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This essay addresses the recent deceleration in the pace of global FDI and asks whether multinational corporations are actually in retreat. It identifies the forces that are slowing the expansion of FDI, and sketches the role that multinational corporations will play in the future.

Research background: The authors are providing an update to the ongoing process of Brexit and the negotiations between the UK and the EU, following their own previous research in this area. Purpose of the article: In 2019, the aviation sector in the UK ranked as the third largest in the world. London Heathrow, a hub to many UK airlines, ranked as Europe’s busiest airport and seventh busiest in the world. [1] Brexit negotiations between the UK and the EU, in the context of globalization and the existing deep ties within the EU institutions, presents a complex task. Following the Brexit referendum in June 2016, where the majority of the electorate decided that Britain should leave the EU, events have progressed significantly by the UK leaving the EU formally at 23:59 on the 31st January 2020. However, negotiations are still ongoing and when it comes to Aviation, the outcome in many key areas is still uncertain. Methods: The article is based on data and information collation as well as the authors’ experience within the industry. Findings & Value added: Once the transition period terminates on the 31st December 2020, Brexit will have a significant influence on trading in the European domestic market and globally on the international market. This paper discusses available options for the UK and the EU that follow from existing decisions in the Brexit bill, as well as outlining possible future developments. Furthermore, in light of the existing threats to the Aviation industry from the ongoing COVID-19 pandemic and the cessation of air travel for many weeks, adjustments to the Brexit plan might be required.

Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half-life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function. Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics. Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose-response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once- or twice-daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide. Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate. Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase. [ABSTRACT FROM AUTHOR]

Enalapril is the result of a targeted research programme to develop a non-mercapto converting enzyme inhibitor with a long duration of action and an improved safety profile for use in the therapy of hypertension and congestive heart failure. Over 3500 patients world-wide have received enalapril or enalaprilat. Long-term experience at present includes over 2500 patients. While enalapril and captopril produce similar efficacy, enalapril is better tolerated and appears not to be associated with occurrence of captopril-type side-effects, particularly the skin rash, taste loss, leukopenia and proteinuria. Enalapril and other converting enzyme inhibitors may be associated with renal insufficiency when given to patients with bilateral renovascular hypertension. [ABSTRACT FROM AUTHOR]

The aim of the study was to determine the physical properties of gbafi lo fruit and kernel, namely, axial dimension, geometrical and arithmetic mean diameter, sphericity, aspect ratio, 1000 unit mass, surface area, true and bulk density, porosity angle of repose and coeffi cient of static friction. Investigation of physical properties of gbafi lo (Chrysobalanus icaco) is important for the design of appropriate equipment for processing, transporting, cleaning, sorting, packaging and storage processes. The mean length, width and thickness of gbafi lo fruit (Chrysobalanus icaco) were determined at 8.3% moisture content (d.b.). The analysis of variance showed that variations in the values obtained for fruit and kernel for axial dimensions were signifi cantly different at 5% probability level. The arithmetic and geometric mean diameter for gbafi lo fruit were 24.95 mm and 24.74 mm. The sphericity, surface area and as well as 1 000 unit mass of gbafi lo kernel were 0.82, 1 056.70 mm2 and 2 804.64 g. True and bulk densities were 989.19 kg/m-3 and 652.53 kg/m-3 for kernel. Angle of static friction of gbafi lo fruit and kernel were 19.34° and 17.61°. Data obtained were subjected to analysis of variance (ANOVA) and Duncan Multiple Range (DMR) using Statistical Analysis System. The static coeffi cient of friction of plywood structural surface was observed to be the highest followed by galvanized steel sheet and glass. This is an indication that plywood interior lining would not be suitable material for chute design. All the gbafi lo fruit and kernel parameters investigated were signifi cantly different (P < 0.05). This fi nding could therefore be useful in the design and fabrication of gbafi lo processing machines.

This paper gives an overview of a combined experimental-numerical study on vascular self-healing (SH) systems for cementitious composite materials. The work aimed to bridge the gap between numerical and experimental investigations for this type of SH system and to provide a set of data for developing, calibrating and validating a finite element model for these materials. The study investigated both healing-agent transport and mechanical damage-healing processes, including healing-agent curing. The experimental programme included mechanical tests on notched concrete beams and compact direct-tension specimens with inbuilt vascular healing systems, as well as tests to measure the transport properties of healing-agent within discrete concrete cracks and through the concrete matrix. The new coupled model employs elements with embedded strong discontinuities to simulate cracks and mechanical healing behaviour. A damage-healing constitutive model is described that simulates multiple damage-healing ‘events’. This mechanical model is coupled to discrete and continuum flow models that simulate healing-agent transport. The transport model accounts for pressurised and capillary flow, as well as curing-dependent flow properties. The main focus of this contribution is to show how these parallel programmes of work were combined so that the experimental observations guided the numerical developments and modelling questions were answered using experimental findings.

Abstract Background Outer membrane proteins (OMPs) of Pasteurella multocida have various functions related to virulence and pathogenesis and represent important targets for vaccine development. Various bioinformatic algorithms can predict outer membrane localization and discriminate OMPs by structure or function. The designation of a confident prediction framework by integrating different predictors followed by consensus prediction, results integration and manual confirmation will improve the prediction of the outer membrane proteome. Results In the present study, we used 10 different predictors classified into three groups (subcellular localization, transmembrane β-barrel protein and lipoprotein predictors) to identify putative OMPs from two available P. multocida genomes: those of avian strain Pm70 and porcine non-toxigenic strain 3480. Predicted proteins in each group were filtered by optimized criteria for consensus prediction: at least two positive predictions for the subcellular localization predictors, three for the transmembrane β-barrel protein predictors and one for the lipoprotein predictors. The consensus predicted proteins were integrated from each group into a single list of proteins. We further incorporated a manual confirmation step including a public database search against PubMed and sequence analyses, e.g. sequence and structural homology, conserved motifs/domains, functional prediction, and protein-protein interactions to enhance the confidence of prediction. As a result, we were able to confidently predict 98 putative OMPs from the avian strain genome and 107 OMPs from the porcine strain genome with 83% overlap between the two genomes. Conclusions The bioinformatic framework developed in this study has increased the number of putative OMPs identified in P. multocida and allowed these OMPs to be identified with a higher degree of confidence. Our approach can be applied to investigate the outer membrane proteomes of other Gram-negative bacteria.

Abstract Background Cardiac arrest affects 30-35, 000 hospitalised patients in the UK every year. For these patients to be given the best chance of survival, high quality cardiopulmonary resuscitation (CPR) must be delivered, however the quality of CPR in real-life is often suboptimal. CPR feedback devices have been shown to improve CPR quality in the pre-hospital setting and post-event debriefing can improve adherence to guidelines and CPR quality. However, the evidence for use of these improvement methods in hospital remains unclear. The CPR quality improvement initiative is a prospective cohort study of the Q-CPR real-time feedback device combined with post-event debriefing in hospitalised adult patients who sustain a cardiac arrest. Methods/design The primary objective of this trial is to assess whether a CPR quality improvement initiative will improve rate of return of sustained spontaneous circulation in in-hospital-cardiac-arrest patients. The study is set in one NHS trust operating three hospital sites. Secondary objectives will evaluate: any return of spontaneous circulation; survival to hospital discharge and patient cerebral performance category at discharge; quality of CPR variables and cardiac arrest team factors. Methods: All three sites will have an initial control phase before any improvements are implemented; site 1 will implement audiovisual feedback combined with post event debriefing, site 2 will implement audiovisual feedback only and site 3 will remain as a control site to measure any changes in outcome due to any other trust-wide changes in resuscitation practice. All adult patients sustaining a cardiac arrest and receiving resuscitation from the hospital cardiac arrest team will be included. Patients will be excluded if; they have a Do-not-attempt resuscitation order written and documented in their medical records, the cardiac arrest is not attended by a resuscitation team, the arrest occurs out-of-hospital or the patient has previously participated in this study. The trial will recruit a total of 912 patients from the three hospital sites. Conclusion This trial will evaluate patient and process focussed outcomes following the implementation of a CPR quality improvement initiative using real-time audiovisual feedback and post event debriefing. Trial registration ISRCTN56583860

Abstract Background The role of the innate immune protein mannose-binding lectin (MBL) in host defence against severe respiratory infection remains controversial. Thoracic empyema is a suppurative lung infection that arises as a major complication of pneumonia and is associated with a significant mortality. Although the pathogenesis of thoracic empyema is poorly understood, genetic susceptibility loci for this condition have recently been identified. The possible role of MBL genotypic deficiency in susceptibility to thoracic empyema has not previously been reported. Methods To investigate this further we compared the frequencies of the six functional MBL polymorphisms in 170 European individuals with thoracic empyema and 225 healthy control individuals. Results No overall association was observed between MBL genotypic deficiency and susceptibility to thoracic empyema (2 × 2 Chi square = 0.02, P = 0.87). Furthermore, no association was seen between MBL deficiency and susceptibility to the Gram-positive or pneumococcal empyema subgroups. MBL genotypic deficiency did not associate with progression to death or requirement for surgery. Conclusions Our results suggest that MBL genotypic deficiency does not associate with susceptibility to thoracic empyema in humans.

Abstract Background The Mannheimia species encompass a wide variety of bacterial lifestyles, including opportunistic pathogens and commensals of the ruminant respiratory tract, commensals of the ovine rumen, and pathogens of the ruminant integument. Here we present a scenario for the evolution of the leukotoxin promoter among representatives of the five species within genus Mannheimia. We also consider how the evolution of the leukotoxin operon fits with the evolution and maintenance of virulence. Results The alignment of the intergenic regions upstream of the leukotoxin genes showed significant sequence and positional conservation over a 225-bp stretch immediately proximal to the transcriptional start site of the lktC gene among all Mannheimia strains. However, in the course of the Mannheimia genome evolution, the acquisition of individual noncoding regions upstream of the conserved promoter region has occurred. The rate of evolution estimated branch by branch suggests that the conserved promoter may be affected to different extents by the types of natural selection that potentially operate in regulatory regions. Tandem repeats upstream of the core promoter were confined to M. haemolytica with a strong association between the sequence of the repeat units, the number of repeat units per promoter, and the phylogenetic history of this species. Conclusion The mode of evolution of the intergenic regions upstream of the leukotoxin genes appears to be highly dependent on the lifestyle of the bacterium. Transition from avirulence to virulence has occurred at least once in M. haemolytica with some evolutionary success of bovine serotype A1/A6 strains. Our analysis suggests that changes in cis-regulatory systems have contributed to the derived virulence phenotype by allowing phase-variable expression of the leukotoxin protein. We propose models for how phase shifting and the associated virulence could facilitate transmission to the nasopharynx of new hosts.

This paper describes the implementation of INFIBRA, a machine vision system used in the quality control of acrylic fibre production. The system was developed by INETI under a contract with a leading industrial manufacturer of acrylic fibres. It monitors several parameters of the acrylic production process. This paper presents, after a brief overview of the system, a detailed description of the machine vision algorithms developed to perform the inspection tasks unique to this system. Some of the results of online operation are also presented.

When rapid eye movement (REM) sleep occurs, noradrenergic cells become silent, with the abolition of activity in locus coeruleus (LC) neurons seen as a key event permissive for the occurrence of REM sleep. However, it is not known whether silencing of other than LC noradrenergic neurons contributes to the generation of REM sleep. In urethane-anesthetized rats, stereotyped REM sleep-like episodes can be repeatedly elicited by injections of the cholinergic agonist, carbachol, into a discrete region of the dorsomedial pons. We used this preparation to test whether inhibition of ventrolateral pontine noradrenergic A5 neurons only, or together with LC neurons, also can elicit REM sleep-like effects. To silence noradrenergic cells, we sequentially injected the α(2)-adrenergic agonist clonidine (20-40 nl, 0.75 mM) into both A5 regions and then the LC. In two rats, successful bilateral clonidine injections into the A5 region elicited the characteristic REM sleep-like episodes (hippocampal theta rhythm, suppression of hypoglossal nerve activity, reduced respiratory rate). In five rats, bilateral clonidine injections into the A5 region and then into one LC triggered REM sleep-like episodes, and in two rats injections into both A5 and then both LC were needed to elicit the effect. In contrast, in three rats, uni- or bilateral clonidine injections only into the LC had no effect, and clonidine injections placed in another six rats outside of the A5 and/or LC regions were without effect. The REM sleep-like episodes elicited by clonidine had similar magnitude of suppression of hypoglossal nerve activity (by 75%), similar pattern of hippocampal changes, and similar durations (2.5-5.3 min) to the episodes triggered in the same preparation by carbachol injections into the dorsomedial pontine reticular formation. Thus, silencing of A5 cells may importantly enable the occurrence of REM sleep-like episodes, at least under anesthesia. This is a new role for noradrenergic A5 neurons.

Background: Obstructive sleep apnea (OSA) is associated with glucose intolerance. Both chronic sleep disruption and recurrent blood oxygen desaturations (chronic-intermittent hypoxia, CIH) may cause, or exacerbate, metabolic derangements., Methods: To assess the impact of CIH alone, without accompanying upper airway obstructions, on the counter-regulatory response to glucose load and cardiorespiratory parameters, we exposed adult male Sprague-Dawley rats to CIH or sham room air exchanges for 10 h/day for 7, 21, or 35 days and then, 1 day after conclusion of CIH exposure, conducted intravenous glucose-tolerance tests (ivgtt) under urethane anesthesia. Additional rats underwent 35 days of CIH followed by 35 days of regular housing, or had 35 day-long CIH exposure combined with daily administration of the type 1 angiotensin II receptor antagonist, losartan (15 mg/kg, p.o.), and then were also subjected to ivgtt., Results: Compared with the corresponding control groups, CIH rats had progressively reduced glucose-stimulated insulin release and impaired glucose clearance, only mildly elevated heart rate and/or arterial blood pressure and slightly reduced respiratory rate. The differences in insulin release between the CIH and sham-treated rats disappeared in the rats normally housed for 35 days after 35 days of CIH/sham exposure. The losartan-treated rats had improved insulin sensitivity, with no evidence of suppressed insulin release in the CIH group., Conclusion: In adult rats, the glucose-stimulated insulin release is gradually suppressed with the duration of exposure to CIH, but the effect is reversible. Elimination of the detrimental effect of CIH on insulin release by losartan suggests that CIH disrupts glucoregulation through angiotensin/catecholaminergic pathways. Accordingly, treatment with continuous positive airway pressure may ameliorate pre-diabetic conditions in OSA patients, in part, by reducing sympathoexcitatory effects of recurrent nocturnal hypoxia.

Recently, we reported that the suppression of hypoglossal (XII) motoneuronal activity that occurs during the carbachol-induced, rapid eye movement (REM) sleep-like state is abolished by the microinjection into the XII nucleus of a drug mix that antagonizes aminergic excitation and amino acid-mediated inhibition (prazosin, methysergide, bicuculline and strychnine). We now assess the role of glycinergic inhibition in the depression of XII motoneuronal activity and estimate the distribution of the antagonists around the XII nucleus at the time when they are effective. Towards the first goal, REM sleep-like episodes were elicited in urethane-anesthetized rats by 10 nl carbachol microinjections into the dorsomedial pons prior to, and at different times after, combined microinjections into the XII nucleus of only three antagonists (strychnine omitted). As in our previous study, the carbachol-induced depression of XII activity was abolished during tests performed 42-88 min after the antagonists, whereas other characteristic effects of carbachol (appearance of hippocampal theta, cortical activation, decreased respiratory rate) remained intact. The depressant effect of carbachol on XII motoneurons partially recovered after 2.5 h. Towards the second goal, using a drug diffusion model, we determined that the tissue concentrations of the antagonists at the time when they were effective were within the range of their selective actions, and the drugs acted within 0.9-1.4 mm from the injection sites, thus within a space containing XII motoneurons and their dendrites. We conclude that antagonism of alpha-adrenergic, serotonergic, and GABA(A) receptors are sufficient to abolish the REM sleep-like atonia of XII motoneurons.

Rationale: Studies of hypoglossal (XII) motoneurons that innervate the genioglossus muscle, an upper airway dilator, suggested that the suppression of upper airway motor tone during REM sleep is caused by withdrawal of excitation mediated by norepinephrine and serotonin., Objectives: Our objectives were to determine whether antagonism of aminergic receptors located in the XII nucleus region can abolish the REM sleep-like atonia of XII motoneurons, and whether both serotonergic and noradrenergic antagonists are required to achieve this effect., Methods: REM sleep-like episodes were elicited in anesthetized rats by pontine carbachol injections before and at various times after microinjection of prazosin and methysergide combined, or of only one of the drugs, into the XII nucleus., Measurements and Main Results: Spontaneous XII nerve activity was significantly reduced, by 35 to 81%, by each antagonist alone and in combination, indicating that XII motoneurons were under both noradrenergic and serotonergic endogenous excitatory drives. During the 32 to 81 min after microinjections of both antagonists, pontine carbachol caused no depression of XII nerve activity, whereas other characteristic effects (activation of the hippocampal and cortical EEG, and slowing of the respiratory rate) remained intact. A partial recovery of the depressant effect of carbachol then occurred parallel to the recovery of spontaneous XII nerve activity from the depressant effect of the antagonists. Microinjections of either antagonist alone did not eliminate the depressant effect of carbachol., Conclusions: The REM sleep-like depression of XII motoneuronal activity induced by pontine carbachol can be fully accounted for by the combined withdrawal of noradrenergic and serotonergic effects on XII motoneurons., Competing Interests: Statement : V.B.F. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript. R.O.D. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript. L.K. acted as a one-time consultant for the following commercial entities interested in pharmacologic treatments for the obstructive sleep apnea syndrome for which he received honoraria not exceeding $2,500 per any one instance: Hypnion, Sepracor, and Cypress Bioscience.

Study Objectives: Two pontine reticular regions are implicated in cholinergic triggering of rapid eye movement (REM) sleep: the dorsomedial tegmental region and the ventral nucleus pontis oralis. We previously determined that, in urethane-anesthetized rats, microinjections of a cholinergic agonist, carbachol, into the dorsal region produce REM sleep-like effects comprising cortical activation, hippocampal theta rhythm, suppression of hypoglossal (XII) nerve activity, and silencing of pontine noradrenergic neurons. Our goal was to determine whether carbachol injections into the ventral nucleus pontis oralis elicits comparable effects., Design: Recording of cortical electroencephalogram, hippocampal activity, XII nerve activity, and discharge of noradrenergic cells of the locus coeruleus., Setting: Basic neurophysiologic research laboratory., Participants and Interventions: Urethane-anesthetized, paralyzed, and artificially ventilated or nonparalyzed and spontaneously breathing rats with microinjections of carbachol (10 nL, 10 mM) into the ventral nucleus pontis oralis., Measurements and Results: In artificially ventilated rats, carbachol injections repeatedly elicited cortical activation and hippocampal theta rhythm. Concomitantly, the activity of locus coeruleus neurons increased from 2.0 per second +/- 0.4 (SE) to 2.6 per second +/- 0.4 (P < .05, n = 8), as did XII nerve activity (by 42.5% +/- 8.8%; P < .01). In spontaneously breathing animals, carbachol similarly activated the cortical electroencephalogram and hippocampal activity, whereas XII nerve activity was reduced by 6.7% +/- 2.5% (P < .05) together with increased ventilation, as indicated by reduced end-expiratory CO2., Conclusion: Carbachol injections into the ventral nucleus pontis oralis activate, rather than silence, noradrenergic locus coeruleus neurons. This is not compatible with the state of REM sleep.

It is hypothesized that the suppression of motor activity (atonia) that occurs during REM sleep is caused by the combined inhibition of motoneurons by glycine or GABA and withdrawal of excitation mediated by serotonin and norepinephrine. However, it is not known whether these mechanisms can fully account for the atonia. In urethane-anesthetized, paralyzed and artificially ventilated rats, REM sleep-like episodes can be repeatedly elicited by microinjections of a cholinergic agonist, carbachol, into the dorsomedial pons. We used this model to determine whether microinjections of a combination of antagonists of serotonergic, adrenergic, GABA(A) and glycinergic receptors (methysergide, prazosin, bicuculline and strychnine) into the XII nucleus can abolish the carbachol-induced depression of XII motoneuronal activity. REM sleep-like episodes were elicited prior to, and at different times after, antagonist microinjections. In all six rats studied, the depression of XII motoneuronal activity did not occur when tested 30-60 min after the antagonists, whereas other characteristic features of the response (latency, duration, the appearance of hippocampal theta rhythm, activation of the cortical EEG, slowing of the respiratory rate) remained intact. The carbachol-induced depression partially recovered after 2-3 hours. We conclude that the REM sleep-like depression of XII motoneuronal activity can be fully accounted for by all or some of the following mechanisms: a withdrawal of motoneuronal excitation mediated by norepinephrine and serotonin and increased inhibition mediated by GABA and glycine.

The A5 noradrenergic neurons are considered important for cardiorespiratory regulation. We hypothesized that A5 cells are silenced during rapid eye movement (REM) sleep, thereby contributing to cardiorespiratory changes and suppression of hypoglossal (XII) motoneuronal activity. We used an anesthetized, paralyzed, and artificially ventilated rat in which pontine microinjections of carbachol trigger signs of REM sleep, including hippocampal theta rhythm, motor suppression, and silencing of locus coeruleus neurons. All 16 putative noradrenergic A5 cells recorded were strongly suppressed when the REM sleep-like episodes were elicited and also after intravenous clonidine. Antidromic mapping showed that none of six neurons tested projected to the XII nucleus, whereas three of five projected to the nucleus of the solitary tract and two of four to the rostral ventrolateral medulla. Bilateral microinjections of clonidine into the A5 regions did not alter XII nerve activity. These data suggest that A5 neurons are silenced during natural REM sleep. This will lead to decreased norepinephrine release and may alter synaptic transmission in the nucleus of the solitary tract and rostral ventrolateral medulla without, however, a detectable impact on XII motoneurons.

In individuals with compromised upper airway anatomy, genioglossus (GG), the main protruder muscle of the tongue, is an important upper airway dilator which helps prevent upper airway obstructions. During rapid eye movement (REM) sleep, both the tonic and inspiratory-modulated components of GG activity are suppressed in parallel with the characteristic postural atonia. We tested whether the REM sleep-related reduction in the respiratory activity of GG may, in part, result from a reduced inspiratory drive relayed to hypoglossal (XII) motoneurons from their premotor medullary inspiratory neurons. In 15 urethane-anesthetized, paralyzed, vagotomized and artificially ventilated rats, we recorded XII nerve activity and the extracellular activity of medullary inspiratory-modulated neurons antidromically activated with latencies of 0.8 ms +/- 0.3(SD) from within (n = 19) or adjacent to (n = 11) the XII nucleus. Carbachol (10-20 nl, 10 mM), a cholinergic agonist, was microinjected into the dorsomedial pons. Such injections trigger a REM sleep-like state in chronically instrumented, intact animals and, in anesthetized rats, produce respiratory and electrocortical changes similar to those of REM sleep. Following the injections, the respiratory component of XII nerve activity was depressed by 51 +/- 22%, while the mean inspiratory firing rate of the neurons decreased by only 7.4 +/- 13.8% (from 69 +/- 34 Hz to 65 +/- 37 Hz; P < 0.02; n = 30). The activity of ventral respiratory group (VRG) and reticular formation inspiratory neurons with axons within the XII nucleus was reduced by 10 +/- 14% (P < 0.005; n = 19), whereas the activity of neurons located near the VRG that had axons passing below the XII nucleus did not change (n = 5). Thus, the depressant effect of carbachol on medullary inspiratory neurons was slightly more pronounced in reticular formation and VRG cells premotor to XII motoneurons than in other medullary inspiratory cells. For all cells, the magnitude of the decrease of cell activity was not related to the magnitude of depression of XII nerve activity, the simultaneously occurring decrease in respiratory rate or the cell's control firing rate. Since the magnitude of this depressant effect on all cell types was disproportionately small when compared with the depression of XII nerve activity, the REM sleep-like decrease in GG activity must be mainly mediated by non-respiratory premotor pathways.

Microinjections of carbachol into the pontine tegmentum of decerebrate cats have been used to study the mechanisms underlying the suppression of postural and respiratory motoneuronal activity during the resulting rapid eye movement (REM) sleep-like atonia. During REM sleep, distinct respiratory muscles are differentially affected; e.g., the activity of the diaphragm shows little suppression, whereas the activity of some upper airway muscles is quite strong. To determine the pattern of the carbachol-induced changes in the activity of different groups of upper airway motoneurons, we simultaneously recorded the efferent activity of the recurrent laryngeal nerve (RL), pharyngeal branch of the vagus nerve (Phar), and genioglossal branch of the hypoglossal (XII) and phrenic (Phr) nerves in 12 decerebrate, paralyzed, vagotomized, and artificially ventilated cats. Pontine carbachol caused a stereotyped suppression of the spontaneous activity that was significantly larger in Phar expiratory (to 8.3% of control) and XII inspiratory motoneurons (to 15%) than in Phr inspiratory (to 87%), RL inspiratory (to 79%), or RL expiratory motoneurons (to 72%). The suppression in upper airway motor output was significantly greater than the depression caused by a level of hypocapnia that reduced Phr activity as much as carbachol. We conclude that pontine carbachol evokes a stereotyped pattern of suppression of upper airway motor activity. Because carbachol evokes a state having many neurophysiological characteristics similar to those of REM sleep, it is likely that pontine cholinoceptive neurons have similar effects on the activity of upper airway motoneurons during both states.

The loss of tone in upper airway muscles contributes to disorders of breathing during sleep. In an animal model of rapid eye movement sleep atonia, decrements in the activity of upper airway motoneurons are caused by withdrawal of excitation mediated by serotonin and other transmitters, rather than by state-dependent inhibition.

Serotonergic neurons decrease their activity during sleep, especially rapid eye movement sleep, thereby reducing their facilitatory effect on upper airway motoneurons. The magnitude of teh sleep-related loss of tone varies among upper airway muscles (e.g., pharyngeal dilator motoneurons are more suppressed than laryngeal motoneurons). We hypothesized that these differences may be related to the sensitivity of different groups of upper airway motoneurons to serotonin. Experiments were done on decerebrate, vagotomized, paralysed and artificially-ventilated cats. Hypoglossal and laryngeal motoneurons were recorded extracellularly using five-barrel pipettes filled with: serotonin, glutamate and methysergide (serotonergic antagonist) for iontophoresis, and NaCl for recording and current balancing. All but two of the 65 hypoglossal motoneurons (45 inspiratory, 10 expiratory, 10 tonic) and 27 out of 32 laryngeal motoneurons (14 inspiratory, 18 expiratory) were excited by serotonin, and the excitation was abolished by methysergide. To compare the magnitude of the excitatory effect among distinct motoneuronal groups, we applied small ejection currents in a standardized manner (+15 nA for 3 min; 10 mM serotonin in 150 NaCl) onto spontaneously active motoneurons (13 inspiratory hypoglossal, 11 inspiratory laryngeal and 11 expiratory laryngeal). Serotonin increased the number of spikes per respiratory burst of inspiratory hypoglossal motoneurons from 19 +/- 4.0 (S.E.M.) to 35 +/- 4.8, of inspiratory laryngeal motoneurons from 44 +/- 8.3 to 55 +/- 8.8, and of expiratory laryngeal motoneurons from 23 +/- 4.8 to 33 +/- 6.2. The relative increases in activity (to 220% +/- 24, 147% +/- 23 and 148% +/- 9 of control, respectively) were significantly higher in hypoglossal than in laryngeal motoneurons. In addition, the excitatory effect developed significantly faster in hypoglossal than in laryngeal motoneurons. Methysergide reduced the spontaneous activity of about half the hypoglossal and laryngeal motoneurons to 66% +/- 5 of control. Thus, the sensitivity to the excitatory effects of serotonin varies among different pools of upper airway motoneurons. These differences correlate with the pattern of airway muscle hypotonia seen during sleep.

The facilitatory effect of serotonin (5HT) on hypoglossal (XII) motoneurons is likely to be reduced during rapid eye movement (REM) sleep, when the activity of the brainstem serotonergic system reaches its nadir. Therefore, we assessed the hypothesis that application of exogenous 5HT will attenuate the REM sleep-like suppression of XII motoneurons produced in decerebrate cats by pontine microinjections of a cholinergic agonist, carbachol. Microinjections of 5HT or 5-carboxamidotryptamine into the XII nucleus increased XII nerve activity to 182 +/- 53% (standard deviation; SD) of control. Subsequent pontine microinjections of carbachol reduced XII nerve activity by 55 +/- 21% of the pre-5HT level (n = 12). Microinjections of methysergide (a 5HT antagonist) into the XII nucleus reduced XII nerve activity to 54 +/- 17% of the pre-methysergide control (n = 6). Pontine carbachol injections after methysergide further reduced XII nerve activity by 49 +/- 20% of the pre-methysergide level. Treatments with both agonists and the antagonist attenuated the carbachol-induced decrease when compared to two previous studies using the same model: 1) In experiments with no injections of serotonergic agents, pontine carbachol injections decreased XII nerve activity by 90 +/- 6% of control. 2) After enhancement of XII nerve activity by inhibitory amino acid antagonists (to 135 +/- 60%), the subsequent carbachol-induced decrease was even larger, 112 +/- 62% of control. We propose that serotonergic excitation can significantly attenuate the REM sleep-like suppression of XII nerve activity, and that this is achieved, in part, by substituting for the decreased endogenous 5HT in the XII nucleus. The study also demonstrates that other, non-serotonergic, mechanisms also contribute to the carbachol-induced suppression.

1. The activity of most brainstem serotonergic cells is suppressed during sleep, particularly the rapid eye movement (REM) phase. Thus, they may play a major role in state-dependent changes in CNS functioning. Our main goal was to search for medullary raphe cells having axonal branches in the region of the hypoglossal (XII) motor nucleus and assess their behaviour during the atonia produced by microinjections of a cholinergic agonist, carbachol, into the dorsal pontine tegmentum. In chronic animals, such microinjections evoke a desynchronized sleep-like state similar to natural REM sleep; in decerebrate animals, they produce eye movements and a motor suppression similar to the postural atonia of REM sleep. 2. In decerebrate, paralysed, vagotomized and artificially ventilated cats, we recorded extracellularly from medullary raphe cells antidromically activated from the XII nucleus region. Forty-five cells recorded in the raphe obscurus and pallidus nuclei were antidromically activated with latencies characteristic of non-myelinated fibres (4.4-42.0 ms). For thirty-three of the forty-five cells, we found one or more axonal branches within or just below the XII nucleus. The remaining twelve cells, in addition to the XII nucleus, had axonal ramifications in the medial nucleus of the solitary tract (NTS) and/or the dorsal motor nucleus of the vagus (DMV). 3. A subset of fourteen spontaneously active cells with identified axonal projections were held long enough to be recorded during the carbachol-induced atonia, and eight of these also during the subsequent recovery and a systemic administration of the serotonergic 1A receptor agonist (+/-)8-hydroxy-2-(di-N-propylamino)tetrealin hydrobromide (8-OH-DPAT). All but one were suppressed during the atonia in parallel to the suppression of XII, phrenic and postural nerve activities (firing rate, 1.3 +/- 0.7 Hz before and 0.1 +/- 0.2 Hz after carbachol (means +/- S.D.)). Following the recovery from the atonia, the firing rates of the eight cells increased to the pre-carbachol level (1.6 +/- 1.0 Hz). Subsequently, all were silenced by 8-OH-DPAT. 4. These cells fulfil most physiological criteria for serotonergic cells and have the potential to modulate, in a state-dependent manner, activities in the motor XII nucleus, visceral sensory NTS, and DMV. The decrements in serotonergic neuronal activity that occur during the carbachol-induced atonia suggest that a similar withdrawal of serotonergic input may occur during REM sleep and contribute to the characteristic reductions in upper airway motor tone.

The excitability of hypoglossal (XII) motoneurons innervating genioglossal muscles is markedly suppressed during the rapid-eye-movement (REM) stage of sleep. This may contribute to airway obstructions in sleep apnea patients. Based on our earlier studies in decerebrate cats using injections of carbachol into the pons to induce a REM sleep-like atonia and microinjections of serotonin (5HT) into the XII motor nucleus, we hypothesized that a sleep-related withdrawal of the serotonergic excitatory input to XII motoneurons may play a major role in these processes. To test one aspect of this hypothesis, we inserted microdialysis probes into the XII nucleus region of decerebrate, paralyzed, vagotomized and artificially ventilated cats. The probes were perfused without or with the addition of a 5HT reuptake blocker, clomipramine. The levels of 5HT and its metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined using HPLC and electrochemical detection in dialysate samples collected over successive 20 min periods under four successive experimental conditions: control (at least 2 h after probe insertion); during the postural atonia and respiratory depression produced by pontine microinjection of carbachol; recovery from the effects of carbachol produced by pontine microinjection of atropine; and, to verify that the presence of 5HT in the dialysate was related to the activity of serotonergic cells of the brainstem, following administration of 8-OH-DPAT, a 5HT 1A receptor agonist known to suppress activity in the serotonergic cells of the raphe system. After correcting for recovery rates of individual probes, the mean control 5HT level in the extracellular space of the XII nucleus region was 7.9 +/- 4.4 nM (S.D.) in eight experiments without reuptake blockers. During the carbachol-induced depression, it was reduced to 70 +/- 20% of the pre-carbachol level. It increased to the original control level 98 +/- 27% after pontine injection of atropine. 8-OH-DPAT reduced the 5HT level to 43 +/- 14% of the post-atropine level. Changes in the 5HIAA level were not as consistent as for 5HT and did not reach statistical significance under any of the experimental conditions. Thus, a functionally significant amount of 5HT is present in the extracellular space within the XII nucleus region, and its decrement during carbachol-induced, REM sleep-like atonia is likely to reflect that occurring during natural REM sleep; this may contribute to the decreased tone of upper airway muscles and airway patency.

The safety of sotalol was evaluated in 3,257 patients treated for cardiac arrhythmias in double-blind and open-label clinical trials that support United States registration of the drug. In this composite population, 80% of patients had structural heart disease and 42% had life-threatening ventricular arrhythmias, i.e., ventricular tachycardia (VT) or fibrillation (VF). Proarrhythmia was reported in 141 patients (4.3%). Of these, 78 (2.4%) had torsades de pointes and 26 (0.8%) had sustained VT or VF. The overall incidence was higher in patients treated for sustained VT or VF (6.5%). In these patients, serious proarrhythmia was predominantly torsades de pointes (4.1%) and was more prevalent in patients with congestive heart failure and low ejection fraction. Torsades de pointes was observed early in the course of treatment, and its occurrence was related to dose. The overall mortality in patients treated with sotalol was 4.3% (139 patients); in patients with life-threatening arrhythmias, cardiac mortality was 4.8%. In only 27 patients (0.8%) was the death thought to be potentially drug-related. The deaths were not related to dose. Data from a previously reported placebo-controlled postmyocardial infarction trial indicated no significant difference in mortality between sotalol and placebo. Heart failure was reported in 3.3% of patients and was most prevalent in those with a previous history of congestive heart failure, cardiomyopathy, or structural heart disease. The occurrence of heart failure was unrelated to dose or time on drug; in more than half of the patients, sotalol treatment was continued. On average, there was no decrease in ejection fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

The depression of upper airway motor activity that develops during the rapid eye movement (REM) stage of sleep is a major factor allowing upper airway obstructions to occur in patients with sleep apnea syndrome. Microinjections of carbachol, a cholinergic agonist, into the dorsal pontine tegmentum of chronically instrumented cats produce REM sleep. In acutely decerebrate cats, carbachol induces postural atonia, eye movements and a depression of the motor output to respiratory pump and upper airway muscles. In lumbar motoneurons, the depression of activity is due to a glycinergic inhibition that has the same characteristics during natural REM sleep in chronic cats and carbachol-induced atonia in decerebrate cats (Neurophysiology, 57 (1987) 1118-1129). The mechanisms that lead to the suppression of upper airway motoneuronal activity during REM sleep are unknown. In this study, we assessed whether the depression of hypoglossal (XII) nerve activity induced by pontine carbachol injections is caused by inhibitory amino acids acting within the XII nucleus. In decerebrate, paralyzed and artificially ventilated cats, we recorded the activities of both XII nerves (genioglossal branches), one phrenic and a cervical motor branch (to monitor postural activity). Postural atonia and respiratory depression were induced by pontine carbachol injections. The inhibitory amino acid receptor antagonists, strychnine (glycine receptors) or bicuculline (GABAA receptors), were injected (100-250 nl; 1.0-2.5 mM) into one XII nucleus (the other served as control) in an attempt to reduce or abolish the depression subsequently induced by pontine carbachol. Prior to the carbachol injections, both antagonists caused similar elevations of XII nerve activity on the treated side (30-40%). However, following carbachol, the XII nerve activity on the treated side was depressed to about 25% of the (pre-antagonist and pre-carbachol) control level, whereas the depression on the untreated side was slightly greater, to 10-15% of the control. Additional injections of antagonists during the carbachol-induced depression produced no further increase in nerve activity. This minor effect of the antagonists on the carbachol-induced depression of XII nerve activity was in contrast to the marked disinhibitory effects that both antagonists had on the XII nerve response to electrical stimulation of the lingual nerve. The latter was used as a control for the ability of strychnine and bicuculline to exert disinhibitory effects within the XII nucleus. Thus, there is little, if any, contribution of these inhibitory amino acids to the depression of XII motoneurons during the carbachol-induced, REM sleep-like postural and respiratory depression; mechanisms other than fast synaptic inhibition must be involved.

The microinjection of carbachol into the pons of acute decerebrate cats elicits a REM sleep-like atonia and a profound suppression of respiratory motoneuronal activity (J. Appl. Physiol., 69 (1990) 2280-2289). To assess whether this suppression is mediated by medullary neurons that provide respiratory drive to motoneurons of the respiratory pump muscles (diaphragm and intercostals), we studied the effect of pontine carbachol on the activity of neurons of the ventral respiratory group (VRG) in decerebrate, vagotomized, paralyzed and artificially ventilated cats. VRG neurons were recorded extracellularly along with the activity of phrenic and intercostal (external and internal) nerves. Both inspiratory (I) and expiratory (E) VRG neurons had incrementing, ramp-like bursts of activity during their firing periods and were not vagal motoneurons. Carbachol produced a depression of the peak firing rate in most (42/57) neurons studied. However, five cells showed no change and ten had an increase in activity in spite of consistent depression at the motoneuronal level. For the total population of cells (34 I and 23 E), the peak firing was reduced to 88.5% +/- 16.3 (S.D.) of control. The simultaneously recorded phrenic activity was reduced to 77.9% +/- 11.5, while inspiratory intercostal activity fell to 63.4% +/- 21.6 and expiratory to 23.2% +/- 21.2 of control. The carbachol-induced changes in peak firing of both I and E cells were quantitatively similar, and positively correlated to changes in peak phrenic activity. Analysis of this correlation suggested that phrenic and intercostal activities will be depressed to some degree by carbachol even when the average VRG cell activity remains unchanged. In addition, our data show that VRG cells may receive a combination of inhibitory and excitatory inputs during the carbachol-induced depression of respiratory motoneurons. Thus, although some disfacilitation from VRG cells may occur, there must be additional inhibitory or disfacilitatory pathways that mediate the decrease in activity of both phrenic and intercostal motoneurons that accompanies the REM sleep-like atonia.

Microinjections of carbachol into the pons induce a state that resembles rapid eye movement (REM) sleep in intact cats and, in decerebrate, artificially ventilated cats, produce postural atonia accompanied by a powerful depression of the respiratory motor output. In this study, pontine carbachol was used in decerebrate, spontaneously breathing cats to assess the effects of mechanical and chemical respiratory reflexes on the magnitude and pattern of the carbachol-induced depression of breathing, and to determine whether the depression is altered in those animals in which rapid eye movements are present. Phrenic nerve activity and tidal volume were only transiently depressed at the onset of the carbachol-induced postural atonia, whereas the decrease in respiratory rate and the depressions of hypoglossal and intercostal activities persisted until the response was reversed by a pontine microinjection of atropine 15-101 minutes after the onset of carbachol response. Ventilation was reduced to 70% of control during the steady-state conditions. The irregularity of breathing, characterized by the inter-quartile ranges of the distributions of the peak phrenic nerve activity and respiratory timing, did not increase following pontine carbachol. Neither vagotomy nor vigorous eye movements were associated with increased breathing irregularity. This contrasts with the irregular breathing (with minor average changes in ventilation) typical of natural REM sleep. We propose that the carbachol-injected decerebrate cat provides a useful model of the depressant effects that neural events associated with REM sleep may have on breathing.

In decerebrate, paralyzed, vagotomized and artificially ventilated cats, serotonin (5-HT) and its analogues, microinjected into the hypoglossal (XII) motor nucleus, altered the activity of the genioglossal branch of XII nerve. 5-HT, carboxamidotryptamine maleate (5-CT) and DOI (1-5 mM) increased the activity by over 200%. Methysergide reversed this increase. Methysergide, mianserin, or ketanserin (100-250 nl, 1 mM) reduced the spontaneous hypoglossal activity by 20-50%. Buspirone, 8-OH-DPAT and (-)-propranolol were without effect. Thus, 5-HT provides a substantial tonic excitatory drive to XII motoneurons. The 5-HT receptors involved are likely to be type 1C or 2, but uncertainty regarding the affinity profiles of the drugs used in in vivo conditions in the cat precludes a definite identification.

1. The activity of eighty-seven bronchopulmonary vagal afferent neurones with unmyelinated axons (C fibres) was recorded extracellularly in the nodose ganglia of decerebrate, paralysed and artificially ventilated cats. On the basis of their response latencies following the right atrial injection of capsaicin or phenyldiguanide, the cells were classified as having their receptor endings within the reach of pulmonary (latency less than 3.5 s) or bronchial (latency above 3.5 s) circulation. 2. Pulmonary and bronchial receptor cells differed only slightly in their response characteristics (firing rate, burst duration) and the conduction velocity of their peripheral axons. Bronchial C fibres represented about 70% of the population studied. 3. The medullary distributions of the central branches of six pulmonary and six bronchial C fibres were determined by means of the antidromic mapping technique. The two receptor subtypes did not differ in their central projection patterns. 4. Rostral to the obex, the central branches of the bronchopulmonary C fibres were localized within the medial portions of the nucleus tractus solitarii (NTS) and area postrema, and were most densely distributed along the borders of the parvicellular subnucleus of the NTS. Caudal to the obex, the most dense branching was found in the dorsal portion of the commissural subnucleus. Projections to the contralateral NTS were found, but these were of a much lower density. 5. The central distribution of bronchopulmonary C fibres is compared to the projection patterns of vagal and glossopharyngeal afferents of other modalities that are involved in respiratory and cardiovascular control. This is discussed in relation to the concept of a modality-specific organization of the NTS.

The injection of carbachol into the pontine tegmentum of decerebrate cats evokes a postural motor atonia that has many of the characteristics of the atonia of natural rapid-eye-movement (REM) sleep (Morales et al. J. Neurophysiol. 57: 1118-1129, 1987). We have used the carbachol-injected decerebrate cat to study the changes in respiratory neuronal activity that accompany the atonia. The activities of representative respiratory motor nerves--phrenic, intercostal, and hypoglossal--and that of a motor branch of C4 were recorded in decerebrate, vagotomized, paralyzed, and artificially ventilated cats. After the microinjection of carbachol, there was a profound suppression of activity in all the nerves and a decrease in respiratory rate. This was a consistent stereotyped response in which the magnitude of the suppression of respiratory-related activity was phrenic (to approximately 65% of control) less than inspiratory intercostal (approximately 50%) less than hypoglossal (approximately 10%) less than expiratory intercostal (approximately 5%). The decrease in respiratory rate (to approximately 70% of control) was caused by a prolongation of both inspiratory and expiratory durations. Complete reversal of the carbachol effect was elicited by the microinjection of atropine into the same site as the carbachol injection. This allowed us to produce a second episode of atonia by the injection of carbachol into the contralateral pons. Thus we have demonstrated the existence of neural pathways originating in the cholinoceptive cells of the pons that have the potential to powerfully and differentially depress various respiratory motoneuronal pools and to reduce the respiratory rate. These pathways are likely to be activated along with the atonia of REM sleep.

Muscle atonia is a feature of normal rapid-eye-movement sleep (REMS). The suppression of accessory respiratory muscle activity has been investigated and a role for sleep-disordered breathing hypothesized, but the suppression of diaphragmatic activity has rarely been considered. We hypothesized that the activity of the diaphragm was suppressed by an area of the dorsolateral pons during REMS. Lesions in this region have previously been shown to abolish the atonia of REMS. The diaphragmatic electromyogram (EMG) activity was analyzed in five naturally sleeping cats before and after pontine lesions leading to REMS without atonia. Although respiratory timing parameters were not altered by the lesion, the inspiratory rate of rise was significantly increased in all cats, and the brief pauses (40-100 ms) in the diaphragmatic EMG normally seen in REMS were virtually abolished. We conclude that the dorsolateral pons has a role in suppressing diaphragmatic activation during REMS. This suppression affects the average rate of rise of diaphragmatic activity and also leads to brief intermittent complete cessation of ongoing muscle activity. These decrements in diaphragm activity could jeopardize ventilation during REMS.

Tonic inhibition of some respiratory muscles occurs as part of the generalized muscle atonia of rapid-eye-movement sleep (REMS). A second type of inhibition of the diaphragm during REMS, fractionations, consists of brief pauses in the diaphragmatic electromyogram (DIA EMG) in association with phasic events. Because motor inhibition can occur as part of the startle response, and the brain is highly activated during REMS, we hypothesized that the neural basis of the fractionations might be activation of a startle network. To test this hypothesis, tone bursts (100 dB, 20-ms duration at 15-s intervals) were applied to cats at a fixed inspiratory level in the DIA moving average during REMS, non-rapid-eye-movement sleep (NREMS), and wakefulness. Parallel sham studies (no tone applied) were obtained for each state. The response of the DIA EMG was averaged over 100 ms by using the tone pulse as a trigger, and the following parameters of the DIA EMG were measured: latency to peak and/or nadir, increment or decrement in activity, and duration of peak and/or nadir. After a tone, all five animals studied displayed a profound suppression of DIA activity during REMS (latency to nadir 42.4 +/- 10.0 ms, duration of suppression 35.9 +/- 17.6 ms). Similarly, DIA activity was suppressed in all cats during NREMS (latency to nadir 40.9 +/- 13.3 ms, duration 23.9 +/- 13.4 ms). An excitatory response was observed in only two cats during NREMS and wakefulness. The similarity of startle-induced DIA EMG pauses to spontaneous fractionations of DIA activity during REMS suggests that the latter result from activation of a central startle system.

1. The effect of oesophageal distension and swallowing on the activity of medullary respiratory neurones was recorded in decerebrate, spontaneously breathing cats. The distension, produced by inflating a balloon in the thoracic portion of the oesophagus, was of sufficient magnitude to induce inhibition of the peri-oesophageal part of the crural diaphragm, with little effect on the respiratory function of the diaphragm as measured by the activity in the C5 branch of the phrenic nerve. 2. 424 neurones were tested. They were located bilaterally, in the region of the nucleus tractus solitarius (dorsal respiratory group) or the ambiguous complex (ventral respiratory group). No cell exhibited a change in activity during periods of strong inhibition of crural electrical activity induced by distension or swallowing. The activity of all cells paralleled that of the C5 phrenic neurogram, which was unaffected by the tests. 3. We conclude that the reflex inhibition of the crural diaphragm during oesophageal distension does not result from an inhibition of medullary premotor inspiratory neurones of the dorsal and ventral groups. Additional central pathways must exist that inhibit motoneurones to the crural diaphragm during gastrointestinal reflexes.

Sixteen male patients with typical angina pectoris secondary to coronary atherosclerosis performed two daily standardized exercise tests during two consecutive days. Three hours before each exercise they received placebo or 400 mg practolol administered orally in double-blind fashion in order to complete a cross-over design. Practolol significantly prolonged the exercise duration by 30.6% and delayed the appearance time of ischaemic electrocardiographic changes by 67.7%. Maximal heart rate, systolic pressure, and pressure-rate product were also reduced after medication. In order to investigate further the effects of this beta blocking agent, myocardial function and metabolism at rest and during supine exercise were assessed in 12 male patients with coronary artery disease before and after practolol 30 mg, iv. At rest, practolol produced a decrease in tension-time index (18%), cardiac index (17%), heart rate (10%), and stroke index (7%). A significant reduction was also observed in resting stroke work index (14%) and systolic and mean aortic pressure (6%). Left ventricular end-diastolic pressure remained unchanged. During supine exercise, only time-tension index (12%), heart rate (12%), and cardiac index (10%) were significantly reduced after the beta blocking agent. Practolol did not significantly change the arterial glucose, lactate, inorganic phosphate, potassium, calcium, magnesium, pH, PCO2, or PO2. The beta blocking agent did not modify the myocardial extraction of any of these substrates at rest or during exercise. In the dosage used in both studies, practolol significantly improved the exercise tolerance and reduced the ischaemic manifestations. The efficacy of practolol in angina pectoris may result mostly from its ability to decrease heart rate and systolic pressure during exercise.

The activity of pulmonary rapidly adapting receptor (r.a.r.) neurones was recorded extracellularly in the nodose ganglion of the decerebrate cat. The receptors were identified by their rapid adaptation to 'ramp and hold' hyperinflations of the lung. The antidromic mapping technique was used to determine the sites of projection and branching patterns within the nucleus of the tractus solitarius (n.t.s.) of eleven r.a.r.s. The medulla was explored with a stimulating electrode to activate the r.a.r.s. antidromically. In each penetration, depth-threshold measurements were made for each antidromic response characterized by a distinct latency. Using the anatomical sites of the minimum threshold points, the locations of central branches of individual r.a.r.s. were determined. The main axons of all of them coursed within the tractus solitarius (t.s.) at levels from 2 mm rostral to 0.5 mm caudal to the obex. The axonal conduction velocities within the t.s. were 6.2-9.7 m/s, where the peripheral conduction velocities were 11.2-20.4 m/s (28 degrees C). Different latencies of response evoked in a single penetration were considered to indicate branching. The densest branching was found in the ipsilateral commissural subnucleus of the n.t.s. at levels 0.3-1.3 mm caudal to the obex and, to a lesser degree, in the contralateral commissural subnucleus. All r.a.r.s. sent a few branches to the medial n.t.s. rostral to the obex. Four r.a.r.s. ramified in the ventrolateral n.t.s. where inspiratory cells are located. Depth-threshold graphs were interpolated by best fitting parabolic equations: Ith = Ad2 + Bd + C; where Ith is the threshold current, d the corresponding depth of stimulation, and A, B and C are coefficients. Coefficient A is a measure of steepness of the parabola. The A coefficients were inversely related to the conduction velocity (v) of the stimulated branch. An analysis of the data from the present study (v = 5.0-9.7 m/s) combined with data from the literature (v = 2.2-85 m/s) led to a simple relationship between the A coefficient and the conduction velocity of the stimulated fibre: A = 6500/v, where A is expressed in microA/mm2 and v is expressed in m/s. Within the range 3-35 m/s, the formula is useful in predicting the effective current spread when the conduction velocity is known, or to estimate the conduction velocity from the shape of a depth-threshold curve. Two slowly adapting pulmonary stretch receptors (p.s.r.s) were studied.(ABSTRACT TRUNCATED AT 400 WORDS)

The distribution of taste buds on the fungiform and circumvallate papillae of the cow tongue has been determined. The two tongues studied were from Holstein-Friesian cows four to six years of age; they contained 14,765 and 21,691 taste buds, respectively. The tip of the tongue is well supplied with fungiform papillae, and the posterior portion contains the circumvallate papillae. The midportion of the tongue contains relatively few taste papillae. The fungiform papillae contained 1,580 and 1,838 taste buds on the two tongues, respectively, and the circumvallate papillae were estimated to contain 13,185 and 19,853 taste buds. The highest concentration of taste buds therefore occurs in the circumvallate papillae; these relatively few papillae contain approximately 90% of the taste buds. On a circumvallate papilla, taste buds are found only on the papillary sidewall, with none either on the apical surface of the papilla or on the outer wall of the moat.

The effects of diflunisal, a nonacetylated difluorinated salicylate, on platelet function were compared with those of aspirin and placebo. In a randomized, double-blind trial, normal subjects were given diflunisal, 250, 500, or 1,000 mg twice daily; aspirin, 650 or 1,300 mg twice daily; or placebo for 8-day periods. Diflunisal, 250 mg, had no effect on platelet function, whereas 500 mg induced minimal inhibition of collagen-induced release of platelet serotonin, and 1,000 mg inhibited platelet malondialdehyde production, moderately prolonged template bleeding times (p = NS), and increased fecal blood loss (p < 0.05). In contrast, aspirin, 650 mg, markedly inhibited collagen-induced platelet aggregation and serotonin release, and 1,300 mg prolonged bleeding time (p < 0.01) and increased fecal blood loss (p < 0.01). The effects of aspirin lasted for up to 5 days, whereas changes induced by diflunisal had returned to baseline 24 hours after the drug was discontinued. We conclude that in doses in the same range as those of aspirin diflunisal inhibits platelet function less., (1983 Pharmacotherapy Publications Inc.)

General anesthesia is provided in the dental office primarily to reduce fear, block pain, produce amnesia, and provide a more comfortable surgical environment. Because the perception of pain is a major obstacle to the obtainment of dental health in the United States, general anesthesia has become an essential part of the practice of dentistry. It benefits both the patient and the surgeon to make dentistry a pleasant, painless experience.

Respiration in rapid-eye-movement sleep (REMS) is known to be highly variable. The purpose of this study was to investigate the source of this variability and to determine which ordering principles remained operative in REM sleep. In unrestrained, naturally sleeping cats we recorded the electroencephalogram, electrooculogram, neck electromyogram, and diaphragmatic electromyogram (EMG) and computed its moving average (MAdi). As a reference, we first examined MAdi during "tonic" REMS, since breathing is fairly regular in this state. "Control" ranges for peak amplitude (PEMG), inspiratory time (TI), duration of postinspiratory inspiratory activity, expiratory time, and the calculated inspiratory slope (PEMG/TI) were determined by overlaying individual breath traces of the time course of MAdi during tonic REMS to form a composite tracing. Next, the time course of the EMG during individual breaths in slow-wave sleep (SWS) and a complete period of consecutive breaths in REMS (both tonic and phasic) were compared with this tonic REMS composite. The number of eye movements per breath was tabulated as an index of phasic activity. The inspiratory slopes during SWS and tonic REMS were similar. However, during phasic REMS, many breaths displayed either increases (excitation) or decreases (inhibition) in slope compared with the "typical" breaths seen in tonic REMS. The occurrence of these altered slopes increased with the frequency of phasic events. TI was inversely related to the slope of the EMG, which tended to minimize changes in PEMG.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric injury resulting from nonsteroidal anti-inflammatory drugs is thought to require direct contact of the drug with the gastric mucosa. An inactive form of a drug (as a prodrug) should protect against mucosal damage. Because sulindac sulfoxide has little effect on prostaglandin synthesis until it is reduced to sulindac sulfide after absorption, we performed a double-blind, crossover endoscopic study in 15 normal subjects to compare the prodrug sulindac sulfoxide (200 mg b.i.d.), the active sulfide metabolite sulindac sulfide (100 mg b.i.d., which yields similar sulfide blood concentrations), a positive control (aspirin, 650 mg q.i.d.), and a negative control (placebo). Each drug was taken for 1 week and gastric mucosa were endoscopically assessed before and after 2, 5, and 7 days of dosing. Aspirin predictably damaged the gastric mucosa, whereas the effects of sulindac sulfoxide and sulindac sulfide could not be distinguished from those of the placebo. We conclude that sulindac sulfoxide as a prodrug is not directly responsible for the reduced severity of gastric mucosal lesions. Both sulindac sulfoxide and sulindac sulfide are poorly soluble in acid gastric contents and the reduced damage may relate to the inability of high concentrations of the drug to enter gastric mucosal cells.

The effects of diflunisal, a nonacetylated difluorinated salicylate, on platelet function were compared with those of aspirin and placebo. In a randomized, double-blind trial, normal subjects were given diflunisal, 250, 500, or 1,000 mg twice daily; aspirin, 650 or 1,300 mg twice daily; or placebo for 8-day periods. Difunisal, 250 mg, had no effect on platelet function, whereas 500 mg induced minimal inhibition of colagen-induced release of platelet serotonin, and 1,000 mg inhibited platelet malondialdehyde production, moderately prolonged template bleeding times (P = NS), and increased fecal blood loss (P less than 0.05). In contrast, aspirin, 650 mg, markedly inhibited collagen-induced platelet aggregation and serotonin release, and 1,300 mg prolonged bleeding time (P less than 0.01) and increased fecal blood loss (P less than 0.01). The effects of aspirin lasted for up to 5 days, whereas changes induced by diflunisal had returned to baseline 24 hr after the drug was discontinued. We conclude that in doses in the same range as those of aspirin diflunisal inhibits platelet function less.

In normal humans sulindac, a prodrug, undergoes two major biotransformations: irreversible oxidation to the inactive sulfone metabolite and reversible reduction to the pharmacologically active sulfide metabolite. To assess any effect of end-stage renal failure on sulindac biotransformation, six patients were given 200 mg sulindac orally. Plasma was sampled over 24 hours. Protein binding of sulindac and metabolites was determined by equilibrium dialysis. Results were compared with historic controls. AUC(0-12) for sulindac and the sulfone were similar to controls. AUC(0-12) for the sulfide was significantly reduced to 4.85 micrograms X hr/ml from 13.1 micrograms X hr/ml (P less than 0.02). Protein binding of all three compounds was significantly reduced by renal failure. When corrected for protein binding, the AUC(0-12) for sulindac and the sulfone was twice that of controls whereas that of the sulfide was 42 ng X hr/ml compared with 83 ng X hr/ml in normal individuals (P less than 0.001). This suggests that end-stage renal failure impairs the reduction of sulindac to the active sulfide whereas oxidation to the sulfone is intact.

Studies of the metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-[14C]cyanopyridine (I) have been performed in humans, dogs, and spontaneously hypertensive rats. After an iv injection of I (5 mg/kg), a substantial fraction of the radioactivity was excreted in the feces of rats (32%) and dogs (31%). After oral administration of I (5 mg/kg) the urinary recoveries of radioactivity for rat and dog were 19% and 53%, respectively, and represented a minimum value for absorption because of biliary excretion of radioactivity. In man, bililary excretion of I appeared to be of minor significance because four male subjects, after receiving 6 mg of I p.o., excreted 76% and 9% of the dose of radioactivity in the urine and feces, respectively. Unchanged I represented 58% of the radioactivity excreted in human urine. The half-life for renal elimination of I was determined to be 4.0 +/- 0.9 /hr. In contrast, unchanged I represented 7% and 1% of excreted radioactivity in rat and dog urine, respectively. A metabolite of I common to man, dog, and rat was identified as 5-hydroxy-I, which represented approximately 5% of the excreted radioactivity in all species. Minor metabolites of I in which the pyridine nucleus had undergone additional hydroxylation were present in dog urine along with an oxyacetic acid metabolite, also bearing a hydroxylated pyridine nucleus.