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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
PubMed1995

Postural hypotension in diabetic autonomic neuropathy: a review.

Postural hypotension is uncommon in diabetes but can occur secondary to autonomic neuropathy. Symptoms are rare and include dizziness, weakness, blurred vision, tiredness, and loss of consciousness. The pathophysiology of postural hypotension is not clear, but changes in intravascular volume, heart rate, cardiac output, and splanchnic vascular resistance are similar in patients and controls. The main factors producing hypotension are a blunted catecholamine response to standing, and failure of lower limb vascular resistance to increase adequately. Treatment for symptomatic postural hypotension includes avoidance of dehydration, adequate salt intake, and fludrocortisone. Other treatments are reviewed but are less helpful. Patients with postural hypotension have intermittent symptoms over the years but rarely become severely disabled. They have a poorer prognosis than patients with symptomatic autonomic neuropathy without postural hypotension.

Autonomic Nervous System↗
PubMed1995

The splanchnic circulation and postural hypotension in diabetic autonomic neuropathy.

Postural hypotension results from sympathetic failure to cause superior peripheral vasoconstriction. The importance of the splanchnic circulation was studied by measuring mesenteric artery blood flow with duplex Doppler scanning. Nine normal and 9 Type 1 diabetic controls were compared to 8 Type 1 patients with autonomic neuropathy whose pressure fell 40-113 mmHg (range) on tilting. Measurements were made supine and after vertical tilt, fasting without insulin and after a 550 kcal meal. Superior mesenteric artery diameter decreased on tilting in normal controls but not in diabetic control or neuropathy groups (supine vs tilted: controls. 6.3 +/- 0.9 to 5 +/- 0.9 mm, p = 0.004, diabetic controls: 6.0 +/- 0.6 to 6.0 +/- 1.0 mm, and neuropathy group: 6.4 +/- 0.9 to 5.6 +/- 0.9 mm), but proportional blood flow changes were similar in all subjects (controls: 407 +/- 154 to 255 +/- 67 ml min-1 (-31%, p = 0.03), diabetic controls: 379 +/- 140 to 306 +/- 149 ml min-1 (-8%, p = 0.28), neuropathy group: 639 +/- 371 to 435 +/- 142 ml min-1 (-23%, p = 0.10). Postprandially supine superior mesenteric artery flow increased in all subjects but this did not affect the degree of systolic blood pressure drop on tilting (fasting vs postprandial blood flow: controls: 407 +/- 154 to 775 +/- 400 ml min-1 (p = 0.04), diabetic controls: 379 +/- 140 to 691 +/- 262 ml min-1 (p = 0.01), neuropathy group: 639 +/- 371 to 943 +/- 468 ml min-1 (p < 0.06)). The similarity of superior mesenteric artery responses to tilting in the three groups, and the lack of exacerbation of postural hypotension in the presence of postprandial hyperaemia indicates that control of splanchnic blood flow is less important in the aetiology of diabetic autonomic postural hypotension than previously thought.

Adult↗
PubMed1995

Reduction of gangrene and amputations in diabetic renal transplant patients: the role of a special foot clinic.

This 4-year prospective study investigated the reasons for high levels of gangrene and major amputation in diabetic renal transplant patients and whether regular multidisciplinary foot care could reduce morbidity. All foot lesions were documented and investigated in 50 diabetic patients, mean age 49.2 +/- 11.0 (SD) years, duration of diabetes 25.3 +/- 9.0 years, time since renal transplantation 60.2 +/- 35.1 months, who attended a special foot clinic monthly for education, vascular and neurological assessment, podiatry and footwear. Foot lesions included: neuropathic ulcers, ischaemic ulcers, traumatic lesions, Charcot's arthropathy, pathological fracture. Treatment included antibiotics, podiatry, footwear, and angioplasty or distal bypass where appropriate. Only 13 patients were deemed ischaemic but peripheral neuropathy was a very common finding (mean VPT 24.8 +/- 12.9 V). Gangrene and major amputations showed a decrease on previous years and healing times for lesions were similar to those previously reported in diabetic patients without renal transplants. The majority of foot lesions, both in soft tissue and bone, were related to neuropathy and trauma and responded well to optimal foot care within the renal unit. Gangrene and major amputations were usually preventable.

Ambulatory Care Facilities↗
PubMed1995

Lower limb venous pressure in diabetic neuropathy.

OBJECTIVE: Distended turgid veins have been noted in the feet of patients with diabetic neuropathy. This study assessed the supine venous pressure and its correlation with diabetic neuropathy and arteriovenous (AV) shunting in the feet of type I and type II diabetic subjects. RESEARCH DESIGN AND METHODS: Seventeen patients with chronic Charcot joints, 11 patients with a history of neuropathic foot ulceration, 14 diabetic control subjects, and 11 normal control subjects were studied. Neuropathy was assessed by vibration and thermal thresholds and standard cardiovascular autonomic neuropathy tests. Supine venous pressure was measured by insertion of a 21-gauge needle connected to a strain gauge manometer into the veins on the dorsum of the foot. Venous PO2 was used as a measure of AV shunting. RESULTS: Venous pressure was raised in the group with chronic Charcot joints (18.9 +/- 4.2 mmHg, P < 0.001 vs. the diabetic control group [11.3 +/- 2.6 mmHg]), the normal control group (12.3 +/- 2.3 mmHg, mean +/- SD), and the diabetic group with a history of neuropathic foot ulceration (16.0 +/- 3.7 mmHg, P = 0.008 vs. diabetic control subjects and P = 0.04 vs. normal control subjects), with a maximum of 28 mmHg. Venous pressure was correlated with heart rate variation to deep breathing, r = -0.61 (P = 0.001), vibration threshold, r = 0.56 (P = 0.001), Valsalva ratio, r = -0.64 (P -= 0.001), warm threshold, r = 0.69 (P = 0.001), and venous PO2, r = 0.43 (P = 0.02). There was no correlation with skin temperature, duration of diabetes, age, HbA1c, random blood glucose, ankle/brachial Doppler index, height, or serum creatinine. CONCLUSIONS: Venous pressure is much higher in the neuropathic diabetic limb and is correlated with the severity of neuropathy and with AV shunting.

Adult↗
PubMed1995

Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation.

We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus.

Adult↗
PubMed1994

A comparison of perineurial and vascular basal laminal changes in diabetic neuropathy.

Measurements were made of the thickness of the basal lamina of perineurial cells in the sural nerve in a series of patients with diabetic neuropathy and compared with a group of patients with type I hereditary motor and sensory neuropathy (HMSN) and with organ donor control cases. The thickness was significantly greater in the diabetic patients as compared both with the HMSN cases and the organ donor controls. This was most obvious for the intermediate layers of the perineurium. Perineurial basal laminal thickness was only slightly greater in the HMSN cases than in the organ donor controls and the difference was not statistically significant. The thickening of the perineurial cell basal laminae was compared with the thickening of the basal laminal zone around the endoneurial microvessels. No significant correlation was found either for the diabetic neuropathy or HMSN cases or for the organ donor controls. As had been observed previously, the basal laminal zone around the endoneurial capillaries was of increased thickness both in the diabetic neuropathy and the HMSN cases and, although it was greater for the diabetic neuropathy patients, the difference was not statistically significant. Taken together, these findings indicate that the thickening of the basal lamina of the perineurial cells is a more characteristic feature of diabetic neuropathy than is thickening of the basal laminal zone around the endoneurial capillaries. The results suggest that the causative mechanisms are likely to differ, a conclusion supported by the morphological appearances: the basal laminal thickening around the perineurial cells is uniform, whereas that around the capillaries consists of basal laminal reduplication.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

An investigation of antibodies to nerve growth factor in diabetic autonomic neuropathy.

Nerve growth factor (NGF) is required for development and maintenance of autonomic nervous function and is highly expressed in the iris. An association between sensory and autonomic diabetic neuropathy and NGF function has been postulated. In light of the evidence for an autoimmune component to the pathogenesis of autonomic neuropathy in Type 1 diabetes mellitus, an enzyme linked immunosorbent assay (ELISA) was established to investigate the presence of autoantibodies to mNGF in: 20 patients with long-standing Type 1 diabetes with abnormal autonomic function tests, of whom 14 had symptomatic autonomic neuropathy, 3 had an episode of iritis, and 6 had no autonomic symptoms; 9 age-matched patients with Type 1 diabetes and no complications; 10 healthy control subjects. Insulin antibodies by ELISA and autoantibodies to other endocrine targets were also measured. The specificity of anti-mNGF autoantibody ELISA was further confirmed by immunodepletion on mNGF-Sepharose 4B. No differences in antibody binding to mNGF were detected, between any of the patient groups and control subjects. There was no relationship between age, sex, and diabetes duration and mNGF binding. High levels of anti-mNGF autoantibodies were found in only one diabetic patient who had no evidence of neuropathy, raising the possibility that an autoimmune component to NGF might precede the development of autonomic dysfunction. It remains to be established whether autoantibodies to NGF play a role in diabetic autonomic neuropathy and prospective studies will be required to investigate whether the autoantibodies are a feature of evolving but not established neuropathy.

Adult↗
PubMed1994

The value of the Neurometer in assessing diabetic neuropathy by measurement of the current perception threshold.

The Neurometer is a relatively new device for assessing neuropathy by measuring current perception threshold (CPT). The study aim was to assess the ability of the Neurometer to distinguish between different types of nerve fibre damage by using different frequencies (2000 Hz, 250 Hz, and 5 Hz) of electric stimulus (high frequencies for large fibres and low frequencies for small fibres) and comparing the results with standard sensory tests of vibration perception threshold (VPT) and thermal perception threshold (TPT). CPT was determined on index finger and great toe of 51 patients with diabetic neuropathy and 28 non-diabetic control subjects, age and sex matched. CPT in neuropathic patients could be distinguished from controls at all three frequencies in both feet and hands (p < 0.05). The best correlation was found between CPT at 2000 Hz and VPT (r = 0.48, p < 0.001) in the feet suggesting a degree of neuroselectivity. Internal correlations between CPT at the three frequencies showed the weakest correlation between CPT at 2000 Hz and 5 Hz (r = 0.27, p < 0.005), suggesting also that possibly different types of fibres were examined. CPT reproducibility was better in control (CV = 6.4-27.7%), than in neuropathic subjects (CV = 28.4-52.3%), although the coefficient of variation was comparable to that of standard tests of sensory function, VPT and TPT. The Neurometer is a simple instrument to use in clinical practice. It has a degree of neuroselectivity but like all subjective sensory tests has a large variability.

Adult↗
PubMed1994

High prevalence of autoantibodies to glutamic acid decarboxylase in long-standing IDDM is not a marker of symptomatic autonomic neuropathy.

Immune reactivity to the enzyme glutamic acid decarboxylase (GAD), a pancreatic islet autoantigen, is present at the diagnosis of insulin-dependent diabetes mellitus (IDDM). Because GAD is also highly expressed in the nervous system, we investigated the presence of autoantibodies to the isoform GAD65 in patients with diabetic neuropathy, which is a debilitating complication of the disease. We studied 39 patients with autonomic and somatic neuropathy, 28 patients matched for age and IDDM duration, and 13 patients with a shorter duration of IDDM, all with no diabetic complications, as well as 50 recently diagnosed diabetic patients, 23 neurologic patients with idiopathic autonomic failure unrelated to IDDM, and 72 healthy subjects. An immunoprecipitation radioligand assay was used to detect anti-GAD65 autoantibodies with in vitro transcribed and translated human islet GAD65 as antigen. Autoantibodies to GAD65 were present in 56% of the diabetic patients with neuropathy, 57% of the long-duration and 69% of the short-duration diabetic control subjects, 78% of the recently diagnosed patients, and 13% of the nondiabetic neuropathic patients. Among the diabetic patients with neuropathy, there was no correlation between the presence of anti-GAD65 antibodies and the presence of autoantibodies to sympathetic ganglia, vagus nerve, or adrenal medulla structures identified by immunofluorescence. Our study shows that anti-GAD65 antibodies are present in a high proportion of patients with diabetic neuropathy but are not exclusively associated with it, rendering it unlikely that they have a role as a disease marker or that they are pathogenetic.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

CD5+ B-cells at the onset of type I diabetes and in the prediabetic period.

OBJECTIVE: B-cells expressing CD5 are associated with the production of autoantibodies and are present at increased levels in several autoimmune diseases. The aim of this study was to investigate the relationship of these cells to the development of type I diabetes and the presence of organ and non-organ-specific autoantibodies. RESEARCH DESIGN AND METHODS: We measured percentage levels of CD5+ B-cells in patients with recent-onset (n = 34) and long-standing (n = 21) type I diabetes and in a cohort of 18 identical twins of patients with type I diabetes studied prospectively, 8 of whom became diabetic (prediabetic twins) during the study; the rest remained nondiabetic after at least 7 years and are now unlikely to develop the disease. Forty-seven healthy individuals were studied as control subjects. RESULTS: Percentage levels of total B-cells (CD20+) and the proportion expressing CD5 were increased in patients with recent-onset (P < 0.001 for both) but not long-standing type I diabetes compared with control subjects. Percentage levels of CD20+ B-cells were increased in prediabetic twins throughout the prediabetic period (P < 0.05), and there was an increased proportion of CD5-expressing B-cells that failed to reach statistical significance (P = 0.08). Percentage levels of CD20+ B-cells and the proportion expressing CD5 were normal throughout the study in twins remaining nondiabetic. No relationship between percentage levels of CD5+ B-cells and islet cell antibody, thyroid autoantibodies, or non-organ-specific autoantibodies was found. CONCLUSIONS: These results show an increase in B-cell percentage levels at the diagnosis of type I diabetes, which is because of an expansion of the CD5+ subset. These changes are also evident in twins throughout the prediabetic period, which suggests that they are related to the processes that lead to diabetes.

Adult↗
PubMed1994

T cell clones generated from patients with type 1 diabetes using interleukin-2 proliferate to human islet antigens.

T lymphocytes are implicated in the pathogenesis of Type 1 (insulin dependent) diabetes. Activated T lymphocytes expressing IL-2 receptors are found at increased levels in the peripheral blood in the prediabetic period, at diagnosis and for several months after the onset of the disease, but their role in the pathogenesis of the disease is not known. We have used co-culture of peripheral blood lymphocytes with IL-2 alone to selectively generate T cell clones from the in vivo activated T cell population, and examined the phenotype and antigen specificity of the clones derived. From 3 patients with newly-diagnosed Type 1 diabetes 184 clones were generated, the majority of which (39%) were CD4+TCR alpha beta+, whilst 31% were CD8+TCR alpha beta+. From 2 healthy control subjects 90 clones were obtained, of which 62% were CD4+TCR alpha beta+ and 33% were CD8+TCR alpha beta+. Antigen specificity was examined in 46 clones from the patients and 44 from the control subjects in proliferation assays, using as antigens homogenate of human islets of Langerhans, human islet membrane preparation and human liver membrane preparation. Three clones (all CD4+TCR alpha beta+) from the patients, but none from the control subjects, proliferated in a dose dependent fashion in response to stimulation with human islet homogenate presented by autologous APCs, but to neither of the other autoantigen preparations. Our results demonstrate that a relatively high proportion (7%) of T lymphocytes activated in vivo recognise human islet antigens, indicating that they may have a role in the pathogenesis of the disease.

Adult↗
PubMed1993

Determination of isomeric N-oxide metabolites of some substituted 2,4-diaminopyrimidines by reversed-phase ion-pair high-performance liquid chromatography.

Reversed-phase ion-pair high-performance liquid chromatography has been investigated for the separation, detection, identification and quantitation of the isomeric 1N- and 3N-oxide metabolites of metoprine, pyrimethamine and trimethoprim. A rapid and sensitive analytical method for the simultaneous determination of the isomeric 1N- and 3N-oxides of metoprine and pyrimethamine was devised for in vitro metabolic studies by optimisation of mobile phase pH, pairing-ion concentration, secondary-ion concentration and percentage organic modifier.

Animals↗
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↗