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Biomedical subjects

P J Watkins

Publications and source records attributed to P J Watkins.

At least 19 recordsLinked to original sources
PubMed1992

Linkage of type 2 diabetes to the glucokinase gene.

Maturity-onset diabetes of the young (MODY) is a subtype of type 2 diabetes that presents from the second decade and has an autosomal dominant mode of inheritance. We have investigated the glucokinase gene, a candidate gene for diabetes, in two MODY pedigrees. In a large 5-generation pedigree (BX) with 15 diabetic members, use of a microsatellite polymorphism revealed linkage of diabetes to the glucokinase locus on chromosome 7p. A peak lod score of 4.60 was obtained at a recombination fraction (theta) of zero. This finding suggests that a defective glucokinase gene contributes to the diabetes phenotype in this pedigree. This is not universal in MODY since linkage to the glucokinase locus was excluded in a second pedigree M (lod score = -7.36 at theta = 0). The affected members in pedigree BX were diagnosed either when young (in pregnancy or on screening) or when they presented symptomatically in middle and old age; most of them were treated by diet alone. Defects in the glucokinase gene may play an important part in the pathogenesis of type 2 diabetes.

Adolescent↗
PubMed1992

Clinical observations and experiments in diabetic neuropathy.

Diabetic neuropathies form a group of diverse conditions, which can be distinguished between those which recover (acute painful neuropathies, radiculopathies, mononeuropathies) and those which progress (sensory and autonomic neuropathies). These two main groups can be distinguished in several ways: sensory and autonomic neuropathies are classic diabetic complications progressing gradually in patients with long-standing diabetes who often have other specific complications, while the reversible neuropathies do not have these features. The latter are characterised by their occurrence at any stage of diabetes, often at diagnosis, they may be precipitated on starting insulin treatment, and they are more common in men; they can occur at any age, though more often in older patients, and are unrelated to other diabetic complications. The two groups of neuropathies also show differences in nerve structural abnormalities and with regard to distinctive blood flow responses. The underlying mechanisms responsible for these very different forms of neuropathy remain speculative, but evidence for an immunological basis for the development of severe symptomatic autonomic neuropathy is presented.

Diabetic Neuropathies↗
PubMed1992

Selective neuropathy and preserved vascular responses in the diabetic Charcot foot.

Charcot arthropathy is a disabling complication of diabetic neuropathy. It is however, unclear why it occurs in only a small number of neuropathic patients. We have studied 12 diabetic patients (10 insulin-dependent) with an acute Charcot arthropathy, and compared their neuropathy and vascular responsiveness with 12 diabetic patients (10 insulin-dependent) with recurrent neuropathic foot ulceration, 12 diabetic control subjects (9 insulin-dependent) and 10 normal non-diabetic subjects. The Charcot arthropathy patients demonstrated a preservation of warm perception, 6 (5.5) degrees C, but complete loss of peripheral cold perception, 10 (0) degrees C, p less than 0.001 (median (interquartile range)). This contrasted with the ulcerated neuropathy patients, who had equally severe impairement of both warm and cold sensory thresholds, 10(0.5) degrees C vs 10(1) degrees C, respectively, the diabetic control subjects who were able to detect a 2 (1.3) degrees C warm stimulus and 3 (3.5) degrees C cold stimulus and the normal subjects, whose warm threshold was 2 (1) degrees C and cold was 2 (1) degrees C. Light touch perception at the foot was preserved in the Charcot patients 4 (4) g vs 100 (50) g, p less than 0.0002, in the ulcerated neuropathy patients. Vibration perception at the great toe and cardiovascular autonomic function tests (heart rate variability, Valsalva ratio and postural systolic blood pressure fall) were abnormal in both the Charcot patients and ulcerated neuropathy group, with no differences seen between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Arthropathy, Neurogenic↗
PubMed1991

Isatin (indole-2,3-dione) in urine and tissues. Detection and determination by gas chromatography-mass spectrometry.

A simple procedure based upon capillary column gas chromatography-mass spectrometry (GC-MS) is described for the detection and determination of isatin (indole-2,3-dione) in body fluids and tissues. After addition of 5-methylisatin as internal standard to urine or tissue homogenates, organic extracts are dried and derivatized successively with hydroxylamine hydrochloride and the reagent N-tert.-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA). The tert.-butyldimethylsilyl derivatives obtained show good GC-MS properties and allow quantification by selected-ion monitoring of m/z 333 (isatin) and m/z 347 (internal standard). Adult and newborn human urine output values lie in the ranges 0.4-3.2 mg/mmol of creatinine (5-30 mg per 24 h) and 0.002-0.518 mg/mmol of creatinine, respectively. There is a discontinuous regional distribution in rat tissues. The GC-MS properties of a number of derivatives formed by successive reaction of isatin with hydroxylamine hydrochloride (or methoxyaminehydrochloride or ethoxyamine hydrochloride) and MTBSTFA, bis(trimethylsiyl)trifluoroacetamide, pentafluoropropionic anhydride or pentafluorobenzyl bromide are also described.

Acetamides↗
PubMed1991

Falsely raised ankle/brachial pressure index: a method to determine tibial artery compressibility.

The ankle/brachial index (abPI) may be falsely raised, notably in diabetes, due to the relative incompressibility of the tibial artery. This paper presents a method of determining tibial artery compressibility by deriving abPIs with the patient supine and with legs raised in increments up to 0.55 m (ankle to heart). The effective negative hydrostatic pressure superimposed on the blood pressure at the ankle was converted to mmHg, normalised with respect to the brachial systolic pressure and then expressed as a hydrostatic pressure index (hPI). abPI was regressed on hPI and the gradient of the regression line calculated. If the arterial wall offers no significant resistance to compression the measured pressure will equal intraluminal pressure. In this case regression of the changing arterial pressure with the applied hydrostatic pressure would be expected to produce a gradient of -1. With resistance to compression the measured pressure is greater than the intraluminal pressure and a steeper gradient would be expected. The method was tested using age and sex matched groups, (A) controls (16 arteries), (B) patients with PVD and no diabetes (17 arteries), and (C) diabetics with PVD (34 arteries). There was no significant difference between the regression line gradients of groups A and B but both differ significantly from group C. The difference between the medians of groups B and C was 0.46, the 95% confidence interval for the difference being 0.66 to 0.02. Twelve of the diabetic arteries had a gradient steeper than -1.8 compared with one from group (B) and none from group (C).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Mass spectrometry software for biochemical analysis in electrospray and fast atom bombardment modes.

New mass spectrometry techniques, such as electrospray ionization (ESI), allow the study of large biomolecules and peptide mixtures. The data produced are complex and interpretation can be a long and tedious process. A new suite of data-processing software is described which allows many of these operations to be carried out in a rapid, automated way. Software is described for the deconvolution of the spectra of multiply charged ions, for both pure compounds and mixtures. The rapid peptide mapping of protein digests from h.p.l.c.-m.s. data and peptide sequence confirmation from multiple-stage (MS)-m.s. data using tandem quadrupole m.s. are also described. In addition preliminary results are presented on first principle sequencing of unknown peptides from MS-m.s. experiments.

Amino Acid Sequence↗
PubMed1991

Influence of neuropathy on the microvascular response to local heating in the human diabetic foot.

1. The diabetic neuropathic foot exhibits excess arteriovenous anastomotic shunt flow due to a reduced sympathetic vasoconstrictor tone. Local axon reflexes (mediating postural vasoconstriction, for example) are preserved even in severe diabetic neuropathy. This excess shunt flow and its local neurogenic control may be important in the development of complications of the neuropathic limb. 2. The response of arteriovenous anastomoses to local heating was assessed in 13 diabetic patients with neuropathy (12 insulin-dependent), 10 diabetic control patients (seven insulin-dependent) and 10 normal control subjects. The aim was to study the local reflex control of arteriovenous flow when central sympathetic tone had been largely removed. 3. The change in skin blood flow on local heating to 44 degrees C was measured by using a laser Doppler flowmeter in standard environmental conditions with the foot at heart level. Two sites were assessed: (i) the plantar surface of the great toe (a site in which skin blood flow is dominated by arteriovenous shunt flow) and (ii) the dorsum of the foot (a site without anastomotic flow). 4. It was found that when heat was applied to the plantar surface of the great toe in the diabetic patients with neuropathy a paradoxical decrease in flow through arteriovenous anastomoses occurred, flow declining to 65% (P less than 0.05) of its resting value. This could be compared with an increase in flow over the same time period of 262% and 228% (P less than 0.01) in diabetic control patients and normal subjects, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Sural nerve morphometry in diabetic autonomic and painful sensory neuropathy. A clinicopathological study.

Observations have been made on a selected series of insulin-dependent patients with neuropathy, subdivided into three groups: (1) severe autonomic neuropathy with an accompanying painless sensory neuropathy; (2) severe autonomic neuropathy with a chronic painful sensory neuropathy; and (3) chronic or acute painful sensory neuropathy with no autonomic neuropathy. All three groups showed a loss of large and small myelinated nerve fibres in sural nerve biopsy specimens which was greater in Groups 1 and 2. Regenerative activity was prominent in all three groups, but least in Group 3. Teased fibre studies showed evidence both of axonal regeneration and remyelination. Active fibre degeneration was rare. Measurements of g ratio (axon diameter:total fibre diameter) gave no indication of axonal atrophy. The density of unmyelinated axons was reduced in all three groups, as was their median diameter. Vibration sense threshold was positively correlated with the total number of myelinated fibres and thermal sensory threshold with median unmyelinated axon diameter but not with total unmyelinated axon numbers. No correlation between the occurrence of pain and active degeneration of myelinated fibres or with regenerative activity either in myelinated or unmyelinated axons was detectable. Assessment of differential loss of large or small myelinated nerve fibres was difficult because of the presence of large numbers of small regenerating myelinated axons. The results are discussed in relation to the concept of 'diabetic small fibre neuropathy' and the causation of pain in diabetic neuropathy.

Adult↗
PubMed1991

Disabling postural hypotension complicating diabetic autonomic neuropathy.

A 35-year-old Type 1 diabetic man with severe disabling postural hypotension was studied for physiological abnormalities, precipitating factors, and effect of current treatment. A 24-h blood pressure profile indicated a diurnal variation in systolic blood pressure with the lowest values recorded between 0100 and 0600 h, during which the patient often lost consciousness on standing (mean standing systolic pressure 78 mmHg at night vs 105 mmHg in the afternoon, p less than 0.001). Food induced a profound fall in systolic pressure, both while supine and while standing erect. The systolic pressure fall during euglycaemia was 49 mmHg vs 3 mmHg during hypoglycaemia. Plasma noradrenaline and adrenaline levels were low during euglycaemia, but increased during hypoglycaemia. Therapeutic manoeuvres aimed at increasing heart rate (by atrial tachypacing) and reducing the peripheral pooling of blood (vasoconstricting drugs and gravity suit), together with the somatostatin analogue octreotide, proved ineffective. These observations demonstrate the phenomenon of post-prandial exacerbation of postural hypotension in a Type 1 diabetic patient, and indicate that despite failure of conventional methods of treatment, hypoglycaemia increased plasma catecholamines and was effective in abolishing the blood pressure fall on standing.

Adult↗
PubMed1991

The natural history of diabetic femoral neuropathy.

Diabetic femoral neuropathy is an uncommon, unpleasant and sometimes disabling condition, on account of both pain and muscular atrophy, whose long-term prognosis has not previously been documented. We have reviewed a group of 27 patients up to 14 years (median 62 months) after diagnosis; 18 of these were re-examined after an average of nearly 4 years (median 45 months). The condition was more common in non-insulin-dependent diabetics (88 per cent), in men (59 per cent) and in older patients (median age at diagnosis 64 years). The neuropathy was bilateral (10 cases) or unilateral (17 cases); five patients with unilateral neuropathy developed femoral neuropathy on the opposite side, usually within a few weeks of the first episode. Recovery was apparent after 3 months and usually complete by 18 months; only two of the 27 patients had severe relapses. No patients remained disabled, although there were minor residual symptoms and signs in half of the patients (2 cm reduction in thigh circumference and diminished reflexes). The outlook for femoral neuropathy, even in its most severe form, is therefore very good: residual features are demonstrable but do not cause symptoms, and relapses after the first few weeks are very rare.

Adult↗
PubMed1990

Evaluation of arylmethylaminopropanediols by a novel in vitro pharmacodynamic assay: correlation with antitumor activity in vivo.

The pharmacodynamics of a new series of antitumor DNA intercalators, known as arylmethylaminopropanediols (AMAPs), has been evaluated in vitro against adherent (MCF-7 human breast cancer) and nonadherent (P388 murine leukemia) cell lines. Previous work had shown that the in vitro antitumor activity of the model AMAP crisnatol was a function of exposure (Cn x T), rather than concentration alone. A unique exposure parameter, the minimum C x T, was proposed as an end point for antitumor activity in cell culture. Comparison of crisnatol to several established agents by the minimum C x T versus the standard concentration producing 10% survival indicated that these end points were not equivalent. The current work examined the validity of the pharmacodynamic approach using AMAP isomers from three different ring systems that were known to exhibit a spectrum of activity against the P388 tumor in vivo. The results indicated that antiproliferative, but not cytotoxic, activity of AMAPs in the pharmacodynamic assay correlated with their differential activity in vivo, expressed as percentage of increase in life span. In contrast, the concentration producing 10% survival either at 1 h or after continuous exposure did not show a similar correlation. The pharmacodynamic assay also revealed that certain AMAPs, while equipotent by concentration alone, required significantly less time and therefore less overall exposure for efficacy. Finally, the activity of AMAP isomers in P388 cells differed from that in MCF-7 cells, which may indicate AMAP selectivity for certain tumor types. Since AMAP action was a function of exposure, drug effects on cellular targets could likewise depend on exposure rather than concentration. These findings emphasize the importance of relating drug mechanisms to the pharmacodynamics of anticancer agents.

Animals↗
PubMed1990

Morphometry of endoneurial capillaries in diabetic sensory and autonomic neuropathy.

Nerve biopsies were obtained from 27 patients with diabetic neuropathy. All had a symmetric distal sensory and autonomic neuropathy or a purely sensory neuropathy. Mean age was 39.8 years (range 23-57 years). Two patients had Type 2 (non-insulin-dependent) diabetes mellitus and the remainder Type 1 (insulin-dependent) diabetes. Morphometric observations on endoneurial capillaries were compared with results from organ donor control cases and from patients with type 1 hereditary motor and sensory neuropathy. The area of the lumen of the capillaries did not differ between the three groups. The area occupied by the capillary endothelial cells in transverse section and the number of endothelial cell nuclei were increased both in the patients with diabetic neuropathy and hereditary motor and sensory neuropathy, as was the thickness of the surrounding basal laminal zone. 'Closure' of endoneurial capillaries in diabetic neuropathy, reported in another study, was not confirmed. Capillary density and nearest-neighbour distances were similar in the diabetic and organ donor control cases. Capillary density was reduced in the patients with hereditary motor and sensory neuropathy, this being related to increased fascicular area consequent upon the presence of hypertrophic changes. The presence of thickening of the pericapillary basal laminal zone and endothelial cell hyperplasia both in diabetic and hereditary motor and sensory neuropathy, the latter being a neuropathy in which a vascular basis can be discounted, makes it difficult to use such changes as an argument favouring a vascular cause for diabetic neuropathy. There were differences in the basal laminal zone between the diabetic and hereditary motor and sensory neuropathy cases suggesting that the reduplicated basal lamina was more persistent in the diabetic patients.

Adult↗
PubMed1990

Hyperparathyroid bone disease in diabetic renal failure.

Hyperparathyroid bone disease is a common complication of end stage renal failure, particularly in patients on maintenance haemodialysis. Several studies have, however, shown a near absence of hyperparathyroid bone disease in diabetic patients who have been receiving haemodialysis for periods of up to 4 years. We have studied biochemical indices of mineral metabolism in 54 consecutive pre-dialysis patients with moderate to severe renal impairment. Deteriorating renal function was associated with developing hypocalcaemia and hyperphosphataemia. Hypocalcaemia was strongly related to increased severe alkaline phosphatase activity (p less than 0.001), suggesting the development of hyperparathyroidism. Five patients with hypocalcaemia and increased alkaline phosphatase were studied in detail. All had elevated serum concentrations of parathyroid hormone and histological signs of hyperparathyroidism on bone biopsy. Three of the patients had low serum 25 hydroxyvitamin D levels with associated osteomalacia, the other 2 patients were notable for their long duration of renal failure. In the long-term (greater than 4 years) we also observed the development of hyperparathyroidism in a small group of diabetic patients maintained on haemodialysis. We conclude that diabetic patients are not uniquely protected against renal osteodystrophy. Although the prevalence of hyperparathyroidism may be lower in diabetic patients than in those with other types of renal disease, the same factors which predispose to bone disease in non-diabetic patients (long duration of renal failure, low serum 25 hydroxyvitamin D and long periods on haemodialysis) also operate in the diabetic population.

Adult↗
PubMed1990

Progression of diabetic autonomic neuropathy over a decade in insulin-dependent diabetics.

The prognosis for diabetics with autonomic neuropathy is little known. We therefore studied the progress of young insulin-dependent diabetics, first identified as having abnormal autonomic function 10-15 years ago. We have shown that the mortality of diabetics with symptomatic autonomic neuropathy is increased, but is less than previously reported. Mortality in asymptomatic diabetics with an isolated abnormality in autonomic function tests is not increased. The heart rate variability declines at 1.02 +/- 0.47 (SD) per annum in diabetics with an initially normal heart rate variability. While symptoms of autonomic neuropathy do not usually remit even over a decade, they do not commonly progress. Three groups of young insulin-dependent diabetics had heart rate variability tested between 1972 and 1977 and have been reviewed 10-15 years later. Group A (n = 49) had symptomatic autonomic neuropathy and an abnormal heart rate variability (less than 12), Group B (n = 24) were asymptomatic yet had an abnormal heart rate variability and Group C (n = 38) were asymptomatic and had a normal heart rate variability (16-26). The 10-year survival in Group A (73.4 per cent) was less (P less than 0.05) than in Groups B (91.7 per cent) or C (89.5 per cent) which did not differ from each other. The 18 Group A deaths were due predominantly to renal failure (n = 4), myocardial infarction in patients with nephropathy (n = 3) and sudden unexpected death (n = 3). The chief symptoms of autonomic neuropathy--diarrhoea, postural hypotension and gustatory sweating, were very persistent but did not necessarily deteriorate or become disabling in the majority of patients. The development of autonomic symptoms in asymptomatic patients with abnormal heart rate variability was uncommon over a decade.

Adult↗