Zero-Bias Anti-Ohmic Behaviour in Diradicaloid Molecular Wires.

Open-shell materials bearing multiple spin centres provide a key route to efficient charge transport in single-molecule electronic devices. They have narrow energy gaps, and their molecular orbitals align closely to the Fermi level of the metallic electrodes, thus allowing efficient electronic transport and higher conductance. Maintaining and stabilising multiple open-shell states-especially in contact with metallic electrodes-is however very challenging, generally requiring a continuous chemical or electrochemical potential to avoid self-immolation of the open-shell character. To overcome this issue, we designed, synthesised, and measured the conductance of a series of bis(indeno) fused acenes, where stability is imparted by a close-shell quinoidal conformation in resonance with the diradical electronic configuration. We show here that these compounds have anti-ohmic behaviour, with conductance increasing with increasing molecular length, at an unprecedented rate and across the entire bias window ( ± 1 . 3 V ${\pm 1.3\ V}$ ). Density Functional Theory (DFT) calculations support our findings, showing the rapidly narrowing HOMO-LUMO gap, unique to these diradicaloid structures, is responsible for the observed behaviour. Our results provide a framework for achieving efficient transport in neutral compounds and demonstrate the promise that diradicaloid materials have in single-molecule electronics, owing to their great stability and unique electronic structure.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

Cortical spreading depression and migraine: new insights from imaging?

The possibility that spreading depression (SD) of cortical activity, a phenomenon observed in all vertebrates, causes the aura of migraine remains an open question in spite of nearly half a century of investigation. SD is also thought to be associated with the progressive neuronal injury observed during cerebral ischaemia. Thus, the ability to detect and investigate SD in humans might prove clinically significant. Animal studies of cortical spreading depression (CSD) have benefited greatly from the advent of relatively non-invasive imaging techniques. The use of these new imaging techniques for clinical studies will accelerate progress in this area of neurobiology.

Pharmacological magnetic resonance imaging: a new application for functional MRI.

Various methods, including functional magnetic resonance imaging (fMRI), have recently been developed to allow investigators to study functional activity in the living brain. Such techniques are now being used to investigate regionally specific brain activity associated with the administration of CNS-active drugs. fMRI in particular is increasingly recognized as being a relatively non-invasive way to perform pharmacological investigations in experimental animals, healthy human volunteers, and individuals with CNS disease. This use of fMRI, dubbed 'pharmacological MRI' or 'phMRI', holds the promise of providing relatively straightforward pharmacodynamic assays and can be used to establish brain-penetrability parameters, or dose-ranging information for novel therapeutic compounds.

Mapping the effects of the selective dopamine D2/D3 receptor agonist quinelorane using pharmacological magnetic resonance imaging.

Dopamine agonists with a high affinity for D2 and D3 receptors have a biphasic effect on rodent locomotion, inducing hypolocomotion at low doses and hyperlocomotion at higher doses. Controversy surrounds the role of the D3 receptor in mediating the hypolocomotor response to low agonist doses. This study examines patterns of neuronal activation induced by varying doses of the D2/D3 receptor agonist quinelorane using blood oxygen level dependent (BOLD) pharmacological magnetic resonance imaging (phMRI), and compares them with corresponding behavioural responses. Quinelorane (3 microg/kg) induced hypolocomotion in rats naive to the testing environment, and in phMRI experiments increased neuronal activity within the anterior olfactory nuclei, nucleus accumbens and islets of Calleja, regions containing a high density of D3 receptors. A 30 microg/kg dose of quinelorane resulted in biphasic locomotor effects, with initial hypolocomotion followed by sustained hyperlocomotion. phMRI indicated that this higher dose increased cerebral activity within limbic and olfactory regions, as did the lower drug dose, but induced additional activation in the caudate-putamen and globus pallidus, areas dense in D2 receptors but containing few D3 receptors. The more restricted pattern of activation at low agonist doses and close temporal relationship between behavioural and BOLD signal responses to quinelorane suggest that those nuclei most dense in D3 receptors play a key role in mediating the hypolocomotor effects of quinelorane. However, the presence of D3 receptors in activated brain regions may be coincidental, and further studies are required to show definitively which class of receptors mediates agonist-induced hypolocomotion. In contrast, the activation of D2 receptors within the striatum appears necessary for quinelorane-induced hyperlocomotion.

A prospective observational study of the use of the Proseal laryngeal mask airway for postpartum tubal ligation.

BACKGROUND: Though controversial, the risk of pulmonary aspiration during general anaesthesia in the immediate postpartum period appears low. The efficacy of the Proseal laryngeal mask airway was studied prospectively in a group of patients undergoing postpartum tubal ligation. METHODS: The Proseal laryngeal mask airway was employed for airway management in 90 fasted patients undergoing tubal ligation via minilaparotomy at least 8 h after normal vaginal delivery (mean 36.5, range 8-96 h). Gastric volume and pH were measured, using aspiration through a gastric tube. RESULT: Proseal laryngeal mask airway insertion was successful in all patients, requiring one attempt in 75 patients (83%). The median (range) leak pressure was 35 (23-40) cmH2O. Twenty-two patients (25%) had a leak pressure of 40 cmH2O or greater. Gastric tube placement was successful in all patients, described as easy in 79 (87%), and difficult in 11 (13%). The mean initial volume of gastric aspirate was 10.7 (0-64) mL and the final volume 15.6 (0-71) mL. The mean pH of the gastric aspirate was 2.6 (1.2-6.6). There were no incidents of suspected fluid regurgitation or aspiration, but two patients required intubation during surgery. Ten patients (11.1%) complained of sore throat in the recovery room, nine of which were described as mild. All patients reported being satisfied with their anaesthesia. CONCLUSION: The Proseal laryngeal mask airway provides an effective airway for general anaesthesia in fasted patients undergoing tubal ligation from 8 h after normal vaginal delivery. While the safety of an unprotected airway in this population remains uncertain, this study suggested a low risk of regurgitation, especially in the first 24 h post partum.

Familial Alzheimer's disease: progress and problems.

This paper reexamines recent epidemiologic and molecular genetic studies on the genetic basis of Alzheimer's Disease (AD). Careful analysis of the available epidemiologic data strongly suggests that at least a proportion of AD results from the inheritance of an autosomal dominant gene defect. However, studies of isolated families, of concordance rates in twins, and of risk for AD in relatives of AD probands yield conflicting data. While it is likely that much of the conflict can be ascribed to methodologic differences, it remains premature to conclude that all AD is transmitted as an autosomal dominant trait. Molecular genetic techniques hold the promise of isolation and characterization of the genetic defect(s) in familial AD (FAD). Recently, chromosome 21 has been implicated as the potential site of an autosomal dominant defect in some but not necessarily all FAD pedigrees. However, the results of recent genetic epidemiologic studies suggest that progress in the molecular genetic approach to AD will be difficult.

Role of prolactin in vitamin D metabolism and calcium absorption during lactation in the rat.

Intestinal calcium absorption and plasma levels of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) were measured in lactating and non-lacting rats and the effects of bromocriptine and exogenous prolactin treatment were evaluated. In lacting rats calcium absorption and plasma levels of parathyroid hormone, 1,25(OH)2D3 and alkaline phosphatase activity were significantly increased. Bromocriptine treatment significantly reduced the enhanced calcium absorption and levels of plasma 1,25(OH)2D3 and alkaline phosphatase but had no significant effect on plasma levels of parathyroid hormone. Prolactin administered with bromocriptine to lactating animals prevented all the changes observed with bromocriptine treatment alone. It was concluded that the increased plasma levels of prolacting during lactation lead to high plasma levels of 1,25(OH)2D3 which are responsible for the enhanced intestinal calcium absorption.

Caspase mRNA expression in a rat model of focal cerebral ischemia.

Proteins of the caspase family are involved in the signalling pathway that ultimately leads to programmed cell death (apoptosis), which has been reported to occur in some experimental models of stroke. In a previous paper we used quantitative reverse transcription and polymerase chain reaction (RT-PCR) to characterise changes in the mRNA expression of one member of this family, caspase-3, in a rat model of permanent focal ischemia. Here we have used this technique to study the expression of a further three caspases which are involved in different aspects of caspase signalling. Caspase-8, involved in Fas-mediated apoptosis, was upregulated in the cortex of ischemic rats. Caspase-11, which leads to the synthesis of the functional form of the cytokine interleukin-1 beta, also showed increased expression, but with a different temporal profile from caspase-8. In contrast, caspase-9, which forms part of the pathway signalling through the mitochondria, showed a decrease in expression. The expression of a further four caspases (1, 2, 6 and 7) has also been characterised in a simpler experiment. These caspases all showed distinctive patterns of expression following the induction of ischemia. These data lead us to conclude that caspase expression as a whole is under very strict transcriptional control in this model. Certain elements of caspase signalling, such as the Fas-induced pathway and the events upstream of IL-1 beta processing, are upregulated, while others are not. This may be due to some form of genetic program activated in response to ischemia in the brain and may highlight which biological pathways are modulated.