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There are reports of abnormal pulmonary oxygen uptake (Vo(2)) and deoxygenated hemoglobin ([HHb]) kinetics in individuals with Type 2 diabetes (T2D) below 50 yr of age with disease durations of <5 yr. We examined the Vo(2) and muscle [HHb] kinetics in 12 older T2D patients with extended disease durations (age: 65 ± 5 years; disease duration 9.3 ± 3.8 years) and 12 healthy age-matched control participants (CON; age: 62 ± 6 years). Maximal oxygen uptake (Vo(2max)) was determined via a ramp incremental cycle test and Vo(2) and [HHb] kinetics were determined during subsequent submaximal step exercise. The Vo(2max) was significantly reduced (P < 0.05) in individuals with T2D compared with CON (1.98 ± 0.43 vs. 2.72 ± 0.40 l/min, respectively) but, surprisingly, Vo(2) kinetics was not different in T2D compared with CON (phase II time constant: 43 ± 17 vs. 41 ± 12 s, respectively). The Δ[HHb]/ΔVo(2) was significantly higher in T2D compared with CON (235 ± 99 vs. 135 ± 33 AU·l(-1)·min(-1); P < 0.05). Despite a lower Vo(2max), Vo(2) kinetics is not different in older T2D compared with healthy age-matched control participants. The elevated Δ[HHb]/ΔVo(2) in T2D individuals possibly indicates a compromised muscle blood flow that mandates a greater O(2) extraction during exercise. Longer disease duration may result in adaptations in the O(2) extraction capabilities of individuals with T2D, thereby mitigating the expected age-related slowing of Vo(2) kinetics.

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AIMS/HYPOTHESIS: Microvascular dysfunction is associated with end-organ damage. Macular oedema is an important component of diabetic retinopathy. Macular thickness can be accurately quantified by optical coherence tomography (OCT), enabling accurate assessment of the macular prior to clinically apparent abnormalities. We investigated whether macular (fovea) thickness in non-diabetic individuals is related to the microvascular variables controlling fluid filtration across a blood vessel wall, in particular capillary pressure and the microvascular filtration capacity (Kf). METHODS: We recruited 50 non-diabetic individuals (25 men, 25 women; age range: 26-78 years; BMI range: 20-46 kg/m(2)). Fovea thickness was assessed by OCT. Microvascular assessments included: finger nailfold capillary pressure; Kf; microvascular structural assessments, i.e. skin vasodilatory capacity, minimum vascular resistance (MVR) and microvascular distensibility; and endothelial function. RESULTS: At 214.6 (19.9) microm (mean [SD]), fovea thickness was within normal range. Capillary pressure, adjusted for BMI, was associated with fovea thickness (standardised beta 0.573, p = 0.006, linear regression). Fovea thickness was not associated with Kf, microvascular structural assessments or endothelial function. Capillary pressure was still associated with fovea thickness when adjusted for microvascular variables (Kf, vasodilatory capacity, MVR, microvascular distensibility or endothelial function), or for risk factors for diabetes (systemic blood pressure, insulin sensitivity, inflammation, glycaemic status and lipids) and age. CONCLUSIONS/INTERPRETATION: Capillary pressure, a key determinant of movement of fluid across a blood vessel wall, is associated with fovea thickness in non-diabetic individuals. This suggests that with regard to potential preventative or therapeutic targets, attention should be directed at the mechanisms determining retinal microvascular pressure.

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AIMS/HYPOTHESIS: Hydrogen sulphide is a recently identified endogenous endothelium-dependent vasodilator. Animal models of diabetes have shown that low plasma H(2)S levels are associated with marked endothelial dysfunction and insulin resistance. However, human studies on H(2)S and vascular function in health and disease are lacking. METHODS: Plasma was obtained from male patients with type 2 diabetes (n = 11), overweight (n = 16) and lean (n = 11) volunteers. H(2)S levels were determined by zinc trap spectrophotometry. Anthropometric measurements (BMI/waist:hip ratio), lipid profile, systemic blood pressure, biochemical indices of diabetes (fasting glucose, insulin sensitivity, Hb(1Ac)) and microvascular function (minimum vascular resistance) were determined. RESULTS: Median plasma H(2)S levels (25th, 75th percentiles) in age-matched lean, overweight and type 2 diabetes individuals were 38.9 (29.7, 45.1) micromol/l, 22.0 (18.6, 26.7) micromol/l and 10.5 (4.8, 22.0) micromol/l, respectively. Median plasma H(2)S levels were significantly lower in patients with type 2 diabetes compared with lean (p = 0.001, Mann-Whitney) and overweight participants (p = 0.008). Median plasma H(2)S levels in overweight participants were significantly lower than in lean controls (p = 0.003). Waist circumference was an independent predictor of plasma H(2)S (R (2) = 0.423, standardised beta: -0.650, p < 0.001). This relationship was independent of diabetes, which only contributed a further 5% to the model (R (2) = 0.477). Waist circumference or other measures of adiposity (waist:hip ratio/BMI) remained independent predictors of plasma H(2)S after adjustment for systolic blood pressure, microvascular function, insulin sensitivity, glycaemic control and lipid profile. CONCLUSIONS/INTERPRETATION: Plasma H(2)S levels are reduced in overweight participants and patients with type 2 diabetes. Increasing adiposity is a major determinant of plasma H(2)S levels.

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AIMS/HYPOTHESIS: Adults with type 2 diabetes mellitus have impaired microvascular function. It has been hypothesised that microvascular function may be restored through regular exercise. The aim of this study was to investigate whether 6 months of regular aerobic exercise would improve microvascular function in adults with type 2 diabetes. MATERIALS AND METHODS: Fifty-nine patients with type 2 diabetes (32 males, age 62.9+/-7.6 years, HbA(1c) 6.8+/-0.9%) were randomised to either a 6-month aerobic exercise programme (30 min, three times a week, 70-80% of maximal heart rate) or a 'standard care' control group. Before and after the intervention period, microvascular function was assessed as the maximum skin hyperaemia to local heating and endothelial and non-endothelial responsiveness following the iontophoretic application of acetylcholine and sodium nitroprusside. Maximal oxygen uptake, as an index of aerobic fitness, was assessed using a maximal exercise test. RESULTS: No significant improvement was seen in the exercise group compared with the control group for any of the variables measured: maximal oxygen uptake (control pre: 1.73+/-0.53 [means+/-SD] vs post: 1.67+/-0.40; exercise pre: 1.75+/-0.56 vs post: 1.87+/-0.62 l/min, p=0.10); insulin sensitivity (insulin tolerance test) (control pre: -0.17+/-0.06 vs post: -0.17+/-0.06; exercise pre: -0.16+/-0.1 vs post: -0.17+/-0.07 mmol l(-1) min(-1), p=0.97); maximal hyperaemia (control pre: 1.49+/-0.43 vs post: 1.52+/-0.57; exercise pre: 1.42+/-0.36 vs post: 1.47+/-0.33 V, p=0.85); peak response to acetylcholine (control pre: 1.37+/-0.47 vs post: 1.28+/-0.37; exercise pre: 1.27+/-0.44 vs post: 1.44+/-0.23 V, p=0.19) or to sodium nitroprusside (control pre: 1.09+/-0.50 vs post: 1.10+/-0.39; exercise pre: 1.12+/-0.28 vs post: 1.13+/-0.40 V, p=0.98). CONCLUSIONS/INTERPRETATION: In this group of type 2 diabetic patients with good glycaemic control a 6-month aerobic exercise programme did not improve microvascular function or aerobic fitness.

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AIMS/HYPOTHESIS: Insulin resistance is associated with abnormal microvascular function. Treatment with insulin sensitisers may provoke oedema, suggesting microvascular effects. The mechanisms underlying the peripheral oedema observed during glucose-lowering treatment with thiazolidinediones are unclear. Therefore we examined the effect of pioglitazone on microvascular variables involved in oedema formation. METHODS: Subjects (40-80 years) with type 2 diabetes and on insulin were randomised to 9 weeks of pioglitazone therapy (30 mg/day; n=14) or placebo (n=15). The following assessments were performed at baseline and 9 weeks: microvascular filtration capacity; isovolumetric venous pressure; capillary pressure; capillary recruitment following venous or arterial occlusion; postural vasoconstriction; and maximum blood flow. A number of haematological variables were also measured including vascular endothelium growth factor (VEGF), IL-6 and C-reactive protein (CRP). RESULTS: Pioglitazone did not significantly influence any microcirculatory variable as compared with placebo (analysis of covariance [ANCOVA] for microvascular filtration capacity for the two groups, p=0.26). Mean VEGF increased with pioglitazone (61.1 pg/ml), but not significantly more than placebo (9.76 pg/ml, p=0.94). HbA(1c) levels and the inflammatory markers IL-6 and CRP decreased with pioglitazone compared with placebo (ANCOVA: p=0.009, p=0.001 and p=0.004, respectively). CONCLUSIONS/INTERPRETATION: Pioglitazone improved glycaemic control and inflammatory markers over 9 weeks but had no effect on microcirculatory variables associated with oedema or insulin resistance in type 2 diabetic patients treated with insulin.

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AIMS: Abnormalities of microvascular and endothelial function are present in subjects with Type 2 diabetes. Although statin therapy improves cardiovascular risk in diabetes, dyslipidaemia in diabetes may be more responsive to combined statin and fibrate therapy. We examined the effect of cerivastatin and fenofibrate on microvascular function in subjects with Type 2 diabetes with no clinical evidence of cardiovascular disease and near normal lipid levels. METHODS: Age-, sex-, lipid- and blood pressure-matched subjects with Type 2 diabetes were randomized in double-blind fashion to one of four treatment groups: group 1 placebo/placebo (n=12), group 2 fenofibrate/placebo (n=10), group 3 cerivastatin/placebo (n=20) and group 4 cerivastatin/fenofibrate (n=11). The subjects were recruited from the Lipid in Diabetes Study. Microvascular function was assessed by skin blood flow response to iontophoresis of acetylcholine and sodium nitroprusside and by skin maximum hyperaemia to local heating. Measurements were carried out at baseline and 3 months later. RESULTS: Although all lipid parameters improved in groups 2-4 after 3 months' therapy, no difference was detected in skin blood flow to iontophoresis or maximum hyperaemia in any of the groups. Highly sensitive c-reactive protein (Hs-CRP) did not change with therapy. CONCLUSIONS: In conclusion, we were unable to demonstrate any improvement in microvascular endothelial function in non-hyperlipidaemic Type 2 diabetic subjects treated with single or combination lipid-lowering therapy.

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CapiFlow (CF), a new fully computerized system for the measurement of capillary blood velocity (CBV) was compared to manual frame by frame analysis (a) in a model system, and (b) in finger nailfold capillaries recorded on video tape. In the model the overall agreement between the two methods was very good (figure 1), with no significant differences being noted between the two sets of results and the calculated velocities. However, when comparing frame by frame and CapiFlow directly, CapiFlow read on average 4.50 +/- 5.21% higher than frame by frame analysis (figure 2). The in vivo results obtained by the two methods showed similar dynamic changes although some differences between the overall mean CBVs were noted (capillary 1, manual 0.13 +/- 0.59 mm s-1 versus CF 0.12 +/- 0.02 mm s-1, (mean +/- SD), p = 0.354; capillary 2, manual 0.66 +/- 0.23 mm s-1 versus CF 0.47 +/- 0.09 mm s-1, p < 0.001; capillary 3, manual 2.53 +/- 0.73 mm s-1 versus CF 2.35 +/- 0.34 mm s-1, p = 0.062). Further analyses established the optimum settings of delta limit and cross correlation. Investigations into the effects of changes in window size, window distance or video settings on CBV results obtained by CapiFlow, indicated that only settings radically different from the optimum had a significant effect on the results obtained.

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Steroid hormones influence mechanisms related to oedema formation, including postural vasoconstriction and vascular tone. We studied fifteen patients (7 male, 8 female) with primary adrenal failure on clinically optimal replacement therapy. Five patients, all female, had clinically detectable oedema. Patients with oedema had evidence of mineralocorticoid deficiency, with increased supine and erect plasma renin activity and greater postural fall in blood pressure. Mean morning plasma cortisol levels were significantly higher in the group with oedema, suggesting they were receiving insufficient mineralocorticoid and a possible relative excess of glucocorticoid. There were no significant differences between patients with and without oedema in lower-limb cutaneous blood flow or in postural vasoconstrictor responses measured by laser Doppler flowmetry. The mechanism of oedema formation is unclear, but appears not to be modulated by haemodynamic mechanisms with expansion of intravascular volume or, in contrast to the known effects of sex hormones, by impairment of postural vasoconstriction. Theoretically, excess glucocorticoid replacement may result in oedema formation, by direct action on vascular tone, by altering capillary permeability, or by influencing other factors such as atrial natriuretic peptide. Measurement of plasma renin activity in conjunction with plasma cortisol profiles may be useful in adjusting replacement therapy in patients with Addison's disease and oedema.

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A model of oxygen transport in perfused myocardial tissue is presented. Steady-state conditions are assumed in order to mimic the metabolic rate of the arrested heart. The model incorporates Michaelis-Menten dependence of mitochondrial oxygen consumption, oxymyoglobin saturation and oxyhemoglobin saturation on oxygen partial pressure (PO2). The transport equations model both the advective supply of oxygen via the coronary circulation and the diffusive exchange of oxygen between tissues and environment across the epicardial and endocardial surfaces. The left ventricle is approximated by an axisymmetric prolate spheroid and the transport equations solved numerically using finite element techniques. Solution yields the PO2 profile across the heart wall. Integration of this profile yields the simulated rate of metabolic oxygen uptake determined according to the Fick principle. Correction for the diffusive flux of oxygen across the surfaces yields the simulated true metabolic rate of oxygen consumption. Simulated values of oxygen uptake are compared with those measured experimentally according to the Fick principle, using saline-perfused, Langendorff-circulated, K(+)-arrested, guinea pig hearts. Four perfusion variables were manipulated: arterial PO2, environmental PO2, coronary flow and perfusion pressure. In each case agreement between simulated and experimentally determined rates of oxygen consumption gives confidence that the model adequately describes the advective and diffusive transport of oxygen in the isolated, arrested, saline-perfused heart.

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Topographical evaluations of the optic discs of 17 eyes obtained using a clinical planimeter, the Rodenstock video-ophthalmograph, and the IS 2000 image analyzer were compared. The parameters studied were vertical and horizontal cup-to-disc ratios, cup volumes, rim areas, disc areas, and rim area-to-disc area ratios. There was good correlation between the measurements obtained by the three methods (correlation coefficients ranged from 0.46 to 0.88). For various parameters, the correlations between clinical planimetry and image analysis were higher than either those between image analysis and video-ophthalmography, or those between clinical planimetry and video-ophthalmography. The mean horizontal cup-to-disc ratios and rim areas as measured by clinical planimetry were significantly higher than those measured by image analysis. Image analysis measured significantly higher disc area and rim areas and lower cup volumes than video-ophthalmography.

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In a prospective study of 57 patients with clinically definite, probable, or possible multiple sclerosis (MS), one-half of whom had a history of optic neuritis, retinal nerve fiber layer (RNFL) defects and the neuroretinal rim (NRR) area were quantitatively determined and compared with the visual evoked potential (VEP). There were abnormal VEP latencies in 63% of all patients (definite and probable = 68%, possible = 50%); local or diffuse RNFL defects in 54%, (definite and probable = 54%, possible = 50%); and an abnormally small NRR area in 30% (definite and probable = 32%, possible = 25%). Abnormalities in one or more of the VEP, RNFL, or NRR area occurred in 86% of all patients (definite and probable = 90%, possible = 75%), thus considerably increasing the yield of optic nerve abnormalities over that of the VEP alone. The predominance and extent of the diffuse RNFL defects, which are axonal abnormalities, suggest a more diffuse optic nerve pathology in MS than can be accounted for by a "plaque" pathology and indicate that extensive axonal loss commonly occurs in the optic nerves of MS.

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We randomly photographed 113 eyes in 113 people without ocular disease. The area of the disk and its neuroretinal rim as well as the width of the disk and cup were measured. The measurements were corrected for magnification of each eye by measuring its refraction and axial length. A linear correlation between disk area and neuroretinal rim area was found (r = .75) as well as a correlation between the disk area and the cup area (r = .83). There was no correlation between age and disk area or rim area.

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The video-ophthalmograph (Rodenstock analyzer) records the topography of the optic disk via simultaneous stereoscopic video images which are stored and analyzed with the help of a microcomputer. We performed a prospective study of 49 eyes of 49 patients to compare the vertical cup-disk ratio, the horizontal cup-disk ratio, the neuroretinal rim area, and the optic disk area obtained with the video-ophthalmograph with those obtained with manual analysis of black-and-white stereoscopic photographs. The correlation coefficients were 0.67, for vertical cup-disk ratio (P = .0000), 0.63 for horizontal cup-disk ratio (P = .0000), 0.72 for neuroretinal rim area (P = .0000), and 0.89 for optic disk area (P = .0000).

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To estimate the usefulness of photographs of the retinal nerve fiber layer in demonstrating glaucomatous neural tissue changes, we examined such photographs of 51 patients with glaucoma, 52 patients with ocular hypertension, and 29 normal individuals. The photographs were assessed in a masked fashion. A semiquantitative damage score was given in subsectors of the arcuate, papillomacular, and nasal nerve fiber bundle areas, separately for localized and diffuse loss of nerve fibers. The coefficients of variation of the reproducibility of retinal nerve fiber layer assessment were 0.22 for diffuse damage and 0.11 for localized damage. We detected abnormal retinal nerve fiber layer changes in 48 of the patients with glaucoma, in 27 of those with ocular hypertension, and in five of the normal control subjects. Generalized reduction of nerve fibers with or without localized defects was more common in patients with glaucoma than in those with ocular hypertension whose abnormal findings were primarily localized defects.

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