Haemostatic resuscitation in practice: a descriptive analysis of blood products administered during Operation HERRICK, Afghanistan.

INTRODUCTION: Life-threatening haemorrhage is the leading cause of potentially survivable injury in battlefield casualties. During Operation HERRICK (Afghanistan), mortality rates improved year on year due to a number of advances in trauma care, including haemostatic resuscitation. Blood transfusion practice has not previously been reported in detail during this period. METHODS: A retrospective analysis of blood transfusion at the UK role 3 medical treatment facility (MTF) at Camp Bastion between March 2006 and September 2014 was performed. Data were extracted from two sources: the UK Joint Theatre Trauma Registry (JTTR) and the newly established Deployed Blood Transfusion Database (DBTD). RESULTS: 3840 casualties were transfused 72 138 units of blood and blood products. 2709 adult casualties (71%) were fully linked with JTTR data and were transfused a total of 59 842 units. Casualties received between 1 unit and 264 units of blood product with a median of 13 units per patient. Casualties wounded by explosion required almost twice the volume of blood product transfusion as those wounded by small arms fire or in a motor vehicle collision (18 units, 9 units, and 10 units, respectively). More than half of blood products were transfused within the first 2 hours following arrival at the MTF. There was a trend towards balanced resuscitation with more equal ratios of blood and blood products being used over time. CONCLUSION: This study has defined the epidemiology of blood transfusion practice during Operation HERRICK. The DBTD is the largest combined trauma database of its kind. It will ensure that lessons learnt during this period are defined and not forgotten; it should also allow further research questions to be answered in this important area of resuscitation practice.

Drug design for ever, from hype to hope.

In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly. The recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. The next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data.

Energetic and kinematic consequences of weighting the distal limb.

REASON FOR PERFORMING STUDY: It is well known that adding a load to a horse's back increases its energetic costs of locomotion, but the magnitude of increase obtained by loading the most distal portion of limb has not been measured. OBJECTIVES: To measure oxygen consumption in horses with mass added to the back and hooves. Because such mass distribution alters inertial parameters of the limbs, kinematic measurements were made to quantify the magnitude of change in limb movement. METHODS: Steady-state oxygen consumption was measured in 6 horses with a load of 2.4 kg. The load was either carried on the back or distributed equally between the 4 limbs. Modified bell boots kept the mass at the level of P3. Horses trotted on a treadmill at speeds ranging from 2 to 5 m/sec (in 0.5 m/sec increments). High-speed (250 Hz) digital images were recorded in a sagittal plane and the positions of retroreflective markers located on standard positions on the limbs were digitised for kinematic analysis. RESULTS: Loading of the distal limbs produced a 6.7% increase in metabolic rate, an order of magnitude higher than when the mass was added over the back. Although the stride period was 2% longer in horses with loads on the distal limbs, time of contact and duty factor were not different. Distal limb loading increased the range of motion in hind- but not forelimbs. CONCLUSIONS: The costs of swinging the limbs in the horse are considerable and the addition of weights to the distal limb can have a profound effect on not only the energetics of locomotion but also the kinematics, at least in the hindlimb. POTENTIAL RELEVANCE: The use of weighted shoes, intended to increase animation of the gait, increases the metabolic effort of performance horses a disproportionate amount. The additional mass also increases the joint range of motion and, potentially, the likelihood of injury.

The cost of transport in an extended trot.

We hypothesised that trotters during an extended trot have lower energetic costs of locomotion (CT) than horses not bred for this behaviour. VO2 was measured as a function of speed in 7 Arabian horses (3 trained to extend their trotting speeds) and in 2 horses, of similar mass, bred to trot (Hackney). Both oxygen consumption and CT increased with speed and there was, contrary to our hypothesis, no difference between breeds. In Arabians at 6.5 m/s, CT had increased 25% above the CT at 5.0 m/s (normal transition speed). For Hackneys at 6.8 m/s, the CT was almost 35% higher. Stride frequencies increased linearly in all horses up to 5.0 m/s. At the canter at 5.0 m/s, the frequency increased 9% to 111 strides/min, but then increased minimally with speed. In the Hackneys and the Arabians that extended the trot, stride frequencies were approximately 102 and did not increase with speed. Stride length (SL) increased linearly with speed in both trotting and cantering horses, and cantering SL were lower than trotting (at 5.0 m/s, SL for trotting = 3.04 m and for cantering SL = 2.68 m). There were no differences between breeds in stride frequency or stride length. Extending the trot can have profound energetic requirements that could limit athletic performance and may lead to increased concussive impact on the limbs.

Shellac formulations to reduce epiphytic survival of coliform bacteria on citrus fruit postharvest.

Survival of the coliform bacteria Enterobacter aerogenes and Escherichia coli was monitored in a neutral carboxymethylcellulose formulation and in shellac formulations with various pH and concentrations of ethanol and the preservative paraben; populations were subsequently measured from the surface of citrus fruit coated with these formulations. Numbers of the two bacteria increased over 24 h from 10(6) CFU/ml to approximately 10(8) CFU/ml in the carboxymethylcellulose solution, but over this time numbers remained little changed in the neutral solution of shellac. The Enterobacter was more tolerant of alcohol over a 3-h period: although its numbers in a shellac solution with 10% ethanol dropped from more than 10(6) CFU/ml to just over 10(3) CFU/ml. E. coli and a third species. Klebsiella pneunoniae, declined toward the limit of detection (5 CFU/ ml) during this time. The addition of morpholine to increase the formulation pH to 9.0 caused numbers of bacteria to plummet to an undetectable level within 30 to 60 min. On Ruby Red grapefruit and Valencia oranges in storage at 13 degrees C numbers of E. aerogenes and E. coli declined over 2 weeks from 10(5) CFU/cm2 to less than 2.5 x 10(1), but most of the loss in numbers occurred within 1 day. Numbers remained significantly less on shellacked fruit compared with those applied in the carboxymethylcellulose coating, and a shellac coating prepared from a pH 9 solution was more toxic to these species than one in which 12% ethanol had been added to the neutral formulation. The addition of the preservative paraben in the basic shellac was further inhibitory.

Design and synthesis of a maximally diverse and druglike screening library using REM resin methodology.

A 3042 compound screening library was synthesized using a combination of two solid-phase technologies: REM resin methodology and Lewis acid promoted aminolysis. The exclusivity and structural diversity of the library were enhanced by using a highly divergent synthetic strategy involving 13 different scaffolds (9 of which were custom-made), five different types of resin-bound phenol derivatization chemistry (Mitsunobu, Suzuki, acylation, sulfonylation, and carbamoylation), and three different cleavage strategies (Hofmann elimination, AlCl(3)-promoted aminolysis, base-promoted esterolysis). This is the first example of a solid-phase Suzuki coupling involving a resin-bound aryl triflate being used for library synthesis. Computational analysis suggested that the compounds are likely to have favorable properties for CNS penetration. Analysis of the library by HPLC and MS suggested at least 90% of the sampled members were present in an average purity of approximately 70%. Encouragingly, hits have been identified from high-throughput screening of this library, such as compound 6, which has an affinity of 1.02 microM for the GlyT(2) transporter.

Alpha-amino acid phenolic ester derivatives: novel water-soluble general anesthetic agents which allosterically modulate GABA(A) receptors.

In the search for a novel water-soluble general anesthetic agent the activity of an alpha-amino acid phenolic ester lead, identified from patent literature, was markedly improved. In addition to improving in vivo activity in mice, good in vitro activity at GABA(A) receptors was also conferred. Within the series of compounds good enantioselectivity for both in vitro and in vivo activity was found, supporting a protein-mediated mechanism of action for anesthesia involving allosteric modulation of GABA(A) receptors. alpha-Amino acid phenolic ester 19, as the hydrobromide salt Org 25435, was selected for clinical evaluation since it retained the best overall anesthetic profile coupled with improved stability and water solubility. In the clinic it proved to be an effective intravenous anesthetic in man with rapid onset of and recovery from anesthesia at doses of 3 and 4 mg/kg.

Decontamination issues for chemical and biological warfare agents: how clean is clean enough?

The objective of this assessment is to determine what level of cleanup will be required to meet regulatory and stakeholder needs in the case of a chemical and/or biological incident at a civilian facility. A literature review for selected, potential chemical and biological warfare agents shows that dose information is often lacking or controversial. Environmental regulatory limits or other industrial health guidelines that could be used to help establish cleanup concentration levels for such agents are generally unavailable or not applicable for a public setting. Although dose information, cleanup criteria, and decontamination protocols all present challenges to effective planning, several decontamination approaches are available. Such approaches should be combined with risk-informed decision making to establish reasonable cleanup goals for protecting health, property, and resources. Key issues during a risk assessment are to determine exactly what constitutes a safety hazard and whether decontamination is necessary or not for a particular scenario. An important conclusion is that cleanup criteria are site dependent and stakeholder specific. The results of a modeling exercise for two outdoor scenarios are presented to reinforce this conclusion. Public perception of risk to health, public acceptance of recommendations based on scientific criteria, political support, time constraints, and economic concerns must all be addressed in the context of a specific scenario to yield effective and acceptable decontamination.

Theoretical frameworks for understanding and investigating the therapeutic relationship in psychiatry.

BACKGROUND: Mental health care is delivered through a relationship between a clinician and a patient. Although this therapeutic relationship is of central importance for mental health care, it appears to be relatively neglected in psychiatric research. Empirical research has for the most part adopted concepts and methods developed in psychotherapy and general medical practice. Hence, unpacking the presuppositions that have informed research on the therapeutic relationship to date may be a useful first step in developing this field. METHOD: A review of the literature was carried out. RESULTS: Six central theories are identified as framing the definitions and methods on this topic: role theory, psychoanalysis, social constructionism, systems theory, social psychology and cognitive behaviourism. To date, role theory, psychoanalysis and systems theory appear to be the frameworks most often applied in research in this field. Each perspective offers a unique emphasis in the analysis of the therapeutic relationship, which is reflected in the empirical work from each perspective discussed herein. CONCLUSIONS: None of the theories identified have been fully specified and comprehensively investigated in psychiatric settings. However, more than one approach may be used for thinking about relationships, depending on the treatment situation. Further specification and testing of the theories in psychiatric practice--taking account of the specific context--is warranted to underpin more pragmatic research. A stronger link between fundamental psychological and sociological research and applied health care research would advance our understanding of which elements of positive therapeutic relationships are instrumental in improving patient outcome and ultimately contribute to improving mental health care.

Non-depolarizing neuromuscular blocking activity of bisquaternary amino di- and tripeptide derivatives.

Herein we describe the synthesis of novel di- and tripeptide derivatives with two quaternary nitrogen groups attached and the biological testing of these compounds for neuromuscular blocking (NMB) activity in vitro and in vivo. The short peptide scaffold was selected because it offers potential for desired distance between the two pharmacophoric quaternary nitrogen groups, short duration of action, straightforward synthesis, and compatibility with an injectable formulation. From a small series of compounds 20c,e are identified as effective non-depolarizing NMB agents in vitro and in vivo in anesthetized cats and Rhesus monkeys with potencies similar to those of the clinical reference compounds rocuronium (4) and suxamethonium (2) (monkey ED(90) = 0.68, 0.23, 0.16, 5.04 micromol/kg, respectively). These new peptide derivatives 20c,e have similar potency and onset time but longer duration and slower recovery than the clinically used reference compounds. The structure-activity relationships described for this chemical series lead to the conclusion that the di- or tripeptide fragment can be regarded as an alternative template to the steroid or aliphatic ester of previously reported NMBs and within this tripeptide-derived series clog P correlates well with in vitro NMB activity.

Conformationally constrained anesthetic steroids that modulate GABA(A) receptors.

Various cyclic ether and other 3 alpha-hydroxyandrostane derivatives bearing a conformationally constrained hydrogen-bonding moiety were prepared. Their anesthetic potency and their binding affinity for GABA(A) receptors, measured by intravenous administration to mice and inhibition of [(35)S]TBPS binding to rat whole brain membranes, were compared with that of known anesthetic 3 alpha-hydroxypregnan-20-ones. Synthetic steroids with similar in vitro and in vivo activities to the endogenous 3 alpha-hydroxypregnan-20-ones all had an ether oxygen on the beta-face of the steroid D-ring. These results suggest that for optimal GABA(A) receptor modulation, the hydrogen bond-accepting substituent should be near perpendicular to the plane of the D-ring on the beta-face of the steroid.

Hot water treatment and insecticidal coatings for disinfesting limes of mealybugs (Homoptera: Pseudococcidae).

Hot water immersion and insecticidal coatings were tested to determine if they could be used to disinfest Persian limes, Citrus latifolia Tanaka, of the mealybug pests Planococcus citri Risso and Pseudococcus odermatti Miller & Williams. A 20-min 49 degrees C hot water immersion treatment is effective in killing mealybugs and all other arthropods tested found externally on limes, or under the calyx. No insects or mites were found to survive after the 20-min hot water treatment. In this test, 7,200 limes were treated with 1,308 insects killed and zero survivors. Treatment at 49 degrees C for 20 min did not significantly affect quality when treated fruit were compared with untreated control fruit. Four coatings were tested at a 3% rate: two petroleum-based oils (Ampol and Sunspray oil), a vegetable oil (natural oil), and a soap (Mpede). The coatings gave up to 94% kill (Ampol) of mealybugs, which is not sufficient to provide quarantine security. The coatings might be effective as a postharvest dip before shipment.

The effect of inducible nitric oxide synthase (iNOS) inhibition on smoke inhalation injury in sheep.

Recent studies on smoke inhalation injury have been focused on nitric oxide (NO) as an essential factor of progressive lung injury. We studied the effects of inducible nitric oxide synthase (iNOS) inhibition on inhalation injury in sheep. Sheep (n = 14) were prepared surgically for chronic study. After recovery period, the sheep received 48 breaths of cotton smoke. The animals were then randomised into two groups: MEG group [30 mg/kg mercaptoethylguanidine (MEG), selective inhibitor of iNOS and peroxynitrite scavenger, was given 1 h after injury and then 8 h for 41 h, n = 7] and control group (0.9% NaCl, n = 7). All animals were ventilated mechanically, and airway blood flow was measured using colored microspheres. In the control group, following significant increase in airway blood flow, deterioration in the PaO2/FiO2 ratio was observed. Whereas in the MEG group, it was not observed. In addition, the MEG group did not show significant increase in pulmonary vascular resistance and intrapulmonary shunt fraction. Lung wet/dry ratios, a marker of pulmonary edema, were significantly lower in the MEG group. At 48 h after injury, lung tissue-conjugated dienes, an index of lung oxidative tissue injury, were significantly lower in the MEG group than in the control group. Our data suggest that 1) iNOS-NO produced in the airway circulation plays a major role on the significant increase in airway blood flow, which may contribute to the spread of injury from injured airway to the lung parenchyma; 2) iNOS-NO induced in the pulmonary circulation contributes to the loss of hypoxic pulmonary vasoconstriction; and 3) iNOS-NO plays an important role on the lung oxidative tissue injury.

Expert system assisted pharmacophore identification

An expert system for automatic perception of pharmacophoric groups is presented. Important features include consideration of the protonation state at physiological pH and detection of potential tautomerism. This perception information is used in the generation of pharmacophores using clique detection.

Noradrenaline and nomega-monomethyl-L-arginine (L-NMMA): effects on haemodynamics and regional blood flow in healthy and septic sheep.

This prospective, non-randomized, controlled experimental study looks at the effects of N(omega)-monomethyl-L-arginine (L-NMMA) on haemodynamics, oxygen transport and regional blood flow in healthy and septic sheep, and compares these effects with those of noradrenaline (NA; norepinephrine). All sheep were chronically instrumented. Six sheep received L-NMMA (7 mg.kg(-1).h(-1)), six sheep received NA, and seven sheep received the carrier alone (0.9% NaCl). The NA dosage was continuously and individually adjusted to achieve the same increase in blood pressure as observed in matched sheep of the L-NMMA group (non-septic phase). Treatment was discontinued after 3 h. Sepsis was initiated and maintained by a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, the sheep were again challenged over a treatment period of 3 h with their previously assigned drug (septic phase). During the non-septic phase of the experiment, NA and L-NMMA both caused an increase in mean arterial pressure (MAP) through vasoconstriction. Ater 24 h of sepsis, all sheep developed a hyperdynamic circulatory state. While L-NMMA caused an increase in MAP through intense vasoconstriction, NA caused MAP to increase through a further elevation of the cardiac index. The NA dosage needed was significantly higher in the septic phase compared with the non-septic phase, reflecting a reduced vascular responsiveness to catecholamines during sepsis. Renal blood flow remained unchanged during either treatment in both the non-septic and the septic phases. Nevertheless, urine output increased during NA treatment in both the non-septic and the septic phases, while L-NMMA caused urine output to increase only under septic conditions.

Have the Cross-Informant Syndromes of the CBCL any practical value in identifying grouped ICD10 diagnoses?

120 children referred to a child and adolescent psychiatric service in a university clinic were studied with the aim of deriving predictors for grouped ICD10 diagnoses using the CBCL Cross-Informant-Syndromes (CISs). CIS7 (Delinquent Behaviour) and CIS8 (Aggressive Behaviour) were shown to significantly separate Disruptive Behaviour Disorders from all other disorders. As cross-validation, a separate clinical sample of 118 children from a similar service in another part of the country was used to see to what extent the CIS predictors from the first sample held up in the second sample. Positive and Negative Predictive Powers, all corrected for chance, confirmed that the Disruptive Behaviour Disorder group could be usefully separated from all other disorders using the Delinquent Behaviour and the Aggressive Behaviour Cross-Informant Syndrome scores. There was no good evidence that Emotional (Anxiety-Mood) Disturbance could be usefully separated in the same way using the Anxious-Depressed Syndrome (CIS3) or any other syndrome. Discriminant Function Analysis showed that there was no significant improvement in prediction when more elaborate linear combinations of the syndromes were used.

Population dynamics of postharvest decay antagonists growing epiphytically and within wounds on grapefruit.

ABSTRACT Coating formulations of shellac, sucrose ester, and cellulose were tested that support populations of bacterial and yeast antagonists of postharvest Penicillium decay of grapefruit. Surface populations of Pseudomonas syringae, P. fluorescens, and P. putida were stable between 10(3) and 10(4) CFU/cm(2) on shellacked fruit over 4 months at 13 degrees C, but numbers of the yeast Candida oleophila rose steadily from 2.35 x 10(3) to nearly 10(5). Through the first 15 days of cold storage, surface populations of P. syringae and C. oleophila were greater when applied to fruit within the pH 7.2 shellac than when applied by dipping fruit into an antagonist suspension and drying the fruit prior to shellacking; numbers were generally equivalent thereafter. Within wounds of shellacked fruit, populations of P. syringae were equal regardless of the method of application and increased from 10(4) to more than 1.2 x 10(7) CFU within 2 weeks. In contrast, numbers of C. oleophila in wounds over the first 2 weeks of storage were greater in fruit dipped and coated with shellac than when the antagonist was incorporated in this material; populations stabilized at approximately 6 x 10(6) CFU after 2 weeks. Incorporation of P. syringae and C. oleophila into ester and cellulose coatings, however, initially fostered greater numbers of both antagonists in wounds ( approximately 10(6) CFU) than did the preliminary dip application, and significant population differences persisted for several weeks. In cold storage, although application method did not affect the efficacy of P. syringae, C. oleophila was more efficacious after 3 and 4 months when applied in the shellac than when applied by a preliminary immersion and subsequent drying of fruit prior to shellacking.