Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer.

Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered.

Limitations in Rechargeability of Li-O2 Batteries and Possible Origins.

Quantitative differential electrochemical mass spectrometry (DEMS) is used to measure the Coulombic efficiency of discharge and charge [(e(-)/O2)dis and (e(-)/O2)chg] and chemical rechargeability (characterized by the O2 recovery efficiency, OER/ORR) for Li-O2 electrochemistry in a variety of nonaqueous electrolytes. We find that none of the electrolytes studied are truly rechargeable, with OER/ORR <90% for all. Our findings emphasize that neither the overpotential for recharge nor capacity fade during cycling are adequate to assess rechargeability. Coulometry has to be coupled to quantitative measurements of the chemistry to measure the rechargeability truly. We show that rechargeability in the various electrolytes is limited both by chemical reaction of Li2O2 with the solvent and by electrochemical oxidation reactions during charging at potentials below the onset of electrolyte oxidation on an inert electrode. Possible mechanisms are suggested for electrolyte decomposition, which taken together, impose stringent conditions on the liquid electrolyte in Li-O2 batteries.

Solvents' Critical Role in Nonaqueous Lithium-Oxygen Battery Electrochemistry.

Among the many important challenges facing the development of Li-air batteries, understanding the electrolyte's role in producing the appropriate reversible electrochemistry (i.e., 2Li(+) + O2 + 2e(-) ↔ Li2O2) is critical. Quantitative differential electrochemical mass spectrometry (DEMS), coupled with isotopic labeling of oxygen gas, was used to study Li-O2 electrochemistry in various solvents, including carbonates (typical Li ion battery solvents) and dimethoxyethane (DME). In conjunction with the gas-phase DEMS analysis, electrodeposits formed during discharge on Li-O2 cell cathodes were characterized using ex situ analytical techniques, such as X-ray diffraction and Raman spectroscopy. Carbonate-based solvents were found to irreversibly decompose upon cell discharge. DME-based cells, however, produced mainly lithium peroxide on discharge. Upon cell charge, the lithium peroxide both decomposed to evolve oxygen and oxidized DME at high potentials. Our results lead to two conclusions; (1) coulometry has to be coupled with quantitative gas consumption and evolution data to properly characterize the rechargeability of Li-air batteries, and (2) chemical and electrochemical electrolyte stability in the presence of lithium peroxide and its intermediates is essential to produce a truly reversible Li-O2 electrochemistry.

The contribution of donor management and modified cold blood lung perfusate to post-transplant lung function.

BACKGROUND: Donor organ availability remains the major limiting factor in the treatment of patients with end-stage lung disease by lung transplantation. Maximising the use of available organs is therefore crucial. Details available at the time of organ referral may give a misleading impression of their quality. Intensive donor management may improve the quality of the organs thereby improving the quality of the outcome. METHODS: We performed 56 heart-lung and 5 double lung transplants between November 1990 and September 1993; 49 had adequate documentation for analysis. All organs were preserved with modified cold blood solution with an ischemic time of 197 (117-297) minutes. Assessment of lung function post-implantation was performed using an acute lung injury score as this gives a more accurate indication of overall lung function. Donors were treated intensively by bronchoscopy, optimal fluid management and appropriate lung expansion. RESULTS: Careful management improved donor quality so that the alveolar-arterial oxygen gradient fell significantly from 185 (+/-20) mmHg at arrival to 80 (+/-11) mmHg (p < .0001) immediately prior to harvesting 190 minutes later. This improvement was maintained following harvesting using the modified cold blood preservation solution so that lung injury was assessed as "mild" according to the acute lung injury criteria post-transplantation. There was one instance of primary lung failure following transplantation which was neither related to the quality of the organ at harvesting nor to the method of lung preservation. CONCLUSIONS: Intensive donor management significantly improves the quality of donor organs, providing an improvement in immediate post-transplantation lung function. This improvement is maintained using modified cold blood lung preservation solution.

Plasma oxygen during cardiopulmonary bypass: a comparison of blood oxygen levels with oxygen present in plasma lipid.

1. Although not often appreciated, it is a fact that molecular oxygen is more soluble in lipids than in aqueous solution. We have recently developed a method to monitor oxygen within the lipid content of plasma. Monitoring plasma oxygen is one essential element during open heart surgery using a cardiopulmonary bypass pump and oxygenator. Currently oxygen is monitored electrochemically and is based upon monitoring the partial pressure of oxygen in a gas equilibrated with whole blood. 2. To determine the relative importance of lipid-associated oxygen in blood and assess the potential use of such a measurement we present comparisons of changes in oxygen associated with whole blood and lipid content of plasma before, during and after cardiac surgery. 3. In a limited number of patients studied (n = 28), aged between 34 and 86 years, oxygen in lipid increased with decreased extracorporeal blood temperature during cardiopulmonary bypass, increased in proportion to oxygen supplied and appeared to be a better monitor of oxygen than conventional electrochemical systems currently in use. Oxygen associated with whole blood and plasma lipid was markedly below normal on aortic declamping after cardiopulmonary bypass, suggesting an hypoxic episode at this point. Levels of oxygen in the lipid phase of plasma returned to normal presurgical values 6-8 h after surgery. 4. Calculation of the concentration of lipid-associated oxygen present in plasma suggests that plasma lipids contain up to 25% of that typically ascribed to haemoglobin. Thus, we suggest that monitoring lipid-associated oxygen may prove a better alternative to current methods of measuring oxygen status. Furthermore, we suggest that plasma lipid is a hitherto unsuspected pool of circulating oxygen which may play a significant role in tissue oxygen supply.

Convective warming after hypothermic cardiopulmonary bypass.

In a randomized, controlled study, we found that convective warming after hypothermic cardiopulmonary bypass did not accelerate the rate of warming of the body core or the time to tracheal extubation. The relationship between body core and shell temperature, however, was affected. In all patients inadequate time spent rewarming on cardiopulmonary bypass prolonged body core warming time and time to tracheal extubation. Rate of warming of body core was inversely related to body mass index. Convective warming was delivered using BairHugger (Augustine Medical Inc., MN, USA) and Warm Touch (Mallinckrodt Medical UK Ltd, Northampton, UK) blankets. There was no difference between the performance of each blanket when powered by the BairHugger 500 power unit set at its medium setting of 38 degrees C, and when chest drain and radial artery cannulation sites were left exposed for observation.

Another look at neurological rehabilitation.

Advances in neurophysiological research over the past 20 years have led to dramatic changes in the understanding of the neural control of movement. These newer concepts have directed attention towards possibilities for motor recovery previously discounted. They also imply that changes in health care delivery may be necessary in order to take advantage of the recovery process and achieve maximum potential. If the neurologically disabled are to benefit from the advances of science, and if physical therapy practitioners are to reach and maintain scientific credibility, some fundamental changes in clinical thinking and practice seem indicated. This article discusses some implications for the practice of physical therapy in neurology.

Learning during general anaesthesia: implicit recall after methohexitone or propofol infusion.

Forty-four patients undergoing coronary artery surgery were allocated randomly to receive an infusion of propofol or methohexitone as a hypnotic supplement to a fentanyl-based anaesthetic technique. A taped message was played to the patients, consisting of 10 words associated with prompt sentences and a suggestion for a specific postoperative behavioural response. Twenty patients (10 propofol and 10 methohexitone) (perioperative group) were exposed to the taped message during surgery and in the immediate postoperative period and the other 24 patients (postoperative group) were exposed to the tape only in the postoperative period, after return to the intensive care unit (ICU). No patient had explicit recall of any events during the period when the tape was played. The patients in the propofol group who heard the tape during surgery had significant implicit recall of the word associations compared with the equivalent 10 methohexitone patients (P = 0.004), when tested 48 h after surgery. The patients who were played the tape whilst receiving identical infusion regimens for sedation in the ICU did not demonstrate implicit recall of the word associations in either the propofol or the methohexitone groups. There was no evidence of a response to the specific behavioural suggestion during the postoperative interview. The results confirm that auditory perception can occur during clinically adequate anaesthesia, and that suppression of auditory awareness or learning is a function of both the pharmacological degree of sedation and the degree of surgical stimulation.

Scandium clusters in fullerene cages.

The production and spectroscopic characterization of fullerene-encapsulated metal-atom clusters is reported. In particular, both solution and solid-state electron paramagnetic resonance (EPR) spectra of Sc(3)C(82) have been obtained. ScC(82) also gives an EPR spectrum, but Sc2Cn species-the most abundant metallofullerenes in the mass spectrum-are EPR-silent even though Sc(2) is EPR-active in a rare-gas matrix at 4.2 K. The results suggest that the three scandium atoms in Sc(3)C(82) form an equilateral triangle-as was previously suggested for Sc(3) molecules isolated in a cryogenic rare-gas matrix. The spectrum of ScC(82) has features similar to those found earlier for LaC(82) and YC(82), suggesting that it can also be described as a +3 metal cation within a -3 fullerene radical anion. An implication of this work is that production of macroscopic quantities of clustercontaining fullerenes may make possible the fabrication of exotic new structures with regular arrays of metal-atom clusters isolated in fullerene molecules, resulting in a new type of host/guest nanostructured material.

C60 rotation in the solid state: dynamics of a faceted spherical top.

The rotational dynamics of C(60) in the solid state have been investigated with carbon-13 nuclear magnetic resonance ((13)C NMR). The relaxation rate due to chemical shift anisotropy (1/9T1(CSA)(1)) was precisely measured from the magnetic field dependence of T(1), allowing the molecular reorientational correlation time, tau, to be determined. At 283 kelvin, tau = 9.1 picoseconds; with the assumption of diffusional reorientation this implies a rotational diffusion constant D = 1.8 x 10(10) per second. This reorientation time is only three times as long as the calculated tau for free rotation and is shorter than the value measured for C(60) in solution (15.5 picoseconds). Below 260 kelvin a second phase with a much longer reorientation time was observed, consistent with recent reports of an orientational phase transition in solid C(60). In both phases tau showed Arrhenius behavior, with apparent activation energies of 1.4 and 4.2 kilocalories per mole for the high-temperature (rotator) and low-temperature (ratchet) phases, respectively. The results parallel those found for adamantane.

Bond lengths in free molecules of buckminsterfullerene, c60, from gas-phase electron diffraction.

Electron diffraction patterns of the fullerene C(60) in the gaseous state have been obtained by volatilizing it from a newly designed oven-nozzle at 730 degrees C. The many peaks of the experimental radial distribution curve calculated from the scattered intensity are completely consistent with icosahedral symmetry for the free molecule. On the basis of this symmetry assumption, least-squares refinement of a model incorporating all possible interatomic distances led to the values r(g)(C(1)-C(2)) = 1.458(6) angstroms (A) for the thermal average bond length within the five-member ring (that is, for the bond fusing five- and six-member rings) and r(g)(C(1)-C(6)) = 1.401(10) A for that connecting five-member rings (the bond fusing six-member rings). The weighted average of the two bond lengths and the difference between them are the values 1.439(2) A and 0.057(6) A, respectively. The diameter of the icosahedral sphere is 7.113(10) A. The uncertainties in parentheses are estimated 2sigma values.

Management of foreign-body bronchial obstruction using endoscopic laser therapy.

A case is presented in which the Nd:YAG laser obviated the need for a major thoracic procedure. A 7-year-old boy presented with an 18-month history of persistent nonproductive cough, preceded by a choking spell while eating pistachio nuts. High-grade left mainstem bronchial obstruction was caused by friable granulation tissue secondary to an underlying foreign body. By advancing a laser fiber through the working channel of a 5-mm Storz ventilating bronchoscope, the granulation tissue was vaporized, showing an irregular piece of pistachio nut shell embedded within the bronchial wall. After retrieval of the foreign body, bronchial patency was restored. Recovery was complete and uneventful. The bronchoscopic laser permits the delivery of precise and effective treatment to lesions within confined areas, and has a useful role in the management of some central airway lesions in children.

Management of donors for heart and heart-lung transplantation.

The quality of donor organs will determine the quality of life for the recipient and the importance of optimal management of the multi-organ donor is that the organs may benefit up to five, critically ill, patients. The basic principle is to maintain sufficient preload to minimise the need for inotropic support and it is recommended that all multiple organ donors should have central venous and arterial pressure monitoring in addition to adequate venous access. The importance of the choice of fluid for volume expansion and the management of the hormonal disturbances which follow brain death are considered.

Vortex pumping for routine cardiac surgery: a comparative study.

Vortex pumping has become popular for mechanical assist applications, but has only recently received serious consideration for use as the arterial pump of choice for routine open-heart surgery. We report on a prospective randomized study designed to evaluate this pump in routine use. Sixteen patients undergoing routine coronary artery surgery were randomized into two groups in which the only difference in equipment and technique was the use of a Stockert roller pump in group S and a Biomedicus vortex pump in group B. The groups were compared with respect to haematology, perioperative fluid balance, transfusion requirements, complement activation, haemolysis and microbubble transmission. The groups were reasonably well matched, with slightly longer mean bypass and ischaemic times in group S (94.8 vs 105.5 minutes and 75.7 and 83.8 minutes respectively). Group B patients showed significant improvements over group S patients with respect to preservation of platelet numbers, decreased complement activation and reduced microbubble transmission. The afterload sensitivity of the vortex pump did not present the perfusionist with any practical problems although a different technique is required for initiating and terminating bypass. We conclude that vortex pumping would seem to offer better blood handling for routine use. More extensive testing is required to establish whether or not this would be reflected in clinically measurable improved patient outcome.