Pressure-permeability relationships in crosslinked basement membranes.
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Albumins↗
Biomedical subjects
J E Tooke
Publications and source records attributed to J E Tooke.
The biological zero signal in laser Doppler fluximetry - origins and practical implications.
This study seeks to identify the origin of the signal, known as biological zero, that is obtained using laser Doppler fluximetry when flow is arrested. It makes specific recommendations on how this signal should be measured and handled when undertaking flow studies. The experiments undertaken using flow models, animal and human tissue, organ preparations and human subjects showed that, although there may be contributions to the no-flow laser Doppler signal from vasomotion, Brownian motion from within the vascular compartment and the effects of cuff compression, the predominant contribution is from Brownian motion arising from the interstitial compartment. The biological zero signal is additive to the flow signal providing conditions within the interstitium remain constant with changes in blood flow. It is thus concluded that the biological zero signal arises from Brownian motion of the macro molecules within the interstitium. This signal should be obtained following 3-5 min of cuff occlusion with inflation applied rapidly with the smallest cuff that is compatible with flow arrest. Biological zero should be measured under each experimental condition and subtracted from the flow signal.
Adipose Tissue↗
Magnetic resonance imaging techniques demonstrate soft tissue damage in the diabetic foot.
AIMS: Our objective was to assess the qualitative soft tissue changes which occur in the diabetic neuropathic foot, which may predispose to ulceration, using a specific magnetic resonance imaging (MRI) contrast sequence, magnetization transfer (MT) which produces contrast based on exchange between water bound to macromolecules (e.g. collagen) and free water (e.g. extracellular fluid). METHODS: The first metatarsal head of 19 diabetic neuropathic subjects and 11 diabetic non-neuropathic controls was studied using a 'targeted' radiofrequency coil. Neuropathy was classified using vibration perception threshold (VPT) (< or > 25 V), cold threshold (< 1 degree C or > 4 degrees C) and Michigan neuropathy score (< 5 or > 15). Peripheral vascular disease was excluded. Results were expressed as percentage of tissue MT activity in a cross-sectional area. At autopsy full thickness biopsies were taken from the plantar fat pad of 10 unrelated subjects with diabetic neuropathy. RESULTS: Healthy muscle displays high MT activity, whereas adipose tissue induces little activity. Muscle MT activity was considerably reduced (75+/-20%, 30+/-24%, P<0.001) and fat pad MT activity was considerably increased in subjects with neuropathy (37+/-17% 68+/-21%, P<0.001). Muscle fibre atrophy decreases MT activity, whereas fibrous infiltration of the fat pad increases MT activity, fibro-atrophic post-mortem histological changes were found in the plantar fat pads of all neuropathic subjects examined (n = 10). CONCLUSIONS: Changes in MT activity reflect qualitative structural changes which this study reveals are extensive in the diabetic neuropathic foot. Fibrotic atrophy of the plantar fat pad may affect its ability to dissipate the increased weight-bearing forces associated with diabetic neuropathy.
Adipose Tissue↗
Vascular function in Type 2 diabetes mellitus and pre-diabetes: the case for intrinsic endotheiopathy.
Diabetic angiopathy is a major cause of morbidity and mortality in Type 2 diabetes mellitus (DM). The pathogenesis of vascular complications in this condition appears to be complex, with distinct differences being observed between Type 1 and Type 2 DM. This review outlines the evidence for these differences and identifies endothelial dysfunction as an important associate and antecedent of Type 2DM, which predisposes to characteristic vascular complications and may also have implications for fetal development.
Diabetes Mellitus, Type 2↗
Impaired maximum microvascular hyperaemia in patients with MODY 3 (hepatocyte nuclear factor-1alpha gene mutations).
AIMS: Functional abnormalities of blood flow and capillary pressure may be involved in the pathogenesis of diabetic microangiopathy. Important differences in microvascular behaviour are observed between Type 1 and Type 2 diabetes mellitus, raising the possibility that the pathogenesis of microangiopathy may differ between these. MODY3 patients have hyperglycaemia as a result of genetic defect of beta-cell function rather than increased insulin resistance and are susceptible to microvascular complications and offer an opportunity to examine microvascular behaviour in this setting. METHODS: The maximum microvascular hyperaemic response to local heating of the skin was studied in 12 MODY3 patients and age and sex-matched control subjects using laser Doppler fluximetry. RESULTS: Maximum hyperaemia was reduced in MODY3 patients (median 1.17 (range 0.88-1.92)V vs. 1.70 (1.07-2.19)V normal control subjects; P=0.03) and thus was negatively associated with duration of diabetes (r(s)=-0.79; P = 0.002). CONCLUSIONS: The results suggest that the duration of diabetes is a determinant of impaired microvascular hyperaemia in MODY3 patients. The pattern of vasodilatory impairment is similar to that observed in Type 1 diabetes mellitus and differs from that seen in Type 2 diabetes. This provides support for the concept that beta cell dysfunction and insulin resistance may have differing effects on microvascular behaviour.
Adult↗
The use of digital cameras in a mobile retinal screening environment.
AIMS: To assess how successfully digital camera technology might be incorporated into a mobile screening environment. METHODS: One hundred and ninety-seven people had their fundi photographed using a Topcon/Imagenet digital system and 534 using a Canon CR5/Ris-Lite system in addition to concurrent 45 degrees CR4NM Polaroid photography. One hundred and eighteen randomly selected patients were also sent for 7 field stereo photography as a gold standard. An acceptability questionnaire was answered by a random sample of those photographed. RESULTS: For the detection of any retinopathy, digital pictures had a sensitivity of 0.74 (95% confidence interval (CI) 0.68-0.80) whilst Polaroid was 0.72 (95% CI 0.66-0.78) and for referable retinopathy digital pictures had a sensitivity of 0.85 (95% CI 0.80-0.90) and Polaroid was 0.90 (95% CI 0.86-0.94). A concurrent ophthalmoscopic evaluation improved the sensitivity to 0.92 (95% CI 0.86-0.98) for detection of any retinopathy whilst the sensitivity at the referral level was improved to 0.95 (95% CI 0.91-0.99). Twenty-nine of 176 respondents experienced flash discomfort with the Polaroid system with only four of 154 describing 'some' discomfort from the digital systems which have a lower flash power (10 W vs. 300 W) and a faster recovery time. CONCLUSIONS: This study indicates that digital systems are a feasible and acceptable alternative to Polaroid-based cameras for use in a mobile environment.
Adult↗
Peripheral microvascular parameters in the nephrotic syndrome.
BACKGROUND: Peripheral edema, in combination with severe proteinuria and low serum albumin levels, is pathognomonic of the nephrotic syndrome, yet the exact mechanism of its formation is unknown. Two of the most important of the factors in Starling's forces controlling fluid filtration across the capillary have hitherto not been studied in nephrotic subjects. METHODS: The hydrostatic capillary pressure at the finger nail-fold in actively nephrotic subjects and age and sex matched controls was studied, using direct puncture of the apex of the capillary under video microscopy, and a servonulling apparatus to give a direct measurement of capillary pressure. Capillary filtration capacity (CFC) at the calf was measured noninvasively by a modern derivative of the technique of mercury strain gauge plethysmography. Fifteen nephrotic subjects with a variety of underlying pathological lesions, and age matched controls were studied. RESULTS: Contrary to the assumption of the "overflow" hypothesis of edema formation, there was no evidence of capillary hypertension. The capillary pressure showed no difference between nephrotic subjects and controls: median (range) of 17.6 (12.0 to 24.2) compared with 17.3 (9.0 to 21.6) mm Hg, P = NS. CFC was significantly higher in nephrotic subjects than controls [5.23 (3.28 to 8.52) x 10(-3) versus 3.55 (2.43 to 5.28) x 10(-3) ml/min/100 g/mm Hg, P < 0.01]. CONCLUSIONS: An increase in CFC provides a potentially novel mechanism contributing at least in part to the formation of peripheral edema in the nephrotic syndrome.
Adult↗
Limb capillary filtration coefficient in human subjects: the importance of the site of measurement.
Capillary filtration coefficient is a critical determinant of fluid flux across the microvascular wall. Changes in capillary filtration coefficient have been described in a number of disease processes. Measurement is typically made by venous occlusion plethysmography using either the upper or lower limb, but a variety of measurement protocols have been used and the importance of the site of measurement remains unclear. In this study, forearm and calf capillary filtration coefficient were measured in healthy volunteers, either simultaneously (group A; n = 11) or sequentially in random order (group B; n = 11) using venous occlusion plethysmography, with the subject supine and the limb at heart level. In both studies capillary filtration coefficient was significantly higher when measured at the forearm than at the calf (group A: 6.1 +/- 1.0 versus 3.7 +/- 1.1 x 10(-3) ml min(-1) mmHg(-1) 100 ml(-1) (mean +/- SD), p < 0.01; group B: 5.1 +/- 1.2 versus 3.2 +/- 1.1 x 10(-3) ml min(-1) mmHg(-1) 100 ml(-1), p < 0.01). Isovolumetric venous pressure (the maximum pressure at which there is neither net filtration nor absorption at the microvascular wall) was similar in upper and lower limbs in both groups of subjects. We conclude that limb capillary filtration coefficient is dependent on the site of measurement. Caution is required when comparing data recorded at different sites even if corrected for the volume of soft tissue under study.
Adult↗
Pressure-permeability relationships in basement membrane: effects of static and dynamic pressures.
The glomerular basement membrane (GBM) is an important component of the filtration barrier that is the glomerular capillary wall. Previously GBM permeability has been investigated only under static pressures and often within a supraphysiological range. We used Matrigel as a model of GBM and formed membranes at the base of filtration chamber. We measured membrane permeability under static and dynamic pressures. Matrigel membranes were size and charge selective toward neutrally and negatively charged dextrans. Their permeability (as measured by hydraulic conductivity) was found to decrease from 1.61 +/- 0.06 to 0.75 +/- 0.07 x 10(-6) cm.s-1.cmH2O-1 as static pressure increased from 6 to 78 cmH2O, an effect attributed to membrane compression. In comparison to static pressure, sinusoidal pressure waves with a mean pressure of 50 cmH2O decreased membrane permeability, e.g., fluid flux was reduced by a maximum of 2% to a value of 5.47 +/- 0.38 x 10(-5) cm/s; albumin clearance was reduced by a maximum of 5.2% to a value of 9.63 +/- 1.06 x 10(-6) ml.cm-2.s-1. Such changes were affected by the frequency of pressure wave application and could be attributed to a switching on and off of the membrane compression effect.
Animals↗
Ambulatory blood pressure monitoring for hypertension in general practice.
Ambulatory blood pressure monitoring (ABPM) is being increasingly used in general practice. There is at present little published evidence regarding the clinical utility of ABPM in the care of patients with established hypertension in this setting. We examined this issue by undertaking ABPM in a group of patients with established hypertension. 40 patients (aged 33-60 years) currently being treated for hypertension were randomly selected from a general practice list and underwent a single 24-hour ABPM study. ABPM values were compared with clinic blood pressure (CBP) values obtained on the day of monitoring together with previous readings taken by the general practitioner (GP). In the case of mean arterial pressure, 24-hour, awake and asleep ABPM values were found to underestimate CBP values by 14 mmHg (95% confidence interval 11-16 mmHg), 9 mmHg (95% C16-12 mmHg) and 24 mmHg (95% CI 21-27 mmHg), respectively. When used to classify blood pressure control, ABPM values produced equivalent results to CBP except by the criterion of BP load, for which 24-hour ABPM showed a higher rate of unsatisfactory control. 5 patients classified by CBP to have satisfactory BP control according to current international guidelines were found to have unsatisfactory BP control by ABPM. This study demonstrates the potential value of ABPM in patients with essential hypertension in a general practice setting. ABPM provided information over and above that obtained by CBP in a substantial proportion of patients.
Adult↗
Endotheliopathy precedes type 2 diabetes.
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Arteries↗
Relationship of insulin resistance to microvascular dysfunction in subjects with fasting hyperglycaemia.
Microvascular hyperaemia is decreased in subjects at risk of developing non-insulin-dependent diabetes mellitus (NIDDM) who have fasting hyperglycaemia. Such microvascular abnormalities may be involved in the pathogenesis of diabetic microangiopathy. To investigate the relationship of reduced microvascular hyperaemia to metabolic and blood pressure abnormalities associated with the prediabetic state, we studied 24 subjects with fasting hyperglycaemia and 24 age- and sex-matched control subjects. The microvascular hyperaemic response to local heating of the skin on the dorsum of the foot measured by laser Doppler fluximetry was reduced in the subjects with fasting hyperglycaemia (1.18 [0.87-1.83] volts vs 1.51 [1.30-2.14] volts normal subjects; p = 0.0002) and was negatively correlated with fasting plasma insulin concentration (Rs = 0.70; p = 0.001) and positively related to insulin sensitivity determined by continuous infusion of glucose with model assessment (CIGMA) (Rs = 0.52; p = 0.01), but showed no association with fasting plasma glucose, beta-cell function 24 h ambulatory blood pressure profiles or serum lipid concentrations. These results suggests that hyperinsulinaemia, as a result of insulin resistance, may have a detrimental effect on microvascular function in the prediabetic state.
Adult↗
Capillary filtration coefficient and urinary albumin leak at altitude.
Rapid ascent to altitude risks the development of acute mountain sickness. This study demonstrates changes in peripheral capillary filtration coefficient and renal protein loss in subjects suffering from various degrees of mountain sickness after passive ascent to 4559 m. Capillary filtration coefficient of the calf capillary bed, measured by computer-based multistep strain gauge plethysmography, increased significantly after 23.5 h at altitude when symptoms were most severe: 4.45 (2.76-6.03) to 6.31 (3.86-11.07) ml min(-1) per 100 g of tissue mmHg(-1), median (range) (P < 0.02). Urinary albumin excretion was increased after one night at altitude from 1.1 (0.6-1.5) to 2.45 (1.0-6-8) mg of albumin per mmol of creatinine (P < 0.05). These results demonstrate simultaneous leakage of a peripheral capillary bed to fluid measured by strain gauge plethysmography, and renal albumin leak, and suggest a systemic process of increased capillary leakage for different-sized molecules caused by rapid exposure to hypobaric hypoxia.
Adult↗
Skin capillary density in subjects with impaired glucose tolerance and patients with type 2 diabetes.
In view of recent interest in the role of impaired early development and the pathogenesis of cardiovascular disease and carbohydrate intolerance in adults, this study examines whether reduced skin capillary density contributes to the limited microvascular hyperaemic responses observed in patients with Type 2 diabetes and subjects with impaired glucose tolerance (IGT). Fifteen patients with Type 2 diabetes, 15 subjects with IGT and 15 matched non-diabetic control subjects were studied. Capillary videomicroscopy was used to record images of the skin capillaries on the dorsum of the middle phalanx of the left middle finger before and after 10 min venous occlusion at 35 mmHg. There were no significant differences between the three groups in either basal capillary density (112 (71-144) caps mm-2 Type 2 patients (median and range) vs 107 (76-140) caps mm-2 IGT subjects vs 112 (76-138) caps mm-2 control subjects; p = 0.9, Kruskal Wallis), or following venous occlusion (122 (87-157) caps mm-2 vs 121 (90-143) caps mm-2 vs 123 (81-147) caps mm-1; p = 0.9). In addition there were no differences in blood pressure, BMI or skin temperature. These results do not support the concept of impaired early development of the skin microcirculation in patients with Type 2 diabetes or IGT and suggest that mechanisms other than reduced capillary density are involved in limiting microvascular vasodilation.
Adult↗
Magnetic resonance imaging reveals micro-haemorrhage in the feet of diabetic patients with a history of ulceration.
Soft tissue haemorrhage in the foot is a possible precursor of ulceration in patients with diabetic peripheral neuropathy. High resolution 'targetted' magnetic resonance imaging was used to scan the forefoot. Neuropathic patients with and without previous ulceration were matched for degree of neuropathy, mean vibration perception threshold 33.5 +/- 4.2 V (previous ulcer) vs 31.0 +/- 6.9 V (no ulcer), age, sex, and duration of diabetes against non-neuropathic controls. There were nine patients in each category. Paramagnetic materials, e.g. iron compounds, cause a signal void ('drop-out') on gradient-echo images which disappear on spin-echo images. Evidence of haemorrhage was seen in 6 patients with previous ulceration, and none in the other groups (p = 0.009, chi square test). Autologous injection of 20 microliters of blood into the foot of a healthy volunteer produced similar images, a 'drop-out' 1 cm across being visible on magnetic resonance scanning 3 days later. Peak vertical forefoot pressures were not significantly different in the neuropathic groups 0.67 +/- 0.20 vs 0.60 +/- 0.13 Pa but were lower in the non-neuropathic group, 0.43 +/- 0.11 Pa (p = 0.0004, Mann-Whitney), and do not explain the appearance of these haemorrhages. Magnetic resonance imaging provides a sensitive way of detecting micro-haemorrhage and its presence may predict an increased risk of foot ulceration.
Blood Pressure↗
Endothelium: the main actor or choreographer in the remodelling of the retinal microvasculature in diabetes?
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Diabetic Retinopathy↗
Microvascular functional abnormalities in diabetes: the role of the endothelium.
The development of techniques for measuring microvascular pressure, flow and permeability in man has allowed the construct of a pathophysiological framework for the development of diabetic microangiopathy. In insulin dependent disease the abnormalities observed conform to the haemodynamic hypothesis with early elevation of capillary pressure playing a primary role. In non insulin dependent diabetes differences are apparent, supporting the concept that changes in microvascular vasodilatory mechanisms may antedate the emergence of diabetes. Given the crucial role played by the endothelium in the regulation of local microvascular haemodynamics it is not surprising that disturbance of this tissue has been implicated in the pathogenetic process, an assertion supported by mounting experimental evidence suggesting that the nitric oxide pathway is crucially involved.
Diabetes Mellitus, Type 1↗
Peripheral microvascular disease in diabetes.
In recent years a variety of techniques have been developed for studying peripheral microvascular function in man, which have provided important information regarding the functional breakdown of the microcirculation in diabetes mellitus. In insulin dependent diabetes a sequence of physiological changes have been described which support the so-called haemodynamic hypothesis: control-dependent increases in capillary pressure result in microvascular sclerosis leading to limitation of hyperaemia and loss of autoregulation. Furthermore, capillary pressure appears to be especially raised in patients with incipient nephropathy who are at particular risk of microangiopathy. The limitation of maximum hyperaemia is duration related, may be observed in early childhood, and is correlated with the degree of basement membrane thickening. In contrast in normotensive non-insulin dependent patients a different array of functional disturbances are described: Capillary pressure and capillary filtration coefficient are normal whereas maximum hyperaemia is profoundly depressed even at diagnosis. This differential pattern of abnormalities arguably reflects the impact of a prediabetic insulin resistant phase on the subsequent expression of microangiopathy. An understanding of the physiological breakdown of the microcirculation in diabetes permits the generation of plausible candidate cellular and molecular mechanisms, knowledge of which will accelerate the development of protective therapy.
Blood Pressure↗