced factors that significantly (p < 0.001) enhanced eosinophil migration to a degree directly related to mite numbers (r = 0.993 +/- 0.005 (SD)). The identity of the factor(s) responsible is uncertain, but their presence suggests that mites may be capable of directly activating eosinophils in vivo, and raises the possibility that mites could directly influence, perhaps even initiate, the rapid early tissue eosinophilic response observed in experimental sheep scab infections.

Variable adaptation of molecular mechanisms in relation to the use of autologous striated muscle to augment myocardial function.

Significant recent advances in molecular biology and protein biochemistry have allowed the examination of muscle function at gene and protein level. This article reviews the variable adaptation of molecular mechanisms in striated muscle. The adaptation and transformation of fast skeletal muscle in response to chronic electrical stimulation may have considerable importance in relation to the use of autologous skeletal muscle to augment myocardial function.

Synaptic remodelling and astrocytic hypertrophy in rat cerebral cortex from early to late adulthood.

Ultrastructural observation of the molecular layer of the parietal cortex of rats, aged 3, 6, 10 and 17 months, revealed various atypical synaptic profiles besides typical synapses. The atypical synapses were frequently in the vicinity of hypertrophied astrocytic profiles, and were sometimes completely surrounded by astrocytic processes. The presynaptic terminal contained either no vesicles or a few small distorted vesicles. Vacant postsynaptic terminals were occasionally seen. The total surface area of astrocytic profiles and the numbers of atypical synapses increased significantly between 3 and 10 months. The astrocytic acquisition of degenerating terminals was repeatedly observed over this period. Since there was no decrease in total synaptic number at this age, the astrocytic phenomenon may represent a stage in a continuous cycle of synaptic loss and replacement in the normal brain. By 17 months, when total synapse numbers decrease, synaptic replacement may be less than optimal.

Perforated synapses and plasticity. A developmental overview.

Against a background of existing models relating perforated synapses to synaptic plasticity, the numerical density and frequency of perforated synapses in rat neocortex have been assessed from 1 d to 22 mo of age using the disector procedure, and changes in their morphology were assessed using 3-D computer reconstructions. The data point toward perforated and nonperforated synapses being separate synaptic populations from early in development, and with perforated synapses playing a part in the maintenance of neuronal postsynaptic density surface area from mid-adulthood onwards. This suggests that they play a crucial role in synaptic plasticity, although its nature may be different from that postulated by most recent workers.

Isolation of a novel protein kinase-encoding gene from yeast by oligodeoxyribonucleotide probing.

We have identified a novel protein kinase-encoding gene, KIN3, in the genome of the budding yeast Saccharomyces cerevisiae. The gene was isolated from a library of cloned genomic fragments by probing with an oligodeoxyribonucleotide mixture corresponding to part of a highly-conserved region in the catalytic domain of protein serine-threonine kinases. KIN3 is unique in the yeast genome, maps to chromosome VI and is actively expressed in mitotically dividing cells to produce a 1400 nucleotide (nt) message. The nt sequence of KIN3 predicts a protein product of 43.4 kDa which contains all of the conserved elements found in known protein serine-threonine kinases, although the organisation of these elements in the KIN3 gene product differs significantly from the consensus. The function of the KIN3-encoded protein kinase is unclear although it appears not to be essential for growth, conjugation or sporulation.

An analysis of contemporary morphological concepts of synaptic remodelling in the CNS: perforated synapses revisited.

Perforated synapses refer to a synaptic type found in the central nervous system. They are characterized by their large size and by a discontinuity of the postsynaptic density when viewed in transverse sections, and by a doughnut or horseshoe shape when viewed in en face views. Of recent morphological studies, one approach has followed their characteristics throughout development and maturity, while others have concentrated on their probable roles in activities including kindling, long-term potentiation, spatial working memory, differential rearing, and the functioning of neuroleptics. An assessment is made of the hypotheses and models that have proved determinative in the emergence of perforated synapses as being significant in synaptic plasticity. Their distribution and frequency are summarized, with emphasis on the importance of unbiased stereological procedures in their analysis. Using three-dimensional approaches various subtypes are recognized. Of these, a complex or fragmented subtype appears of especial significance in synaptic plasticity. Ideas regarding the life-cycle of perforated synapses are examined. The view that they originate from conventional, non-perforated synapses, enlarge, and subsequently split to give rise to a new generation of non-perforated synapses, is critically assessed. According to an alternative model, perforated and non-perforated synapses constitute separate populations from early in their development, each representing complementary forms of synaptic plasticity. An attempt is also made to discover whether synaptic studies on the human brain in normal aging and in Alzheimer's disease throw light on the role of perforated synapses in synaptic plasticity. The loss of synapses in Alzheimer's disease may include a loss of perforated synapses - of particular relevance for an understanding of certain neuropathological conditions.

Reducing overnight secretion of acid to heal duodenal ulcers. Comparison of standard divided dose of ranitidine with a single dose administered at night.

This study was undertaken to assess the clinical usefulness of a single nighttime dose of ranitidine in the short-term healing of duodenal ulcer. One hundred and nine patients with endoscopically diagnosed duodenal ulcer were randomly allocated to treatment with ranitidine, either 150 mg twice daily or 300 mg as a single nighttime dose for four weeks, in a prospective double-blind, double-placebo trial. Of the 102 patients who completed the study, 48 of 57 (84 percent) healed endoscopically on ranitidine 150 mg twice daily, and 43 of 45 (96 percent) healed on 300 mg at nighttime (Mantel-Haenszel test without continuity correction: X2 = 2.9, p = 0.09). One patient treated with ranitidine 150 mg twice daily had a transient episode of cholestatic hepatitis that did not necessitate stopping the drug; in this patient the ulcer healed after 28 days of treatment. There were no other unwanted effects in either group and no significant abnormal biochemical or hematologic changes. This study shows that ranitidine 300 mg given as one nighttime dose is as safe as 150 mg twice daily, and equally as effective. Three hundred milligrams at night appear to confer protection against the adverse effect of smoking in ulcer healing.

2'-substituted chalcone derivatives as inhibitors of interleukin-1 biosynthesis.

A series of 2'-substituted chalcone derivatives has been found to show potent inhibition of the production of IL-1 beta from human peripheral blood monocytes stimulated with lipopolysaccharide (LPS), with IC50 values in the 0.2-5.0-microM range. Some members of the series have also shown inhibition of septic shock induced in mice by injection of LPS, although with low potency. Qualitative structure-activity relationships have shown that the enone is required for activity, which may be mediated by conjugate addition of a biological nucleophile to the chalcone. Electron-poor aromatic rings beta to the ketone give enhanced potency. Although electronic effects in the other ring (directly attached to the ketone) are minimal, this ring must possess an ortho substituent for good activity without cytotoxicity, suggesting a degree of selectivity which would not be expected for simple, nonspecific alkylating agents.

Lithium entry into neural cells via sodium channels: a morphometric approach.

Rat cerebral cortical explants prepared from 18-day-old embryos were grown for 18 days in vitro. Cultures were exposed to Na+, Li+ and choline+ media, respectively, in the presence or absence of tetrodotoxin and/or veratridine, and processed for electron-microscopy. Veratridine (50 microM) induced an increase in summated and mean areas of neuronal profiles in Na+- and Li+-media but not in the choline+-medium: the summated perimeters did not change. The mean value of the neuronal form factor was significantly elevated following exposure to veratridine in a Na+- or Li+-dependent manner, indicating that the shape of the sectioned neuronal elements shifted towards an (ideal) circle. Qualitative assessment revealed an increased electron-lucency of the cytoplasm of neuronal profiles in Na+- and Li+-media containing veratridine. The veratridine-induced neuronal changes were inhibited by simultaneous addition of tetrodotoxin (1 microM) to the media. In the case of the glial cells, the values of the summated area and form factor did not change in the various experimental groups. The area of the extracellular space per unit area of sections significantly decreased in the Na+- and Li+-media following veratridine exposure; this did not occur in the choline+-medium. The results indicate a considerable swelling of the neuronal elements, reflecting cation, Cl- and water uptake following prolonged sodium channel activation in the presence of Na+ or Li+ ions. The quantitative ultrastructural data strongly suggests an entry of Li+ ions into cultured rat cerebral cells via sodium channels.

Nigral and cerebellar synaptic terminals in the intermediate and deep layers of the cat superior colliculus revealed by lesioning studies.

The presence of degenerating nigral and cerebellar synaptic terminals in the intermediate and deep layers of the cat superior colliculus was demonstrated by electron microscopy following lesions of the substantia nigra or brachium conjunctivum. The superior colliculus was taken for analysis 4-5 days after operation. Nigral terminals underwent a dark type of degeneration following kainic acid lesion of the pars reticulata of the substantia nigra. The majority of nigral degenerating terminals and axons were found in the stratum griseum intermediale with a few in the stratum griseum profundum. Two kinds of cerebellar terminals were distinguished by general appearances such as size, type of synaptic contact and type of synaptic vesicle and by the pattern of degenerative changes following electrical lesion of the brachium conjunctivum. Large elongated synaptic terminals 4-7 microns in diameter, were found mainly in the stratum griseum profundum. They often had double termination with conventional dendrites and with vesicles containing dendrites. This kind of terminal had a filamentous type of degeneration. A second type of degenerating cerebellar terminal, characterized by an electron-lucent type of degeneration, was predominantly located in the stratum griseum intermediale. These terminals were circular, about 4 microns in diameter, and did not have synaptic contact with vesicle-containing profiles. The finding of the two types of degenerating terminal after lesion of the brachium conjunctivum can be considered as evidence of the coexistence of at least two kinds of cerebellar terminals in the superior colliculus. The presence of nigral and cerebellar terminals in the intermediate and deep layers of the superior colliculus implicates the involvement of the substantia nigra and cerebellum in control of collicular visuomotor function.

The assay of gastrin using the perfused rat stomach.

1. A method is described for the bio-assay of gastric secretagogues using the perfused rat stomach in which the acid output can be readily and accurately quantified.2. This technique increases the sensitivity of the perfused rat stomach so that 10-20 ng of synthetic human gastrin I can be detected.3. It is possible to assay secretagogues, relative to a standard with fiducial limits of less than +/-30%.4. The use of this system is illustrated by assays comparing synthetic human gastrin I with pentagastrin, pure hog gastrin and gastrin added to plasma.