Polybacterial challenge effects on cytokine/chemokine production by macrophages and dendritic cells.

OBJECTIVE: To investigate the polymicrobial infection of periodontal disease, which elicits inflammatory mediators/cytokines/chemokines in the local gingival tissues, and a polybacterial challenge of antigen-presenting cells, e.g. macrophages and dendritic cells (DCs), at the mucosal surface. MATERIALS AND METHODS: The cytokine/chemokine profiles of human macrophages and DCs in response to polybacterial challenges were investigated. RESULTS: Oral Gram-negative bacteria elicited significantly greater IL-8 levels from macrophages, compared to Gram-positive bacteria. Gram-positive bacteria did not show synergism in inducing this chemokine from macrophages. In contrast, pairs of oral Gram-negative bacteria elicited synergistic production of IL-8 by macrophages. Similar results were not observed with TNFα, which only appeared additive with the polybacterial challenge. Selected Gram-negative bacterial pairs synergized in IL-6 production by immature DCs. In mature DCs (mDCs), a Porphyromonas gingivalis/Fusobacterium nucleatum and Porphyromonas intermedia/F. nucleatum polybacterial challenge resulted in significant synergism for IL-6 and TNFα levels. However, only the Pi/Fn combination synergized for IL-12 production and there appeared to be no polybacterial effect on IL-10 production by the mDCs. CONCLUSIONS: These results indicate that a polybacterial challenge of cells linking innate and adaptive immune responses results in varied response profiles that are dependent upon the characteristics of the microorganisms that are components of the polybacterial complex.

The DEBIT trial: an intervention to reduce antipsychotic polypharmacy prescribing in adult psychiatry wards - a cluster randomized controlled trial.

BACKGROUND: Clinical guidelines advise against prescribing more than one antipsychotic with limited exceptions. Despite this, surveys continue to report high antipsychotic polypharmacy rates. The aim of the study was to investigate the effectiveness of a multi-faceted intervention in reducing prescribing of antipsychotic polypharmacy on general adult psychiatry wards, compared with guidelines alone. METHOD: A pragmatic cluster randomized controlled trial recruited 19 adult psychiatric units (clusters) from the South West of England. Participants were all ward doctors and nurses. The multi-faceted intervention comprised: an educational/CBT workbook; an educational visit to consultants; and a reminder system on medication charts. RESULTS: The odds of being prescribed antipsychotic polypharmacy in those patients prescribed antipsychotic medication was significantly lower in the intervention than control group when adjusted for confounders (OR 0.43, 95% CI 0.21-0.90, p=0.028). There was considerable between-unit variation in polypharmacy rates and in the change in rates between baseline and follow-up (5 months after baseline). CONCLUSION: The intervention reduced levels of polypharmacy prescribing compared to guidelines alone although the effect size was relatively modest. Further work is needed to elicit the factors that were active in changing prescribing behaviour.

Resetting of the carotid arterial baroreflex during dynamic exercise in humans.

Recent investigations have demonstrated that at the onset of low-to-moderate-intensity leg cycling exercise (L) the carotid baroreflex (CBR) was classically reset in direct relation to the intensity of exercise. On the basis of these data, we proposed that the CBR would also be classically reset at the onset of moderate- to maximal-intensity L exercise. Therefore, CBR stimulus-response relationships were compared in seven male volunteers by using the neck pressure-neck suction technique during dynamic exercise that ranged in intensity from 50 to 100% of maximal oxygen uptake (VO(2 max)). L exercise alone was performed at 50 and 75% VO(2 max), and L exercise combined with arm (A) exercise (L + A) was performed at 75 and 100% VO(2 max). O(2) consumption and heart rate (HR) increased in direct relation with the increases in exercise intensity. The threshold and saturation pressures of the carotid-cardiac reflex at 100% VO(2 max) were >75% VO(2 max), which were in turn >50% VO(2 max) (P < 0.05), without a change in the maximal reflex gain (G(max)). In addition, the HR response value at threshold and saturation at 75% VO(2 max) was >50% VO(2 max) (P < 0.05) and 100% VO(2 max) was >75% VO(2 max) (P < 0.07). Similar changes were observed for the carotid-vasomotor reflex. In addition, as exercise intensity increased, the operating point (the prestimulus blood pressure) of the CBR was significantly relocated further from the centering point (G(max)) of the stimulus-response curve and was at threshold during 100% VO(2 max). These findings identify the continuous classic rightward and upward resetting of the CBR, without a change in G(max), during increases in dynamic exercise intensity to maximal effort.

Cardiovascular control during concomitant dynamic leg exercise and static arm exercise in humans.

1. Skeletal muscle blood flow is thought to be determined by a balance between sympathetic vasoconstriction and metabolic vasodilatation. The purpose of this study was to assess the importance of high levels of sympathetic vasoconstrictor activity in control of blood flow to human skeletal muscle during dynamic exercise. 2. Muscle sympathetic nerve activity to the exercising leg was increased by static or static ischaemic arm exercise added to on-going dynamic leg exercise. Ten subjects performed light (20 W) or moderate (40 W) dynamic knee extension for 6 min with one leg alone or concomitant with bilateral static handgrip at 20% of maximal voluntary contraction force with or without forearm muscle ischaemia or post-exercise forearm muscle ischaemia. 3. Muscle sympathetic nerve activity was measured by microneurography (peroneal nerve) and leg muscle blood flow by a constant infusion thermodilution technique (femoral vein). 4. Activation of an exercise pressor reflex from the arms, causing a 2- to 4-fold increase in muscle sympathetic nerve activity and a 15-32% increase in mean arterial blood pressure, did not affect blood flow to the dynamically exercising leg muscles at any level of leg exercise. Leg vascular conductance was reduced in line with the higher perfusion pressure. 5. The results demonstrate that the vasoconstrictor effects of high levels of muscle sympathetic nerve activity does not affect blood flow to human skeletal muscle exercising at moderate intensities. One question remaining is whether the observed decrease in muscle vascular conductance is the result of sympathetic vasoconstriction or metabolic autoregulation of muscle blood flow.

Acute and adaptive responses in humans to exercise in a warm, humid environment.

Acute and repeated exposure for 8-13 consecutive days to exercise in humid heat was studied. Twelve fit subjects exercised at 150 W [45% of maximum O2 uptake (V.O2,max)] in ambient conditions of 35 degrees C and 87% relative humidity which resulted in exhaustion after 45 min. Average core temperature reached 39.9 +/- 0.1 degrees C, mean skin temperature (T-sk) was 37.9 +/- 0.1 degrees C and heart rate (HR) 152 +/- 6 beats min-1 at this stage. No effect of the increasing core temperature was seen on cardiac output and leg blood flow (LBF) during acute heat stress. LBF was 5.2 +/- 0.3 l min-1 at 10 min and 5.3 +/- 0.4 l min-1 at exhaustion (n = 6). After acclimation the subjects reached exhaustion after 52 min with a core temperature of 39.9 +/- 0.1 degrees C, T-sk 37.7 +/- 0.2 degrees C, HR 146 +/- 4 beats min-1. Acclimation induced physiological adaptations, as shown by an increased resting plasma volume (3918 +/- 168 to 4256 +/- 270 ml), the lower exercise heart rate at exhaustion, a 26% increase in sweating rate, lower sweat sodium concentration and a 6% reduction in exercise V.O2. Neither in acute exposure nor after acclimation did the rise of core temperature to near 40 degrees C affect metabolism and substrate utilization. The physiological adaptations were similar to those induced by dry heat acclimation. However, in humid heat the effect of acclimation on performance was small due to physical limitations for evaporative heat loss.

Metabolic response and muscle glycogen depletion pattern during prolonged electrically induced dynamic exercise in man.

Muscle glycogen depletion pattern and metabolic responses during voluntary (VOL) and functional electrical stimulated (FES) dynamic knee-extensor exercise with one leg were evaluated. Seven healthy men exercised for 60 minutes at 30 W with an pulmonary oxygen uptake of 0.8 and 1.01 min-1, and respiratory exchange ratios of 0.90 and 0.95 in VOL and FES, respectively. Heart rate reached a level around 90 beats min-1 (VOL) and up to 110 beats min-1 (FES). Muscle glycogen decreased in FES with 260 and 290 mmol kg-1 d.w. in vastus lateralis and m. rectus femoris, respectively, compared with 45 and 160 mmol kg-1 d.w. in VOL (p < 0.05). In FES the percentage of empty and almost empty fibres determined by periodic acid-Schiff staining in vastus lateralis and rectus femoris was 50 and 77% of type I, 63 and 90% of type IIa, and 59 and 84% of type IIb fibres, respectively, whereas in VOL it was 24 and 26% of type I, 7 and 19% of type IIa, and 2 and 3% of type IIb fibres. Muscle lactate reached 30 mmol kg-1 d.w. in FES and was 9 mmol kg-1 d.w. lower in VOL. The changes in blood lactate and NH3 during the exercise were slightly higher in FES than in VOL, whereas the alterations in glucose, FFA, and K+ were small in both exercise modes. The pressure in the two muscle portions at different locations (proximal-distal) and depths was always higher (approximately 50%) in FES than in VOL, reaching levels around 55 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)

Skeletal muscle perfusion in electrically induced dynamic exercise in humans.

Leg blood flow, blood pressure and metabolic responses were evaluated in six men during incremental one-legged dynamic knee extension exercise tests (no load exercise-40 W); one performed with voluntary contractions (VOL) and one with electrically induced contractions (EMS). Pulmonary oxygen uptake was the same in both exercise modes, but the ventilatory coefficient was 2-5 L per L O2 higher in EMS than VOL (P < 0.05). Heart rate and mean arterial pressure were slightly higher with EMS than VOL at all exercise intensities reaching 138 (EMS) and 126 bpm (VOL), as well as 148 (EMS) and 137 mmHg (VOL) at 40 W, respectively (P < 0.05). Leg blood flow, oxygen uptake and conductance were similar in the two exercise modes. At 40 W, mean muscle blood flow was close to 200 (range: 165-220) mL 100 g-1 min-1, mean peak muscle oxygen uptake reached 230 mL kg-1 min-1, and mean conductance became as high as around 45 mL min-1 mmHg-1, and normalized for muscle size and arterial pressure it approached 100 mL min-1 100 g-1 100 mmHg-1. Lactate and ammonia efflux from the leg were higher with EMS than with VOL and the difference became larger with increasing exercise intensity (P < 0.05). Muscle glucose uptake was the same in each exercise mode. Femoral venous K+ concentration increased with exercise intensity and was higher with EMS than with VOL, reaching 5.1 (EMS) and 4.7 mmol L-1 (VOL) at 40 W (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelin release and enhanced regional myocardial ischemia induced by cold-air inhalation in patients with stable angina.

This study was designed to determine the influence of cold-air inhalation on regional myocardial perfusion in patients with ischemic heart disease. A selected group of vasoactive hormones was measured to investigate their possible roles as ischemic agents. Ten men who had recently had a myocardial infarction and anginal symptoms and with verified pathologic ST deviations during a preceding exercise test volunteered to participate in this randomized cross-over study. Two identical exercise tests were performed on different days; one with inhalation of cold (-22 degrees C) air and the other one with inhalation of thermoneutral air (22 degrees C). Scintigraphic imaging (single-photon emission computed tomography) of regional myocardial blood flow was performed with technetium 99m isonitrile flowtracer and a Bull's eye visual display with calculation of the scintigraphic ischemic severity score. The score was significantly higher during exercise with inhalation of cold air as compared to exercise with inhalation of thermoneutral air. Furthermore, only with cold-air inhalation did arterial plasma endothelin concentration increase significantly from rest to exercise and correlate with the change of ischemic severity score. In contrast, no change was observed under thermoneutral conditions. There was no significant difference between peak values of heart rate, systolic blood pressure, adrenaline, and noradrenaline concentrations in the two situations. We conclude that inhalation of cold air during exercise increases the degree of regional myocardial ischemia and that this is not caused by an increased myocardial oxygen demand. We suggest that cold air directly influences the vasomotor tone of the myocardial resistance vessels and that endothelin may be involved in the ischemic response.

Neural control of cardiovascular responses and of ventilation during dynamic exercise in man.

1. Nine subjects performed dynamic knee extension by voluntary muscle contractions and by evoked contractions with and without epidural anaesthesia. Four exercise bouts of 10 min each were performed: three of one-legged knee extension (10, 20 and 30 W) and one of two-legged knee extension at 2 x 20 W. Epidural anaesthesia was induced with 0.5% bupivacaine or 2% lidocaine. Presence of neural blockade was verified by cutaneous sensory anaesthesia below T8-T10 and complete paralysis of both legs. 2. Compared to voluntary exercise, control electrically induced exercise resulted in normal or enhanced cardiovascular, metabolic and ventilatory responses. However, during epidural anaesthesia the increase in blood pressure with exercise was abolished. Furthermore, the increases in heart rate, cardiac output and leg blood flow were reduced. In contrast, plasma catecholamines, leg glucose uptake and leg lactate release, arterial carbon dioxide tension and pulmonary ventilation were not affected. Arterial and venous plasma potassium concentrations became elevated but leg potassium release was not increased. 3. The results conform to the idea that a reflex originating in contracting muscle is essential for the normal blood pressure response to dynamic exercise, and that other neural, humoral and haemodynamic mechanisms cannot govern this response. However, control mechanisms other than central command and the exercise pressor reflex can influence heart rate, cardiac output, muscle blood flow and ventilation during dynamic exercise in man.

Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment.

1. Heat acclimation was induced in eight subjects by asking them to exercise until exhaustion at 60% of maximum oxygen consumption rate (VO2) for 9-12 consecutive days at an ambient temperature of 40 degrees C, with 10% relative humidity (RH). Five control subjects exercised similarly in a cool environment, 20 degrees C, for 90 min for 9-12 days; of these, three were exposed to exercise at 40 degrees C on the first and last day. 2. Acclimation had occurred as seen by the increased average endurance from 48 min to 80 min, the lower rate of rise in the heart rate (HR) and core temperature and the increased sweating. 3. Cardiac output increased significantly from the first to the final heat exposure from 19.6 to 21.4 l min-1; this was possibly due to an increased plasma volume and stroke volume. 4. The mechanism for the increased plasma volume may be an isosmotic volume expansion caused by influx of protein to the vascular compartment, and a sodium retention induced by a significant increase in aldosterone. 5. The exhaustion coincided with, or was elicited when, core temperature reached 39.7 +/- 0.15 degrees C; with progressing acclimation processes it took progressively longer to reach this level. However, at this point we found no reduction in cardiac output, muscle (leg) blood flow, no changes in substrate utilization or availability, and no recognized accumulated 'fatigue' substances. 6. It is concluded that the high core temperature per se, and not circulatory failure, is the critical factor for the exhaustion during exercise in heat stress.

Elevated muscle acidity and energy production during exhaustive exercise in humans.

This study examined the effect of previous intense exercise on energy production during exhaustive exercise. Subjects (n = 6) performed dynamic knee extensor exercise to exhaustion twice (Ex1 and Ex2) separated by 16 min of recovery consisting of 10 min of rest, 3.5 min of very high-intensity intermittent exercise, and a further 2.5 min of rest. This resulted in an elevated muscle lactate concentration of 13.1 mmol/kg wet wt before Ex2. Muscle lactate concentration was the same at end of Ex1 and Ex2, but the accumulation of lactate and net lactate release during Ex2 was reduced (P < 0.05) by 67 and 38%, respectively. The time to exhaustion was 3.73 and 2.98 min, respectively, and the mean rate of net lactate production for Ex2 was lower (P < 0.05) than for Ex1 (4.6 +/- 1.2 and 9.6 +/- 1.7 mmol.min-1.kg wet wt-1, respectively). Leg O2 uptake was the same for Ex1 and Ex2. Muscle pH (6.85) was lowered (P < 0.05) before Ex2, but at the end of Ex2 (6.77) it tended (P < 0.1) to be higher compared with that at the end of Ex1 (6.73). In summary, the net lactate production rate is reduced but the aerobic energy production is not significantly altered when intense exercise is repeated. Fatigue and the lowered glycolysis do not appear to be caused by the elevated acidity per se before exercise.

Maximal oxygen uptake: "old" and "new" arguments for a cardiovascular limitation.

The research performed over the last 100 yr in regard to oxygen transport during exercise is reviewed. Special focus is on major shifts in views held on which link may limit maximal oxygen uptake of an individual exercising with a large fraction of the muscle mass. Initially the pump capacity of the heart was proposed as the critical factor, a view basically unchallenged until results on the plasticity of muscle came about in the 1960-70s. The capillary bed of the muscle and its mitochondrial volumes can be enhanced with training. These adaptations were then suggested to be prerequisites for maximal oxygen uptake to become elevated. The pendulum is slowly swinging back again toward heart and lungs setting the upper limit for the oxygen transport. It appears to be in the range of 80-90 ml.kg-1.min-1 or 150-200 ml.kg-1 muscle.min-1, which can easily be consumed by a fraction of the muscle mass intensely contracting.

Liver transplantation at UCLA: report of clinical activities.

Liver transplantation remains the treatment of choice for many forms of end-stage liver disease. In most large series, 5-year actuarial survival is greater than 70%. The majority of the morbidity and mortality occurs in the first 6 months posttransplant; as these figures have improved, so have overall survival rates. Infants under 1 year of age have a survival rate below that of older patients; in addition, a severe organ shortage for these patients continues. The use of reduced grafts has ameliorated the problem to a certain extent; however, further expansion of the donor pool is still necessary. Progress has also been made in the postoperative management of transplant patients. We currently follow AKBR and TNF levels in all patients to aid in the diagnosis of primary nonfunction and acute rejection, respectively. The introduction of additional immunosuppressive agents has instigated several large clinical trials. CsA, however, remains the gold standard to which these drugs must be compared.

Beta 2-adrenergic stimulation does not prevent potassium loss from exercising quadriceps muscle.

During exercise K+ is released from contracting muscle and plasma K+ concentration rises. Because beta 2-adrenergic agonists stimulate K+ uptake by skeletal muscle in vitro, we tested whether terbutaline, a selective beta 2-agonist, would reduce the loss of K+ from working muscle. Dynamic quadriceps muscle exercise was performed by 12 healthy male volunteers for 50 or 80 min at an average workload of 38 W. A steady K+ loss estimated at 0.16 +/- 0.02 mmol.min-1.kg working muscle-1 and a 0.30 +/- 0.05 mM elevation of arterial plasma K+ concentration were observed. The addition of terbutaline during exercise caused leg blood flow to increase 13% from 5.10 +/- 0.16 to 5.75 +/- 0.13 l/min and arterial K+ concentration to fall monoexponentially by 0.90 +/- 0.05 mM with a rate constant of 0.26 min-1. Terbutaline increased, rather than decreased, the washout of K+ from working quadriceps by 40% to an average value of 0.23 +/- 0.02 mmol.min-1.kg muscle-1. In an additional subject who exercised to exhaustion, terbutaline failed to diminish muscle K+ loss. We conclude that terbutaline does not augment Na(+)-K+ pump activity to a degree sufficient to prevent K+ loss from exercising muscle in humans. On the other hand, the rapid reduction in plasma K+ concentration observed with beta 2-adrenergic stimulation is compatible with an uptake of K+ by nonexercising tissue at an estimated maximal rate of 0.5 micromol.g-1.min-1.

Cardiovascular responses to carotid sinus baroreceptor stimulation during moderate to severe exercise in man.

Our objective was to assess the importance of arterial baroreflexes in maintaining vasoconstriction in active muscle during moderate to severe exercise. Eight subjects exercised for 8-15 min on a cycle ergometer at three levels (averages 94, 194, 261 W) requiring 40-88% of VO2 max. Four times during each exercise level pulsatile negative pressure (-50 mmHg) was applied over the carotid sinuses for 30 s; suction was applied at each ECG R-wave for 250-400 ms. Before and during each neck suction, femoral venous blood flow (FVBF) was measured by constant infusion thermal dilution. At 94 W neck suction significantly reduced blood pressure (BP) (15 mmHg) and heart rate (HR) (7 beats min-1), and raised leg vascular conductance (LVC) (11.4%) without changing FVBF. At 194 W, neck suction reduced BP (9 mmHg), HR (4 beats min-1) and FVBF (5.1%, 240 ml min-1), and raised LVC (5.2%). At 261 W, LVC was unchanged by neck suction, but BP and FVBF both fell (9 mmHg and 650 ml min-1 or 7.4%). We conclude that competing local vasodilation and sympathetic vasoconstriction control muscle blood flow during moderate exercise, and vasoconstrictor tone can be withdrawn by baroreceptor stimulation. High levels of vasoconstrictor outflow to muscle in severe exercise may not originate from baroreflexes.

Norepinephrine spillover from skeletal muscle during exercise in humans: role of muscle mass.

The purpose of this study was to determine the effect of increasing muscle mass involvement in dynamic exercise on both sympathetic nervous activation and local hemodynamic variables of individual active and inactive skeletal muscle groups. Six male subjects performed 15-min bouts of one-legged knee extension either alone or in combination with the knee extensors of the other leg and/or with the arms. The range of work intensities varied between 24 and 71% (mean) of subjects' maximal aerobic capacity (% VO2max). Leg blood flow, measured in the femoral vein by thermodilution, was determined in both legs. Arterial and venous plasma concentrations of norepinephrine (NE) and epinephrine were analyzed, and the calculated NE spillover was used as an index of sympathetic nervous activity to the limb. NE spillover increased gradually both in the resting, and to a larger extent in the exercising legs, with a steeper rise occurring approximately 70% VO2max. These increases were not associated with any significant changes in leg blood flow or leg vascular conductance at the exercise intensities examined. These results suggest that, as the total active muscle mass increases, the rise in sympathetic nervous activity to skeletal muscle, either resting or working at a constant load, is not associated with any significant neurogenic vasoconstriction and reduction in flow or conductance through the muscle vascular bed, during whole body exercise demanding up to 71% VO2max.

Insulin action in human thighs after one-legged immobilization.

Insulin action was assessed in thighs of five healthy young males who had one knee immobilized for 7 days by a splint. The splint was not worn in bed. Subjects also used crutches to prevent weight bearing of the immobilized leg. Immobilization decreased the activity of citrate synthase and 3-OH-acyl-CoA-dehydrogenase in the vastus lateralis muscle by 9 and 14%, respectively, and thigh volume by 5%. After 7 days of immobilization, a two-step euglycemic hyperinsulinemic clamp procedure combined with arterial and bilateral femoral venous catheterization was performed. Insulin action on glucose uptake and tyrosine release of the thighs at mean plasma insulin concentrations of 67 (clamp step I) and 447 microU/ml (clamp step II) was decreased by immobilization, whereas immobilization did not affect insulin action on thigh exchange of free fatty acids, glycerol, O2, or potassium. Before and during the clamp step I, lactate release was significantly higher in the immobilized than in the control thigh. Seven days of one-legged immobilization causes local decreased insulin action on thigh glucose uptake and net protein degradation.

Noradrenaline spillover during exercise in active versus resting skeletal muscle in man.

Increases in plasma noradrenaline (NA) concentration occur during moderate to heavy exercise in man. This study was undertaken to examine the spillover of NA from both resting and contracting skeletal muscle during exercise. Six male subjects performed one-legged knee-extension so that all measurements could be made both in the exercising and in the resting leg. Subjects exercised for 10 min at each of 50% and 100% of the peak performance capacity of the leg. Leg blood flow was measured by thermodilution and blood samples were drawn for the determination of plasma NA and adrenaline, first in the resting leg and then in the exercising leg. To calculate NA spillover, the extraction of NA (NAe) or of adrenalin (Ae) is required: NAe was measured by repeating the experiment under constant [3H]NA infusion following a 40-min rest period. During exercise, NA spillover was significantly larger in the exercising leg than in the resting leg both during 50% and 100% leg exercise. These results suggest that contracting skeletal muscle may contribute to a larger extent than resting skeletal muscle to increasing the level of plasma NA during exercise. Contractile activity may influence the NA spillover from skeletal muscle by a presynaptic and/or postsynaptic influence on the sympathetic nervous activity to this tissue.

A quantitative analysis of plasma osmotic pressure during metamorphosis of the bullfrog, Rana catesbeiana.

The plasma constituents contributing to osmotic pressure are, in decreasing order: Na+, Cl-, HCO3-, K+, glucose, amino acids, urea and protein. Plasma osmotic pressure increases from 180 mmoles/1 to 200 mmoles/1 throughout development.