High time resolution measurements of droplet evaporation kinetics and particle crystallisation.

A refined technique for observing the complete evaporation behaviour of free-falling droplets, from droplet generation to complete solvent evaporation, with ultra-high time resolution is introduced and benchmarked. High-resolution phase-delay stroboscopic imaging is employed to simultaneously resolve the evolving droplet morphology, geometric and aerodynamic diameters, throughout the evaporative lifetime with a user-controlled < µs timescale. This allows rapid, complex morphological changes, such as crystallisation events, to be clearly observed and the corresponding mechanisms to be inferred. The dried particles are sampled for offline SEM analysis and the observed morphologies compared to the inflight imaging. Density changes can be calculated directly from the deviation between the geometric and aerodynamic diameters. The full capabilities of the new technique are demonstrated by examination of the different evaporation behaviours and crystallisation mechanisms for aqueous sodium chloride droplets evaporating under different ambient relative humidity (RH) conditions. The crystallisation window, defined as the time taken from initial to complete crystallisation, is shown to be RH dependent, extending from 0.03 s at 20% RH and 0.13 s at 40% RH. The different crystallisation mechanisms observed during the experiments are also clearly reflected in the final structure of the dry particles, with multi-crystal structures produced at low RH compared to single-crystal structures at higher RH. It is anticipated that this technique will unlock measurements which explore the evaporation behaviour and crystallisation mechanisms for rapid, complex droplet drying events, and with increasingly non-ideal solutions, relevant to industrial applications.

A new approach to determine vapour pressures and hygroscopicities of aqueous aerosols containing semi-volatile organic compounds.

We present a new approach to study the equilibrium gas-particle partitioning of volatile and semi-volatile organic components in aqueous aerosol, deriving a correlational analysis method that examines and interprets simultaneous and correlated fluctuations in particle size and composition. From this approach, changes in particle size driven by organic component evaporation can be clearly resolved from size changes driven by hygroscopicity and fluctuations in environmental conditions. The approach is used to interpret measurements of the evaporation of semi-volatile organic components from binary aqueous/organic aerosol and the hygroscopic growth of involatile inorganic aerosol. The measurements have been made by the aerosol optical tweezers technique, which allows the simultaneous retrieval of particle size and refractive index with high accuracy. We suggest that this approach will be particularly valuable for investigating the thermodynamic behaviour of mixed component aqueous aerosol and will allow the accurate derivation of solution phase equilibrium properties that are prone to large uncertainties when measurements are made simply of the change in particle size with gas phase relative humidity.

Modelling the effect of first-wave COVID-19 on mental health services.

During the first wave of the COVID-19 pandemic it emerged that the nature and magnitude of demand for mental health services was changing. Considerable increases were expected to follow initial lulls as treatment was sought for new and existing conditions following relaxation of 'lockdown' measures. For this to be managed by the various services that constitute a mental health system, it would be necessary to complement such projections with assessments of capacity, in order to understand the propagation of demand and the value of any consequent mitigations. This paper provides an account of exploratory modelling undertaken within a major UK healthcare system during the first wave of the pandemic, when actionable insights were in short supply and decisions were made under much uncertainty. In understanding the impact on post-lockdown operational performance, the objective was to evaluate the efficacy of two considered interventions against a baseline 'do nothing' scenario. In doing so, a versatile and purpose-built discrete time simulation model was developed, calibrated and used by a multi-disciplinary project working group. The solution, representing a multi-node, multi-server queueing network with reneging, is implemented in open-source software and is freely and publicly available.

Step by step: reconstruction of terrestrial animal movement paths by dead-reckoning.

BACKGROUND: Research on wild animal ecology is increasingly employing GPS telemetry in order to determine animal movement. However, GPS systems record position intermittently, providing no information on latent position or track tortuosity. High frequency GPS have high power requirements, which necessitates large batteries (often effectively precluding their use on small animals) or reduced deployment duration. Dead-reckoning is an alternative approach which has the potential to 'fill in the gaps' between less resolute forms of telemetry without incurring the power costs. However, although this method has been used in aquatic environments, no explicit demonstration of terrestrial dead-reckoning has been presented. RESULTS: We perform a simple validation experiment to assess the rate of error accumulation in terrestrial dead-reckoning. In addition, examples of successful implementation of dead-reckoning are given using data from the domestic dog Canus lupus, horse Equus ferus, cow Bos taurus and wild badger Meles meles. CONCLUSIONS: This study documents how terrestrial dead-reckoning can be undertaken, describing derivation of heading from tri-axial accelerometer and tri-axial magnetometer data, correction for hard and soft iron distortions on the magnetometer output, and presenting a novel correction procedure to marry dead-reckoned paths to ground-truthed positions. This study is the first explicit demonstration of terrestrial dead-reckoning, which provides a workable method of deriving the paths of animals on a step-by-step scale. The wider implications of this method for the understanding of animal movement ecology are discussed.

Energetics of crossbridge phosphorylation and contraction in vascular smooth muscle.

Ca(2+)-dependent crossbridge phosphorylation is the primary mechanism governing crossbridge cycling in smooth muscle. A four-state crossbridge model in which phosphorylation is the only proposed regulatory mechanism was successful in predicting the mechanical properties of the swine carotid media including latch (sustained force with reduced crossbridge cycling). This model also predicts that the ATP consumption of crossbridge phosphorylation is approximately equal to that of crossbridge cycling and that ATP consumption will rise hyperbolically with increases in steady-state force. This review shows these predictions to be consistent with the available energetics data for the carotid media. The absolute energetic cost of covalent regulation is modest and less than the energy savings associated with latch. However, covalent regulation should reduce the total mechanical efficiency of smooth muscle relative to striated muscle.

Alcuronium kinetics and plasma concentration-effect relationship.

The kinetics and dynamics of the neuromuscular blocker alcuronium were investigated in 12 surgical patients who received bolus and infusion regimens. In six patients the duration of the infusion was sufficiently long so that a steady-state alcuronium plasma concentration was reached (mean SD, 0.80 +/- 0.23 micrograms/ml). In the remaining six patients a steady state was not reached but the alcuronium concentration at the end of the infusion was 0.91 +/- 0.39 micrograms/ml. Alcuronium kinetic parameters did not differ between the two groups or from those obtained previously after bolus doses. In six patients for whom sufficient alcuronium concentration-time response data were available over the 0 to 100% response range, various mathematic models were used to characterize the concentration-effect relationship. A dynamic model incorporating a separate effect compartment connected to the central compartment was found to be the most appropriate. The (mean +/- SD) rate constant for equilibration of alcuronium concentration and effect was found to be 0.24 +/- 0.11 min-1, whereas the steady-state concentration required to induce 95% paralysis was 0.91 +/- 0.35 micrograms/ml (mean +/- SD).

Altered d-tubocurarine disposition during cardiopulmonary bypass surgery.

Kinetics of the neuromuscular blocker d-tubocurarine (dTc) were investigated in 13 adult patients undergoing surgery involving cardiopulmonary bypass (CPB). Approximately 1 hr before CPB surgery, each received dTc as an intravenous bolus of 0.6 mg/kg and a maintenance infusion of 3 micrograms/kg/min. dTc plasma concentration-time data before CPB did not differ from those reported in normal surgical patients. There was an abrupt discontinuity in the plasma concentration-time profile with the onset of CPB, and both total and free plasma concentrations increased 400% during the period of CPB. Although computer simulations suggest that these rises in dTc plasma concentrations can be attributed to contraction in central compartment volume, there also was decreased renal and total plasma clearance of dTc together with a prolonged elimination 1 1/2, which suggests that clearance processes of dTc are also altered as a result of CPB. A 27% rise in dTc free fraction in plasma during CPB could be attributed to hemodilution associated with the CPB procedure itself. Lower doses of dTc will need to be used in patients undergoing surgery that involves CPB unless the concentration-effect relationship for dTc is so altered that higher concentrations are needed to elicit the same response as in normal patients.

Pharmacokinetic-pharmacodynamic relationships of morphine in neonates.

Morphine pharmacokinetics and pharmacodynamics (analgesia and sedation) were evaluated after continuous intravenous infusion of morphine in 19 neonates, both preterm and term, whose lungs were ventilated to relieve respiratory distress. Elimination half-life, total plasma clearance, and volume of distribution (mean +/- SD) were 9.6 +/- 3.0 hours, 2.55 +/- 1.65 ml/min/kg (area analysis) or 2.09 +/- 1.19 ml/min/kg (steady-state data), and 2.05 +/- 1.05 L/kg, respectively, and were not significantly different in preterm and term neonates. In neonates with adverse effects of morphine, the plasma clearance was decreased twofold. Mean morphine concentration required to produce adequate sedation in 50% of patients was found to be 125 ng/ml, but concentrations above 300 ng/ml may be associated with adverse effects of morphine. Morphine-6-glucuronide was not detected in the plasma of any neonate, which may explain why neonates require high plasma concentrations of unchanged morphine for sedation.

Gallamine disposition in open-heart surgery involving cardiopulmonary bypass.

Kinetics of gallamine, a neuromuscular blocker, were investigated in 22 adult patients undergoing surgery involving cardiopulmonary bypass (CPB). Approximately 60 min before CPB, 11 patients received 480 mg gallamine IV; the other 11 patients received an initial dose of 240 mg IV, followed by another 240 mg through the pump priming fluid at the start of CPB. In 14 of our patients, the time course of gallamine concentrations in the plasma before, during, and after CPB was similar to that in normal surgical patients, indicating little or no effect of cardiac disease or CPB. In the remaining patients, perturbations were not observed before CPB, but with its onset there were varying changes, typically, rises in gallamine concentration ranging from an alteration during the period of CPB only or during the elimination phase, to an alteration at all times after starting CPB. Although the mechanism for this rise in gallamine plasma concentrations during and after CPB is not known, computer simulations suggest that it is due to a contraction in blood volume or decreased tissue perfusion during the period of extracorporeal circulation. Gallamine disposition differed only moderately in our patients from that in control patients. Therefore, from a kinetic viewpoint, provided that renal function is not impaired, gallamine is not contraindicated in CPB surgery.

Hyperalgesia due to nerve injury: role of prostaglandins.

The hypothesis that prostaglandins contribute to hyperalgesia resulting from nerve injury was tested in rats in which the sciatic nerve was partially transected on one side. Subcutaneous injection of indomethacin (a classic inhibitor of cyclo-oxygenase) into the affected hindpaw relieved mechanical hyperalgesia for up to 10 days after injection. Subcutaneous injection of meloxicam or SC-58125 (selective inhibitors of cyclo-oxygenase-2) into the affected hindpaw also relieved mechanical hyperalgesia, but with a shorter time-course. Subcutaneous injection of SC-19220 (an EP1 prostaglandin receptor blocker) into the affected hindpaw produced significant relief of mechanical and thermal hyperalgesia. Comparable injections into the contralateral paw or abdomen had no effect on mechanical or thermal hyperalgesia, suggesting that the effects we observed were local rather than systemic. We conclude that prostaglandins, probably prostaglandin E1 or E2, contribute to the peripheral mechanisms underlying hyperalgesia following nerve injury. These data provide further evidence that inflammatory mediators contribute to neuropathic pain, and may warrant further study of peripherally administered non-steroidal anti-inflammatory drugs as a possible treatment for such pain in patients.

Clinical pharmacokinetics of the non-depolarising muscle relaxants.

Muscle relaxants are of great benefit to the anaesthetist as adjuncts to anaesthesia. These drugs are used to facilitate endotracheal intubation and to reduce muscle tone during surgery, and may also find application in assisting ventilator care in the intensive care situation. The pharmacological effect of the relaxants may be readily assessed by the anaesthetist by means of a variety of techniques to quantify muscular activity in response to electrical stimulation. A number of factors may modify the effects of the muscle relaxants including anaesthetic agents, hypothermia, patient age and disease status and a variety of drugs. The disposition kinetics of the muscle relaxants have been well characterised although information on protein binding and placental transfer is somewhat scanty. A common characteristic of their pharmacokinetics is multicompartmental behaviour. Clearance of the relaxants ranges from total elimination by the kidneys (gallamine) to substantial hepatic clearance (fazadinium), and thus their clearance may be adversely affected by renal or hepatic disease. Dosage regimens have been designed using knowledge of the disposition kinetics of the relaxants to provide for continuous adequate relaxation during prolonged surgical procedures. With the use of sophisticated pharmacokinetic and pharmacodynamic models good relationships have been demonstrated between plasma concentrations of the relaxants throughout the entire range of relaxant response.

Effect of the peripherally selective kappa-opioid agonist, asimadoline, on adjuvant arthritis.

1. Opioids, though widely used as analgesics, have not been seriously considered as therapy for rheumatoid arthritis. The present study evaluated the dose-effect and time-dependence relationships of a new peripherally selective kappa agonist, asimadoline, in rats with adjuvant arthritis. 2. The arthritis was assessed by a pooled severity index combining the comprehensive criteria of oedema, radiography and histological changes, in the hind limbs. Asimadoline was extremely effective in attenuating joint damage (by up to 80%) when administered parenterally (0.5 to 10 mg kg(-1) day(-1), i.p.) throughout the disease or during its early phase; treatment was less successful if confined to the latter stages. Ten fold higher doses were effective orally. 3. Equimolar doses of a peripherally-selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266, fully reversed the peripheral anti-arthritic effects of asimadoline (5 mg kg(-1) day(-1)), indicating that asimadoline acts through peripheral kappa-opioid receptors. However, an equivalent dose of MR2266 did not fully reverse the anti-arthritic effects of the highest dose of asimadoline (40 mg kg(-1) day(-1)), suggesting a loss of kappa-selectivity at this dose. 4. Asimadoline also exhibited analgesic effects (mechanical nociceptive thresholds) in arthritic but not non-arthritic rats, indicating that inflammation is necessary for asimadoline-induced analgesia. 5. These data confirm our previous findings that kappa-opioids possess anti-arthritic properties and that these effects are mediated via peripheral kappa-receptors. The present results are new in showing that the peripherally acting kappa-opioid agonist, asimadoline, is a potent anti-arthritic agent. Such novel drugs, essentially lacking central side effects, herald new treatments for rheumatoid arthritis.

The site of anti-arthritic action of the kappa-opioid, U-50, 488H, in adjuvant arthritis: importance of local administration.

1. Currently available pharmacological therapies treat arthritis inadequately. We have previously found that the kappa (kappa)-opioid, U-50,488H (trans-(+/-)- 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]- benzene-acetamide methane sulphonate), possesses anti-arthritic effects. In light of the finding that opioid receptors in the periphery are upregulated during inflammation, kappa-opioids may represent a novel therapy for arthritis. The primary aim and unique feature of the present study is to investigate whether opioids exert their anti-arthritic effects in the periphery. Thus, the dose-effect relationship of a kappa-opioid agonist, U-50,488H was compared after both local and distant administration. Further, we tested whether the anti-arthritic effects of this drug are stereospecific and receptor-mediated by use of opioid antagonists. 2. Using an adjuvant model of arthritis in male Lewis rats, arthritis was judged by oedema, radiography and histological changes in the contralateral ankle of the hind limb. Treatment with (+/-)-U-50,488H for 3 days during disease onset and 3 days during established disease significantly attenuated arthritis, but the effects of (+/-)-U-50,488H on radiology and histology varied according to treatment time. Administration of (+/-)-U-50,488H during disease onset had a more marked effect on radiography, suggesting that treatment with that drug should be started early to prevent progressive joint destruction. Further, it was found that (+/-)-U-50,488H, administered for 3 days during the disease onset, either by direct subcutaneous injection into the inflamed paw or at a more distant site into the back of the neck, dose-dependently attenuated arthritic damage as measured by an index which pooled all three variables. More importantly however, (+/-)-U-50,488H was approximately fourfold more potent as an 'anti-arthritic' agent after local compared to distant subcutaneous injection (ED50; local vs distant: 5.8 +/- 1.6 vs 19.5 +/- 0.8 mg kg-1). 3. Equivalent doses of the (-)-enantiomer (20 mg kg-1day-1) and the racemate (+/-) of U-50,488H (40 mg kg-1day-1), elicited a similar attenuation of arthritic parameters while the (+/-)-enantiomer exacerbated arthritis, suggesting that the anti-arthritic activity lies solely with the (-)-enantiomer. 4. Both the peripherally selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266 ((-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan), were able to reverse fully the peripheral anti-arthritic effects of U-50,488H, indicating that it exerts its effects through peripheral kappa-opioid receptors. 5. Taken together, these results not only confirm our previous findings that demonstrate anti-arthritic effects of U-50,488H but they indicate that the opioid attenuation of experimental arthritis is mediated via peripheral kappa-receptors in the arthritic joint. Peripherally acting kappa-opioid agonists should lead to new therapies for arthritis.

Aerosol therapy of influenza infections of mice and primates with rimantadine, ribavirin, and related compounds.

Ribavirin administered as small-article aerosols had significant therapeutic effect in the treatment of viral respiratory infections induced by influenza virus. The preliminary experiment using ribavirin to treat influenza infection in the squirrel monkey is encouraging. We expect to extend these experiments by initiating therapy at a later time to investigate the potential value of ribavirin in a clinical situation. Several derivatives of ribavirin are effective antiviral compounds. The tri-O-acetyl derivative appears to offer a potential advantage over ribavirin, although this cannot be stated with certainty since the data were obtained from separate experiments. Radiolabeling has been used as a means of measuring tissue concentration and clearance rates of various drugs. It is hoped that the use of labeled ribavirin and the tri-O-acetyl derivative will assist us in determining whether a depot of antiviral drug is created in pulmonary tissues after administration as a small-particle aerosol. These experiments are now in progress.

Zinc alleviates thermal hyperalgesia due to partial nerve injury.

Zinc has recently been shown to alleviate inflammatory hyperalgesia. In the present study, we showed that intrathecal, intraplantar or systemic injection of zinc chloride significantly relieved thermal hyperalgesia in rats with sciatic nerve injury. Alleviation of thermal hyperalgesia was dose dependent in each case, although higher doses were required for i.p. injections (ED50 = 13.6 nmol) than for intrathecal (ED50 = 0.05 nmol) or intraplantar injections (ED = 0.3 nmol). Neither intrathecal nor intraplantar zinc chloride influenced thermal nociception in normal rats without nerve injury. The results provide the first evidence that zinc alleviates neuropathic hyperalgesia.

Zinc alleviates thermal hyperalgesia due to partial nerve injury.

Zinc has recently been shown to alleviate inflammatory hyperalgesia. In the present study, we showed that intrathecal, intraplantar or systemic injection of zinc chloride significantly relieved thermal hyperalgesia in rats with sciatic nerve injury. Alleviation of thermal hyperalgesia was dose dependent in each case, although higher doses were required for i.p. injections (ED50 = 13.6 nmole) than for intrathecal (ED50 = 0.05 nmole) or intraplantar injections (ED50 = 0.3 nmole). Neither intrathecal nor intraplantar zinc chloride influenced thermal nociception in normal rats without nerve injury. The results provide the first evidence that zinc alleviates neuropathic hyperalgesia.

Effects of the peripherally selective kappa-opioid asimadoline, on substance P and CGRP mRNA expression in chronic arthritis of the rat.

We have previously shown that the kappa-opioid agonist, asimadoline, produces time-dependent changes in neuropeptide concentrations in the joints of rats with chronic arthritis. We hypothesized that asimadoline acts on peripheral terminals to modulate substance P (SP) release. To address this hypothesis, here we have examined neuropeptide expression in their source cells in dorsal root ganglia (DRG) that innervate the joint, as well as in non-neuronal tissue, after treatment with asimadoline. We found an increased production of SP and CGRP in untreated chronic arthritic animals which supports our previous finding of increased SP content in the joint. More importantly, the kappa-opioid asimadoline reduced the expression of both SP and calcitonin gene-related peptide-alpha (alpha-CGRP) in DRG cells but had no effect on the very low expression of neuropeptides in non-neuronal tissue. The fact that SP synthesis is attenuated by asimadoline accords with our hypothesis that the increased tissue levels of SP result from kappa-mediated pre-synaptic inhibition of release leading to augmented tissue stores. These in vivo data confirm literature findings that opioids inhibit SP release from peripheral endings of primary afferent fibres.

The source of coronary perfusion during partial bypass for extracorporeal membrane oxygenation (ECMO).

The proper siting of cannulas to return oxygenated blood to patients on long-term membrane oxygenator support is as yet undecided. This experimental study on adult sheep shows the problems of obtaining perfusion of the coronary arterial tree when blood is returned to the ascending aorta. Our 11 experiments demonstrate that the coronary arterial tree is perfused with blood ejected from the left ventricle except during very high bypass flows (85% bypass) or when the aortic valve is rendered incompetent.

Mammals and scrub typhus ecology in peninsular Malaysia.

The overall comparisons of habitats are given in (Table III). The habitats are arranged in order of extent of alterations by man, with the least disturbed at the top. The highest average blood isolation rates came from the least disturbed areas. The highest monthly maximal rickettsial isolation rates from blood and maximal prevalence rates of antibody per month were also obtained at Bukit Lanjan, the habitat least altered by activities of man. The lowest average blood isolation rate (6%) and the lowest monthly maximal rickettsial isolation and antibody prevalence rates were obtained at Bukit Mandol, the habitat most extensively and intensively altered by man. The intermediate habitats had intermediate rates. We caution anyone interpreting these observations, however, in terms of human disease, which seem to be associated with hyperendemic foci. Here we are not dealing with hyperendemicity from the standpoint of human disease, but present evidence of widespread endemicity from which hyperendemic foci may derive. Also, we have not yet identified the prevalent strains and do not know their infectivity to man.