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Biomedical subjects

Simon Green

Publications and source records attributed to Simon Green.

At least 19 recordsLinked to original sources
PubMed2007

Revisiting the effect of posture on high-intensity constant-load cycling performance in men and women.

It was recently observed that inclining the body from a supine to upright position improved the performance of high-intensity, constant-load cycling to a larger extent in men than women (Egaña et al. in Eur J Appl Physiol 96:1-9, 2006), although this gender-related effect was based on a small number of men (n = 5) and women (n = 5). To explore this effect further, we studied the effect of body tilt on cycling performance in a larger and different group of men (n = 8) and women (n = 18). Peak power, peak VO2 and the ventilatory threshold (VT) were determined during an upright maximal graded cycle test, and a high-intensity test (80% peak power) was performed to failure in both the upright and supine positions. Performance was significantly longer in the upright compared with supine position in men (17.4 +/- 7.7 vs. 7.6 +/- 3.4 min) and women (14.1 +/- 6.0 vs. 6.0 +/- 3.7 min). The magnitude of this postural effect was not significantly different between men and women; whereas it was significantly correlated with the relative intensity of exercise expressed as a function of VT (r = -0.39). These data demonstrate that the postural effect on high-intensity cycling performance is not influenced by gender; but that it is related to the intensity of exercise relative to the ventilatory threshold.

Adipose Tissue↗
PubMed2006

Intensity-dependent effect of body tilt angle on calf muscle fatigue in humans.

Body tilt angle affects the fatigue of human calf muscle at a high contractile force (i.e. 70 %MVC); but the range of forces across which this effect occurs is not known and we sought to determine this in the present study. Fourteen men performed intermittent calf muscle contractions at either 30, 40, 50 and 60 %MVC (Group 1 n = 7) or at 80 and 90 %MVC (Group 2 n = 7). Two tests were performed at each intensity in the supine (tilt angle = 0 degrees) and inclined head-up position (tilt angle = 67 degrees). MVC was measured prior to and during each calf exercise test, and the linear rate of decline in MVC during each test was used to estimate muscle fatigue. MVC prior to each test was unaffected by body tilt angle in Groups 1 and 2. In Group 1 muscle fatigue was significantly lower in the inclined than supine position at 50 %MVC (0.10 +/- 0.05 vs. 0.19 +/- 0.10 N s(-1)) and 60 %MVC (0.22 +/- 0.20 vs. 0.36 +/- 0.33 N s(-1)); but there was no significant difference in fatigue at 30 %MVC (0.07 +/- 0.06 vs. 0.07 +/- 0.07 N s(-1)) and 40 %MVC (0.12 +/- 0.07 vs. 0.18 +/- 0.08 N s(-1)). In Group 2, muscle fatigue was significantly lower in the inclined compared with the supine position at 80 %MVC (0.90 +/- 0.50 vs. 1.49 +/- 0.87 N s(-1)) and 90 %MVC (1.19 +/- 0.47 vs. 1.79 +/- 0.78 N s(-1)). These data demonstrate that the postural effect on calf muscle fatigue during intermittent contractions is manifest at moderate to very high forces, but that it does not occur at low forces.

Adult↗
PubMed2006

Anxiety and sensitivity to eye gaze in emotional faces.

This paper reports three studies in which stronger orienting to perceived eye gaze direction was revealed when observers viewed faces showing fearful or angry, compared with happy or neutral, emotional expressions. Gaze-related spatial cueing effects to laterally presented fearful faces and centrally presented angry faces were also modulated by the anxiety level of participants, with high- but not low-state anxious individuals revealing enhanced shifts of attention. In contrast, both high- and low-state anxious individuals demonstrated enhanced orienting to averted gaze when viewing laterally presented angry faces. These results provide novel evidence for the rapid integration of facial expression and gaze direction information, and for the regulation of gaze-cued attention by both the emotion conveyed in the perceived face and the degree of anxiety experienced by the observer.

Adolescent↗
PubMed2006

Short-term effects of cycle and treadmill training on exercise tolerance in peripheral arterial disease.

BACKGROUND: To explore the efficacy of cycle training in the treatment of intermittent claudication, the present study compared performance and physiologic effects of cycle training with more conventional treadmill walking training in a group of patients with claudication. METHOD: Forty-two individuals with peripheral arterial disease and intermittent claudication (24 men, 18 women) were stratified by gender and the presence or absence of type 2 diabetes mellitus and then randomized to a treadmill (n = 13), cycle (n = 15), or control group (n = 14). Treadmill and cycle groups trained three times a week for 6 weeks, whereas the control group did not train during this period. Maximal and pain-free exercise times were measured on graded treadmill and cycle tests before and after training. RESULTS: Treadmill training significantly improved maximal and pain-free treadmill walking times but did not improve cycle performance. Cycle training significantly improved maximal cycle time but did not improve treadmill performance. However, there was evidence of a stronger cross-transfer effect between the training modes for patients who reported a common limiting symptom during cycling and walking at baseline. There was also considerable variation in the training response to cycling, and a subgroup of responsive patients in the cycle group improved their walking performance by more than the average response observed in the treadmill group. CONCLUSION: These findings suggest that cycle exercise is not effective in improving walking performance in all claudication patients but might be an effective alternative to walking in those who exhibit similar limiting symptoms during both types of exercise.

Aged↗
PubMed2006

Effect of training on the response of plasma vascular endothelial growth factor to exercise in patients with peripheral arterial disease.

Expansion of the capillary network, or angiogenesis, occurs following endurance training. This process, which is reliant on the presence of VEGF (vascular endothelial growth factor), is an adaptation to a chronic mismatch between oxygen demand and supply. Patients with IC (intermittent claudication) experience pain during exercise associated with an inadequate oxygen delivery to the muscles. Therefore the aims of the present study were to examine the plasma VEGF response to acute exercise, and to establish whether exercise training alters this response in patients with IC. In Part A, blood was collected from patients with IC (n=18) before and after (+20 and +60 min post-exercise) a maximal walking test to determine the plasma VEGF response to acute exercise. VEGF was present in the plasma of patients (45.11+/-29.96 pg/ml) and was unchanged in response to acute exercise. Part B was a training study to determine whether exercise training altered the VEGF response to acute exercise. Patients were randomly assigned to a treatment group (TMT; n=7) that completed 6 weeks of high-intensity treadmill training, or to a control group (CON; n=6). All patients completed a maximal walking test before and after the intervention, with blood samples drawn as for Part A. Training had no effect on plasma VEGF at rest or in response to acute exercise, despite a significant increase in maximal walking time in the TMT group (915+/-533 to 1206+/-500 s; P=0.009) following the intervention. The absence of a change in plasma VEGF may reflect altered VEGF binding at the endothelium, although this cannot be confirmed by the present data.

Exercise↗
PubMed2005

Effect of posture on high-intensity constant-load cycling performance in men and women.

The time sustained during a graded cycle exercise is approximately 10% longer in an upright compared with a supine posture. However, during constant-load cycling this effect is unknown. Therefore, we tested the postural effect on the performance of high-intensity constant-load cycling. Twenty-two active subjects (11 men, 11 women) performed two graded tests (one upright, one supine), and of those 22, 10 subjects (5 men, 5 women) performed three high-intensity constant-load tests (one upright, two supine). To test the postural effect on performance at the same absolute intensity, during the upright and one of the supine constant-load tests subjects cycled at 80% of the peak power output achieved during the upright graded test. To test the postural effect on performance at the same relative intensities, during the second supine test subjects cycled at 80% of the peak power output achieved during the supine graded test. Exercise time on the graded and absolute intensity constant-load tests for all subjects was greater (P<0.05) in the upright compared with supine posture (17.9+/-3.5 vs. 16.1+/-3.1 min for graded; 13.2+/-8.7 vs. 5.2+/-1.9 min for constant-load). This postural effect at the same absolute intensity was larger in men (19.4+/-8.5 upright vs. 6.6+/-1.6 supine, P<0.001) than women (7.1+/-2 upright vs. 3.9+/-1.4 supine, P>0.05) and it was correlated (P<0.05) with both the difference in VO2 between positions during the first minute of exercise (r=0.67) and the height of the subjects (r=0.72). In conclusion, there is a very large postural effect on performance during constant-load cycling exercise and this effect is significantly larger in men than women.

Adult↗
PubMed2005

Effect of body tilt on calf muscle performance and blood flow in humans.

To explore the effect of posture on muscle performance, we tested the effects of body tilt angle on the strength, endurance, and fatigue of, and blood flow into, the plantar flexors. Human subjects were fixed to a tilt table that could tilt them from the horizontal (0 degrees ) to upright (90 degrees ) position and enabled force to be applied to a footplate through isometric action of the right calf muscle. In experiment 1, six subjects performed a strength test and graded test (intermittent contractions) to the point of failure at three tilt angles (0, 47, and 90 degrees ). In Experiment 2, seven subjects performed a strength test and constant-force test [70% maximum force (F(max)); intermittent contractions] to the point of failure in the horizontal and three inclined positions (32, 47, and 67 degrees ). In experiment 3, leg blood flow was assessed during constant-force exercise at two intensities (30 and 70% F(max)) and two tilt angles (0 and 67 degrees ) in six subjects. Strength was not affected (P > 0.05) by tilt angle. Time to failure during the graded test was significantly higher at 47 degrees (25.9 +/- 2.0 min) and 90 degrees (25.1 +/- 3.0 min) than 0 degrees (22.2 +/- 2.6 min). Time to failure during the constant-force test was also significantly higher at 32 degrees (7.1 +/- 3.6 min), 47 degrees (8.0 +/- 5.2 min), and 67 degrees (8.6 +/- 5.6 min) compared with 0 degrees (4.0 +/- 2.6 min). When graded or constant-force exercise was performed with arterial flow to the leg eliminated, there were no differences in exercise time between the horizontal and an inclined position. During nonischemic exercise, leg blood flow was significantly higher during exercise in the inclined position. These results demonstrate that head-up tilt improves endurance of the plantar flexors, that this effect occurs in the absence of an effect on strength, and that it depends on an intact peripheral circulation. Moreover, the postural effect on muscle endurance appears to be due to a greater blood flow into the leg, an effect that is established during the initial contractions.

Adaptation, Physiological↗
PubMed2005

Skeletal muscle phenotype is associated with exercise tolerance in patients with peripheral arterial disease.

OBJECTIVE: To better understand the association between skeletal muscle and exercise intolerance in peripheral arterial disease (PAD), we assessed treadmill-walking performance and gastrocnemius muscle phenotype in healthy control subjects and in patients with PAD. We hypothesized that gastrocnemius muscle characteristics would be altered in PAD compared with control subjects and that exercise tolerance in patients PAD would be related to muscle phenotype. METHODS: Sixteen patients with PAD and intermittent claudication and 13 healthy controls of the same age participated. Each subject completed a graded treadmill-walking test and underwent a resting muscle biopsy. Muscle biopsy samples were obtained from the medial gastrocnemius muscle of the most ischemic limb in PAD and a limb chosen at random in controls. Samples were analyzed for fiber type and cross-sectional area, capillary-to-fiber ratio, the number of capillaries in contact with each fiber type, and the optical density of glycogen within each fiber by using histochemical procedures. Total muscle glycogen content was determined biochemically. RESULTS: Exercise capacity measured on the incremental walking test in the PAD group was only 30% to 40% of that observed in controls. The PAD group had a lower proportion of type I muscle fibers (P < .05), fewer capillaries per muscle fiber (P < .05), and tended to have smaller fiber areas (P = .08). The relative area of type I fibers, the capillary-to-fiber ratio, capillary contacts with type I and IIa fibers, and the optical density of glycogen in type I fibers were all positively correlated with exercise tolerance in the PAD group (P < .05) but not controls. CONCLUSIONS: These data suggest that muscle phenotype is altered in PAD and that such alterations are associated with the exercise intolerance in these patients. In light of these findings, therapies such as resistance training or electrical stimulation that target skeletal muscle in PAD may prove beneficial, and further investigation of such therapies is warranted.

Biopsy, Needle↗
PubMed2004

Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery.

Dendritic cells (DCs) are being evaluated for cancer immunotherapy due to their unique ability to induce tumor-directed T-cell responses. Here we report that the type of human DC, the mode of activation, and the strategy for delivery of antigen are 3 critical factors for efficient stimulation of tumor-specific CD8+ and CD4+ T cells. Only CD1c+ blood DCs and monocyte-derived DCs (MoDCs) were capable of presenting epitopes of the full-length tumor antigen NY-ESO-1 on both major histocompatibility complex (MHC) class I (cross-presentation) and MHC II, whereas plasmacytoid DCs were limited to MHC II presentation. Cross-presentation was inefficient for soluble protein, but highly efficient for antigen-antibody immune complexes (NY-ESO-1/IC) and for protein formulated with ISCOMATRIX adjuvant (NY-ESO-1/IMX). DC activation with CD40L further enhanced cross-presentation efficiency. The mode of antigen delivery was found to be a determining factor for cytosolic proteolysis by DCs. Immune complexes (ICs) targeted a slow, proteasome-dependent cross-presentation pathway, whereas ISCOMATRIX (IMX) targeted a fast, proteasome-independent pathway. Both cross-presentation pathways resulted in a long-lived, T-cell stimulatory capacity, which was maintained for several days longer than for DCs pulsed with peptide. This may provide DCs with ample opportunities for sensitizing tumor-specific T cells against a broad array of tumor antigen epitopes in lymph nodes.

Adjuvants, Immunologic↗
PubMed2004

Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4(+) and CD8(+) T cell responses in humans.

NY-ESO-1 is a "cancer-testis" antigen expressed in many cancers. ISCOMATRIX is a saponin-based adjuvant that induces antibody and T cell responses. We performed a placebo-controlled clinical trial evaluating the safety and immunogenicity of recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant. Forty-six evaluable patients with resected NY-ESO-1-positive tumors received three doses of vaccine intramuscularly at monthly intervals. The vaccine was well tolerated. We observed high-titer antibody responses, strong delayed-type hypersensitivity reactions, and circulating CD8(+) and CD4(+) T cells specific for a broad range of NY-ESO-1 epitopes, including known and previously unknown epitopes. In an unplanned analysis, vaccinated patients appeared to have superior clinical outcomes to those treated with placebo or protein alone. The vaccine is safe and highly potent immunologically.

Adjuvants, Immunologic↗
PubMed2004

Immunodominant CD4+ responses identified in a patient vaccinated with full-length NY-ESO-1 formulated with ISCOMATRIX adjuvant.

There is increasing evidence showing the involvement of CD4(+) T cells in initiating and maintaining antitumor immune responses. NY-ESO-1 is expressed by various tumors but not normal tissues except testis. We conducted a cancer clinical trial by using full-length NY-ESO-1 protein formulated with ISCOMATRIX adjuvant and injected into patients intramuscularly. Autologous dendritic cells pulsed with NY-ESO-1 ISCOMATRIX in combination with overlapping synthetic peptides were used to identify immunodominant T cells from a vaccinated patient. We show here the identification and characterization of two novel CD4(+) T cell epitopes. T cells specific to these epitopes not only recognized autologous dendritic cells loaded with NY-ESO-1 but also NY-ESO-1-expressing tumor cell lines treated with IFN-gamma. One of the two responses identified was greater than the previously identified immunodominant HLA-DP4-restricted response and correlated with NY-ESO-1-specific CD8(+) T cell induction after vaccination. This T cell response was vaccinated in most patients who expressed HLA-DR2. This study has systematically surveyed patients vaccinated with full-length tumor antigen for a vaccinated CD4 helper T cell response.

Amino Acid Sequence↗
PubMed2004

NY-ESO-1 protein formulated in ISCOMATRIX adjuvant is a potent anticancer vaccine inducing both humoral and CD8+ t-cell-mediated immunity and protection against NY-ESO-1+ tumors.

NY-ESO-1 is a 180 amino-acid human tumor antigen expressed by many different tumor types and belongs to the family of "cancer-testis" antigens. In humans, NY-ESO-1 is one of the most immunogenic tumor antigens and NY-ESO-1 peptides have been shown to induce NY-ESO-1-specific CD8(+) CTLs capable of altering the natural course of NY-ESO-1-expressing tumors in cancer patients. Here we describe the preclinical immunogenicity and efficacy of NY-ESO-1 protein formulated with the ISCOMATRIX adjuvant (NY-ESO-1 vaccine). In vitro, the NY-ESO-1 vaccine was readily taken up by human monocyte-derived dendritic cells, and on maturation, these human monocyte-derived dendritic cells efficiently cross-presented HLA-A2-restricted epitopes to NY-ESO-1-specific CD8(+) T cells. In addition, epitopes of NY-ESO-1 protein were also presented on MHC class II molecules to NY-ESO-1-specific CD4(+) T cells. The NY-ESO-1 vaccine induced strong NY-ESO-1-specific IFN-gamma and IgG2a responses in C57BL/6 mice. Furthermore, the NY-ESO-1 vaccine induced NY-ESO-1-specific CD8(+) CTLs in HLA-A2 transgenic mice that were capable of lysing human HLA-A2(+) NY-ESO-1(+) tumor cells. Finally, C57BL/6 mice, immunized with the NY-ESO-1 vaccine, were protected against challenge with a B16 melanoma cell line expressing NY-ESO-1. These data illustrate that the NY-ESO-1 vaccine represents a potent therapeutic anticancer vaccine.

Adjuvants, Immunologic↗
PubMed2004

2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.

Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.

Aniline Compounds↗
PubMed2004

Effect of carbohydrate supplementation on walking performance in peripheral arterial disease: a preliminary physiologic study.

OBJECTIVE: In this preliminary study we tested the effect of short-term carbohydrate supplementation on carbohydrate oxidation and walking performance in peripheral arterial disease. METHODS: Eleven patients with peripheral arterial disease and intermittent claudication and 8 healthy control subjects completed several weeks of baseline exercise testing, then were given supplementation for 3 days with a carbohydrate solution and placebo. Maximal walking time was assessed with a graded treadmill test. Carbohydrate oxidation during a submaximal phase of this test was measured with indirect calorimetry. At the end of baseline testing a biopsy specimen was taken from the gastrocnemius muscle, and the active fraction of pyruvate dehydrogenase complex activity was determined. RESULTS: Carbohydrate supplementation resulted in a significant increase in body weight and carbohydrate oxidation during exercise in patients with intermittent claudication and control subjects. Maximal walking time decreased by 3% in control subjects, whereas it increased by 6% in patients with intermittent claudication (group x treatment interaction, P < .05). There was a wide range of performance responses to carbohydrate supplementation among patients with claudication (-3%-37%). This effect was greater in poorer performers, and was negatively correlated (P < .05) with muscle pyruvate dehydrogenase complex activity. CONCLUSION: Preliminary data suggest that carbohydrate oxidation during exercise might contribute to exercise intolerance in more dysfunctional patients with intermittent claudication and that carbohydrate supplementation might be an effective therapeutic intervention in these patients.

Aged↗
PubMed2004

Walking performance, oxygen uptake kinetics and resting muscle pyruvate dehydrogenase complex activity in peripheral arterial disease.

In the present study, we tested the hypothesis that walking intolerance in intermittent claudication (IC) is related to both slowed whole body oxygen uptake (VO2) kinetics and altered activity of the active fraction of the pyruvate dehydrogenase complex (PDCa) in skeletal muscle. Ten patients with IC and peripheral arterial disease [ankle/brachial index (ABI)=0.73 +/- 0.13] and eight healthy controls (ABI=1.17 +/- 0.13) completed three maximal walking tests. From these tests, averaged estimates of walking time, peak VO2 and the time constant of VO2 (tau) during submaximal walking were obtained. A muscle sample was taken from the gastrocnemius medialis muscle at rest and analysed for PDCa and several other biochemical variables. Walking time and peak VO2 were approx. 50% lower in patients with IC than controls, and tau was 2-fold higher (P<0.05). tau was significantly correlated with walking time (r=-0.72) and peak VO2 (r=-0.66) in patients with IC, but not in controls. PDCa was not significantly lower in patients with IC than controls; however, PDCa tended to be correlated with tau (r=-0.56, P=0.09) in patients with IC, but not in controls (r=-0.14). A similar correlation was observed between resting ABI and tau (r=-0.63, P=0.05) in patients with IC. These data suggest that the impaired VO2 kinetics contributes to walking intolerance in IC and that, within a group of patients with IC, differences in VO2 kinetics might be partly linked to differences in muscle carbohydrate oxidation.

Aged↗
PubMed2004

Skeletal muscle metabolic changes in peripheral arterial disease contribute to exercise intolerance: a point-counterpoint discussion.

Patients with claudication have a marked impairment in exercise performance. Several factors contribute to this limitation, including reductions in large vessel blood flow and oxygen delivery as well as metabolic abnormalities in skeletal muscle. The relative contribution of these factors and their role in the pathophysiology of the exercise limitation is discussed using a point-counterpoint approach. Future directions for research conclude the discussion.

Exercise Tolerance↗