Not So Innocent After All: Interfacial Chemistry Determines Charge-Transport Efficiency in Single-Molecule Junctions.

Most studies in molecular electronics focus on altering the molecular wire backbone to tune the electrical properties of the whole junction. However, it is often overlooked that the chemical structure of the groups anchoring the molecule to the metallic electrodes influences the electronic structure of the whole system and, therefore, its conductance. We synthesised electron-accepting dithienophosphole oxide derivatives and fabricated their single-molecule junctions. We found that the anchor group has a dramatic effect on charge-transport efficiency: in our case, electron-deficient 4-pyridyl contacts suppress conductance, while electron-rich 4-thioanisole termini promote efficient transport. Our calculations show that this is due to minute changes in charge distribution, probed at the electrode interface. Our findings provide a framework for efficient molecular junction design, especially valuable for compounds with strong electron withdrawing/donating backbones.

Spectrum of coagulation profiles in severely injured patients - a subgroup analysis from the fluids in resuscitation of severe trauma trial.

BACKGROUND: Trauma-induced coagulopathy (TIC) is a major contributing factor to worsening bleeding in trauma patients. The objective of this study is to describe the spectrum of coagulation profiles amongst severely injured patients. METHODS: This is a retrospective study of all patients with complete baseline TEG coagulation parameters collected prior to randomisation in the FIRST (fluids in resuscitation of severe trauma) trial between January 2007 and December 2009. Parameters recorded for this study included patient demographics, mechanism of injury, admission vital signs, lactate, base excess, coagulation studies prothrombin time (PT), international normalised ratio (INR), thromboelastography (TEG) parameters, volume, and type of fluids administered, volume of blood products administered, length of intensive care unit (ICU) stay and major outcomes. RESULTS: A total of 87 patients were included in this study, with a median injury severity score (ISS) of 20 and 57.5 had a penetrating injury mechanism. Coagulopathy was highly prevalent in this cohort, of which a majority (69%) was diagnosed with hypercoagulopathy and 24% had a hypocoagulopathy status on admission. There was no difference in age, gender and amount of pre-hospital fluids administered across the three groups. The median volume of blood products was higher in the hypocoagulopathy group, although not statistically significant. Overall, the 30-day mortality rate was 13%, with case fatalities occurring in only coagulopathic patients: hypercoagulopathy (15%) and hypocoagulopathy (10%). CONCLUSION: TIC is not an infrequent diagnosis in severely injured patients resulting in increased morbidity and mortality. Determining the coagulation profile using TEG at presentation in this group of patients may inform appropriate management guidelines in order to improve outcome.

The anion study: effect of different crystalloid solutions on acid base balance, physiology, and survival in a rodent model of acute isovolaemic haemodilution.

BACKGROUND: Commercially available crystalloid solutions used for volume replacement do not exactly match the balance of electrolytes found in plasma. Large volume administration may lead to electrolyte imbalance and potential harm. We hypothesised that haemodilution using solutions containing different anions would result in diverse biochemical effects, particularly on acid-base status, and different outcomes. METHODS: Anaesthetised, fluid-resuscitated, male Wistar rats underwent isovolaemic haemodilution by removal of 10% blood volume every 15 min, followed by replacement with one of three crystalloid solutions based on acetate, lactate, or chloride. Fluids were administered in a protocolised manner to achieve euvolaemia based on echocardiography-derived left ventrical volumetric measures. Removed blood was sampled for plasma ions, acid-base status, haemoglobin, and glucose. This cycle was repeated at 15-min intervals until death. The primary endpoint was change in plasma bicarbonate within each fluid group. Secondary endpoints included time to death and cardiac function. RESULTS: During haemodilution, chloride-treated rats showed significantly greater decreases in plasma bicarbonate and strong ion difference levels compared with acetate- and lactate-treated rats. Time to death, total volume of fluid administered: chloride group 56 (3) ml, lactate group 62 (3) ml, and acetate group 65 (3) ml; haemodynamic and tissue oxygenation changes were, however, similar between groups. CONCLUSIONS: With progressive haemodilution, resuscitation with a chloride-based solution induced more acidosis compared with lactate- and acetate-based solutions, but outcomes were similar. No short-term impact was seen from hyperchloraemia in this model.

A randomised comparison of bolus phenylephrine and ephedrine for the management of spinal hypotension in patients with severe preeclampsia and fetal compromise.

BACKGROUND: Studies in healthy patients undergoing elective caesarean delivery show that, compared with phenylephrine, ephedrine used to treat spinal hypotension is associated with increased fetal acidosis. This has not been investigated prospectively in women with severe preeclampsia. METHODS: Patients with preeclampsia requiring caesarean delivery for a non-reassuring fetal heart tracing were randomised to receive either bolus ephedrine (7.5-15mg) or phenylephrine (50-100µg), to treat spinal hypotension. The primary outcome was umbilical arterial base excess. Secondary outcomes were umbilical arterial and venous pH and lactate concentration, venous base excess, and Apgar scores. RESULTS: Among 133 women, 64 who required vasopressor treatment were randomised into groups of 32 with similar patient characteristics. Pre-delivery blood pressure changes were similar. There was no difference in mean [standard deviation] umbilical artery base excess (-4.9 [3.7] vs -6.0 [4.6] mmol/L for ephedrine and phenylephrine respectively; P=0.29). Mean umbilical arterial and venous pH and lactate concentrations did not significantly differ between groups (7.25 [0.08] vs 7.22 [0.10], 7.28 [0.07] vs 7.27 [0.10], and 3.41 [2.18] vs 3.28 [2.44] mmol/L respectively). Umbilical venous oxygen tension was higher in the ephedrine group (2.8 [0.7] vs 2.4 [0.62]) kPa, P=0.02). There was no difference in 1- or 5-min Apgar scores, numbers of neonates with 1-min Apgar scores <7 or with a pH <7.2. CONCLUSIONS: In patients with severe preeclampsia and fetal compromise, fetal acid-base status is independent of the use of bolus ephedrine versus phenylephrine to treat spinal hypotension.

Maternal cardiac output response to colloid preload and vasopressor therapy during spinal anaesthesia for caesarean section in patients with severe pre-eclampsia: a randomised, controlled trial.

We examined the haemodynamic effects of colloid preload, and phenylephrine and ephedrine administered for spinal hypotension, during caesarean section in 42 women with severe early onset pre-eclampsia. Twenty patients with pre-delivery spinal hypotension were randomly allocated to receive an initial dose of either 50 µg phenylephrine or 7.5 mg ephedrine; the primary outcome was percentage change in cardiac index. After a 300-ml colloid preload, mean (SD) cardiac index increased from 4.9 (1.1) to 5.6 (1.2) l.min-1 .m-2 (p < 0.01), resulting from an increase in both heart rate, from 81.3 (17.2) to 86.3 (16.5) beats.min-1 (p = 0.2), and stroke volume, from 111.8 (19.0) to 119.8 (17.9) ml (p = 0.049). Fourteen (33%) and 23 (54.8%) patients exhibited a stroke volume response > 10% and > 5%, respectively; a significant negative correlation was found between heart rate and stroke volume changes. Spinal hypotension in 20 patients was associated with an increase from baseline in cardiac index of 0.6 l.min-1 .m-2 (mean difference 11.5%; p < 0.0001). After a median [range] dose of 50 [50-150] µg phenylephrine or 15 [7.5-37.5] mg ephedrine, the percentage change in cardiac index during the measurement period of 150 s was greater, and negative, in patients receiving phenylephrine vs. ephedrine, at -12.0 (7.3)% vs. 2.6 (6.0)%, respectively (p = 0.0001). The percentage change in heart rate after vasopressor was higher in patients receiving phenylephrine, at -9.1 (3.4)% vs. 5.3 (12.6)% (p = 0.0027), as was the change in systemic vascular resistance, at 22.3 (7.5) vs. -1.9 (10.5)% (p < 0.0001). Phenylephrine effectively reverses spinal anaesthesia-induced haemodynamic changes in severe pre-eclampsia, if left ventricular systolic function is preserved.

Volume therapy in trauma and neurotrauma.

Volume therapy in trauma should be directed at the restitution of disordered physiology including volume replacement to re-establishment of tissue perfusion, correction of coagulation deficits and avoidance of fluid overload. Recent literature has emphasised the importance of damage control resuscitation, focussing on the restoration of normal coagulation through increased use of blood products including fresh frozen plasma, platelets and cryoprecipitate. However, once these targets have been met, and in patients not in need of damage control resuscitation, clear fluid volume replacement remains essential. Such volume therapy should include a balance of crystalloids and colloids. Pre-hospital resuscitation should be limited to that required to sustain a palpable radial artery and adequate mentation. Neurotrauma patients require special consideration in both pre-hospital and in-hospital management.

An infected enlarging abdominal aortic aneurysm after acute cholecystitis.

INTRODUCTION: An abdominal aortic aneurysm (AAA) infection is rare and can be difficult to manage, with high morbidity and mortality. We present a patient who suffered an infected AAA after undergoing a laparoscopic cholecystectomy and discuss the surgical management options. PRESENTATION OF CASE: A 69-year-old male presents with a rapidly enlarging AAA 4 weeks following laparoscopic cholecystectomy. He was managed with open debridement, washout and repair of the aneurysm, but suffered ongoing sequelae of Escherichia coli sepsis. DISCUSSION: The options for surgical management of infected AAA include open, endovascular and combined approaches. Recent papers report successful use of endovascular repair of infected AAAs but this is an ongoing area of research. CONCLUSION: Infection of an AAA is associated with high mortality and long-term morbidity and requires optimal treatment. Surgical options include open debridement and repair, endovascular aneurysm repair (EVAR) or a combined approach.

Efficacy of VBHOM to predict outcome following major lower limb amputation.

PURPOSE: This study tests an existing Vascular Biochemistry and Haematology Outcome Model (VBHOM) on independent data and presents further refinements to the model. METHODS: Data from 306 patients who underwent lower limb amputation over a 4-year period were collated. Urea, creatinine, sodium, potassium, hemoglobin, white cell count, albumin, age, gender, mode-of-admission, and short-term mortality events were extracted from the database. This study tests an existing model and trains a new model for predicting mortality using forward stepwise logistic regression. RESULTS: The existing model suggests a significant lack of fit (c-index = 0.665, P = .04). For the exception of gender and mode-of-admission, all predictor variables had significant univariate associations with short-term mortality (P < .05). The refined model included age, sodium, potassium, creatinine, and albumin and had good discriminatory power (c-index = 0.8, no evidence of lack of fit, P = .616). CONCLUSIONS: Our simplified model had good predictive ability and suggests redundancy in input variables used by the existing models.

Effects of Alzheimer's disease transgenes on neurochemical expression in the mouse brain determined by ¹H MRS in vitro.

Transgenic models of human disease can be used to understand pathology and to discover biomarkers of disease presence, progression and response to therapy. Here we report a study of longitudinal metabolic differences between TASTPM transgenic Alzheimer's disease (AD) mice and their wild type counterparts using (1)H magnetic resonance spectroscopy (MRS) to look for potential biomarkers for use in AD research and drug discovery. Chloroform methanol extractions were performed on the brains of mice aged between 3 and 18 months. (1)H MR spectra were recorded from the aqueous fractions. Absolute metabolite concentrations, determined from resonance integrals relative to an internal standard, were analysed by 2-way ANOVA (genotype x age). Significant effects of age alone were identified for creatine, glutamine and total choline-containing compounds. There was a marked increase in creatine in the oldest (15-18 mo) TASTPM mice. The increase in creatine was unexpected and may be caused by osmotic stress in older animals as plaque load increases. Care should be taken when using creatine as a reference metabolite during scans of these animals in vivo. A significant effect of genotype alone was identified for myo-inositol (MI), which was higher in TASTPM mice at all ages. Succinate, glycerophosphocholine and choline all showed significant effects of age and genotype. No significant effects were detected in N-acetylaspartate (NAA) levels. Increased MI could be a marker of gliosis or microglial activation in TASTPM mice, but the absence of an age dependence for MI levels means it may be a biomarker of disease, but not of disease progression. Decreased succinate is indicative of disrupted neuronal energy metabolism, an effect that has been seen in human AD.

Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma).

BACKGROUND: The role of fluids in trauma resuscitation is controversial. We compared resuscitation with 0.9% saline vs hydroxyethyl starch, HES 130/0.4, in severe trauma with respect to resuscitation, fluid volume, gastrointestinal recovery, renal function, and blood product requirements. METHODS: Randomized, controlled, double-blind study of severely injured patients requiring >3 litres of fluid resuscitation. Blunt and penetrating trauma were randomized separately. Patients were followed up for 30 days. RESULTS: A total of 115 patients were randomized; of which, 109 were studied. For patients with penetrating trauma (n=67), the mean (sd) fluid requirements were 5.1 (2.7) litres in the HES group and 7.4 (4.3) litres in the saline group (P<0.001). In blunt trauma (n=42), there was no difference in study fluid requirements, but the HES group required significantly more blood products [packed red blood cell volumes 2943 (1628) vs 1473 (1071) ml, P=0.005] and was more severely injured than the saline group (median injury severity score 29.5 vs 18; P=0.01). Haemodynamic data were similar, but, in the penetrating group, plasma lactate concentrations were lower over the first 4 h (P=0.029) and on day 1 with HES than with saline [2.1 (1.4) vs 3.2 (2.2) mmol litre⁻¹; P=0.017]. There was no difference between any groups in time to recovery of bowel function or mortality. In penetrating trauma, renal injury occurred more frequently in the saline group than the HES group (16% vs 0%; P=0.018). In penetrating trauma, maximum sequential organ function scores were lower with HES than with saline (median 2.4 vs 4.5, P=0.012). No differences were seen in safety measures in the blunt trauma patients. CONCLUSIONS: In penetrating trauma, HES provided significantly better lactate clearance and less renal injury than saline. No firm conclusions could be drawn for blunt trauma. STUDY REGISTRATION: ISRCTN 42061860.

Is magnesium sulfate by the intrathecal route efficient and safe?

The polypharmacological approach to the treatment of postoperative pain has become routine in an attempt to minimize the adverse side effects of opioids. Magnesium sulphate is a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor and thus can modify nociceptive modulation. Intravenous administration of magnesium sulphate can improve postoperative analgesia and decrease the requirement for postoperative opiates, but the effects are inconsistent and have not been reliably accompanied by a reduction in the incidence of morphine-related adverse events. Several studies have shown that the administration of magnesium by the intrathecal route is safe and, in combination with opiates, extends the effect of spinal anaesthesia in both animal and human studies. The analysis of these studies justifies further investigation of the use of magnesium sulphate by the intrathecal route.

Comparison between pulse waveform analysis and thermodilution cardiac output determination in patients with severe pre-eclampsia.

BACKGROUND: This study compared cardiac output (CO) measurements derived from pulse waveform analysis with values obtained by thermodilution (TD), in patients with post-partum complications of severe pre-eclampsia. METHODS: Eighteen patients were recruited, 24-96 h post-delivery. After central venous calibration of the pulse waveform analysis monitor (LiDCOplus), CO readings were compared with those obtained by the TD method and repeated twice at 15 min intervals. The comparison was repeated after peripheral venous calibration. Further comparisons were made in eight patients at 120 and 240 min after peripheral venous calibration. RESULTS: Data were pooled for measurements at 0, 15, and 30 min after calibration. For the comparison between TD and LiDCOplus using central venous calibration, TD exhibited a significant positive bias of 0.58 litre min⁻¹ [95% confidence interval (CI): 0.77 to 0.39]. After peripheral venous calibration, there was no significant bias [0.16 litre min⁻¹ (95% CI: -0.37 to 0.06)]. The estimated limits of agreement for central and peripheral venous calibrations were -2.12 to 0.96 and -1.50 to 1.20 litre min⁻¹, respectively. When comparing LiDCOplus and TD, there was no time-based effect at 120 or 240 min post-peripheral calibration. CONCLUSIONS: Central and peripheral venous calibrations of the LiDCOplus monitor were associated with clinically insignificant bias when compared with TD. Limits of agreement were within the recommendation of 30% for acceptance of a new CO technique when compared with current reference methods. This form of minimally invasive CO monitoring may have a valuable role in obstetric critical care.

The effect of low molecular weight heparin (enoxaparin) on enhanced coagulation induced by crystalloid haemodilution.

The purpose of this study was to establish whether a low molecular weight heparin (enoxaparin) attenuated or abolished the enhanced coagulation induced by crystalloid fluid therapy. Twenty young, healthy male volunteers were injected subcutaneously with either enoxaparin 40 mg or saline on two separate occasions one week apart, in a randomised, blinded study. Twelve hours later, a blood sample was taken for thrombelastography analysis and haematocrit. Saline 14 ml.kg⁻¹ was then infused over thirty minutes and thrombelastography and haematocrit measurements repeated. There was a significant post-dilutional difference in the alpha angle (p = 0.002) and k-time (p = 0.001) between the two groups. There was a trend towards reduced shortening of r-time in the enoxaparin group compared to the saline control (p = 0.18). The findings suggest that enoxaparin diminished acceleration of clot formation due to haemodilution.

Is it safe to ligate the left renal vein during open abdominal aortic aneurysm repair?

BACKGROUND: Open repair of juxta-renal abdominal aortic aneurysms (AAA) sometimes involves the ligation and division of the left renal vein (LRV). Some surgeons advocate repair, but this is not common practice. The aim was to study the effect of LRV ligation on renal function. METHODS: A retrospective audit of all open AAA repairs between February 2004 and September 2007 in our unit was completed. Pre- and postoperative renal function was assessed with the estimated glomerular filtration rate (eGFR), using an established formula. RESULTS: Two hundred sixty-one open AAA repairs were performed in the study period. The LRV was ligated in 18.8%; mean age was 75.5 years, 35 were men, mean AAA diameter was 7.8 cm, there were 7 elective, 22 urgent, and 19 emergency AAA repairs. Renal function with LRV ligated was compared with the 212 patients without LRV ligation by independent samples t-testing. The baseline mean serum creatinine and glomerular filtration rate in the LRV ligated group were 115.1 micromol/L and 60.6, respectively, which were similar to the LRV not ligated group (p > 0.05). The renal function at postoperative day 1, day 7, and weeks 2-6 was similar in the two groups (p > 0.05). The postoperative renal function on day 1 was significantly worse compared to baseline (p < 0.05), but not at day 7 and weeks 2-6 (p > 0.05). CONCLUSION: In patients undergoing LRV ligation, there is an initial drop in renal function which improves over 2-6 weeks. At each stage, the renal function is similar to patients in whom the LRV is not ligated. LRV ligation is safe during open AAA repair.

Magnesium in obstetrics.

Magnesium is a critical physiological ion, and magnesium deficiency might contribute to the development of pre-eclampsia, to impaired neonatal development and to metabolic problems extending into adult life. Pharmacologically, magnesium is a calcium antagonist with substantial vasodilator properties but without myocardial depression. Cardiac output usually increases following magnesium administration, compensating for the vasodilatation and minimising hypotension. Neurologically, the inhibition of calcium channels and antagonism of the N-methyl-d-aspartic acid (NMDA) receptor raises the possibility of neuronal protection, and magnesium administration to women with premature labour may decrease the incidence of cerebral palsy. It is the first-line anticonvulsant for the management of pre-eclampsia and eclampsia, and it should be administered to all patients with severe pre-eclampsia or eclampsia. Magnesium is a moderate tocolytic but the evidence for its effectiveness remains disputed. The side effects of magnesium therapy are generally mild but the major hazard of magnesium therapy is neuromuscular weakness.