Patient records.
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Continuity of Patient Care↗
Biomedical subjects
N Ashton
Publications and source records attributed to N Ashton.
Bactericidal/permeability-increasing protein and lipopolysaccharide (LPS)-binding protein. LPS binding properties and effects on LPS-mediated cell activation.
We have previously shown that human bactericidal/permeability-increasing protein (BPI) is able to inhibit serum-dependent lipopolysaccharide (LPS)-mediated activation of human monocytes and neutrophils in vitro, and to counteract the lethal effects of LPS challenge in vivo. Lipopolysaccharide-binding protein (LBP) is a serum protein which participates in LPS-mediated activation of cells (Tobias, P. S., Mathison, J., Mintz, D., Lee, J. D., Kravchenko, V., Kato, K., Pugin, J., and Ulevitch, R. J. (1992) Am. J. Respir. Cell. Mol. Biol. 7, 239-245). We have proposed that BPI functions in a negative feedback loop which opposes this activation (Marra, M. N., Wilde, C. G., Collins, M. S., Snable, J. L., Thornton, M. B., and Scott, R. W. (1992) J. Immunol. 148, 532-537). We have now cloned and expressed recombinant forms of human BPI and LBP. Here we demonstrate that purified recombinant human LBP can replace the serum requirement for both LPS binding to human monocytes and LPS-mediated secretion of tumor necrosis factor alpha from these cells. These activities of LBP are inhibited by a neutralizing anti-CD14 monoclonal antibody. We further demonstrate that purified recombinant human BPI can inhibit LBP-mediated LPS binding to cells and their subsequent activation. Comparison of the LPS binding properties of BPI and LBP in enzyme-linked immunosorbent type assays and in the Limulus amebocyte lysate assay suggest that BPI has a stronger affinity for LPS than does LBP. Direct competition between BPI and LBP for LPS may explain the inhibition by BPI of the proinflammatory effects of LBP in the presence of LPS.
Acute-Phase Proteins↗
The reflex effect of changes in renal perfusion on hindlimb vascular resistance in anaesthetized rabbits.
This study was designed to characterise the response of the hindlimb vasculature to reduced renal perfusion in the anaesthetized rabbit and to elucidate whether the stimulus was dependent upon reduced renal perfusion pressure (RPP) or blood flow (RBF). Acute decreases in renal perfusion resulted in rapid and reversible increases in femoral perfusion (FPP). This vascular response was completely abolished following renal denervation indicating that the afferent components of the reflex is neurally mediated. Acute hindlimb responses to changes in renal perfusion pressure were present whether the limb was perfused with homologous blood or cross-perfused with blood from a donor rabbit, demonstrating that the efferent component of the response is also neurally mediated. There was a 28-s latency for initiation of the hindlimb vasoconstriction, which is consistent with recent evidence for renal autocoid stimulation of the afferent renal nerve receptors. Decreasing RPP indirectly, by altering flow, resulted in a hindlimb vasoconstriction below approximately 55 mm Hg (7.3 kPa) RPP or 15 ml/min RBF. However, decreasing RPP by directly reducing pressure in graded steps resulted in increases in FPP, which reflected the changes in renal flow; thus during the autoregulatory phase, where flow did not change as pressure fell, FPP also remained stable. The results of these protocols suggest that a neurally mediated hindlimb vascular reflex is stimulated by decreased renal flow rather than pressure.
Anesthesia↗
Surgical correction of the Wolff-Parkinson-White syndrome.
The results of corrective surgery in 75 consecutive patients with Wolff-Parkinson-White (WPW) syndrome are reported. There were 47 male and 28 female patients with a median age of 27 years. Intraoperative mapping disclosed 88 accessory pathways, of which 83 were successfully divided at the primary operation without mortality. Two patients underwent successful reoperation at three days and two years respectively. Patient success rates were 93% and 96% for first and total operations. Complications, usually minor, occurred in 20 patients, including permanent pacemaker implantation in two. Surgical correction of WPW syndrome is recommended as a safe alternative to lifelong medical treatment.
Adolescent↗
Characteristics of fluid secretion from isolated rat pancreatic ducts stimulated with secretin and bombesin.
1. Micropuncture techniques were used to study the cellular mechanisms of fluid secretion by interlobular ducts isolated from the pancreas of copper-deficient rats. 2. Perifusing ducts with a calcium-free buffer containing 5 mM-EGTA reduced the volume of fluid secreted in the presence of 10 nM-bombesin by 62%, whereas fluid secretion measured in the presence of 10 nM-secretin was reduced by only 26%. 3. The anion selectivities of the fluid secretions evoked by secretin and bombesin were different. The anion sequence for secretin was: Br- = I- = NO3- = Cl- (1.0) much greater than thiocyanate = gluconate (0.3); whereas the sequence for bombesin was: Br- = Cl- (1.0) greater than I- = NO3- (0.6) greater than thiocyanate = gluconate (approximately 0.3). 4. SITS (4-acetamido-4'-isothiocyanatostilbene-2,2'-disulphonic acid; mM), reduced fluid secretion measured in the presence of bombesin by 61%, but had no effect on the response to secretin. 5. The K+ channel blockers, barium (3 mM) and tetraethylammonium (TEA; 10 mM), inhibited fluid secretion measured in the presence of both secretin and bombesin by between 52 and 66%. 6. From these results, we conclude that secretin and bombesin may utilize different intracellular signalling pathways and, furthermore, may activate different anion secretory mechanisms within the pancreatic ductal epithelium. However, the effect of the potassium channel blockers is consistent with both peptides activating secretory mechanisms which are electrogenic, and which depend for their operation on potassium efflux across the basolateral membrane of the duct cell.
4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
Sexual dimorphism in renal function and hormonal status of New Zealand genetically hypertensive rats.
Renal water and electrolyte handling and related plasma hormone levels were measured in male and female New Zealand genetically hypertensive and normotensive rats, in an attempt to establish any potentially important sex-related differences in these parameters. Male hypertensive rats had higher blood pressure than female hypertensive rats, but normotensive rats showed no such sex difference. Both groups of males had higher fluid turnover rates than respective females, and this was associated with raised plasma vasopressin in hypertensive males. Female hypertensive rats excreted more sodium, potassium and chloride in association with lower plasma aldosterone and higher corticosterone levels compared with the other groups. Plasma electrolytes did not differ between the four groups, but plasma osmolality was higher in hypertensive than normotensive rats of both sexes. A higher rate of electrolyte loss and lower fluid turnover in association with reduced plasma vasopressin may contribute to the lower blood pressure of female compared with male hypertensive rats.
Aldosterone↗
Operations for Wolff-Parkinson-White syndrome.
Forty-six patients with symptomatic tachycardia underwent operations to divide 55 atrioventricular accessory pathways. Mean age was 29 years (range 11 to 63). Ten patients (22%) had associated cardiac disease, including two with a congenital diverticulum of the coronary sinus and six (13%) who had concomitant surgical procedures. A bipolar hand-held electrode was used in 22 operations, and simultaneous multisite mapping in the last 24 operations. Ten patients (22%) had multiple accessory pathways. A modified endocardial approach was used. The overall patient success rate was 93% with 91% to 93% of accessory pathways successfully divided. The perioperative morbidity was 17%. There were two reoperations. There were no early or late deaths. Patients have been followed up for a mean of 16 months. There were five recurrences of preexcitation (two early, three late). Two of these patients (both with a congenital diverticulum of the coronary sinus) had reoperation. One patient had late recurrence of atrial fibrillation. Operation for the Wolff-Parkinson-White syndrome has a high probability of success with a low operative risk.
Adolescent↗
Kappa-opioid-receptor agonists modulate the renal excretion of water and electrolytes in anaesthetized rats.
1. Subcutaneous injection of the kappa-opioid agonists U50,488 (10 mg kg-1) and tifluadom (3.5 mg kg-1) into Inactin-anaesthetized, saline-infused rats was associated with a diuresis, antinatriuresis and antikaliuresis which lasted for up to 2 h. A high (5 mg kg-1), but not low (0.1 mg kg-1), dose of naloxone blocked the renal effects of U50,488. 2. U50,488 administration in anaesthetized, vasopressin-deficient Brattleboro DI rats was associated with an attenuated diuresis, though the antinatriuretic response remained intact. 3. The diuretic action of U50,488 was associated with an increase in glomerular filtration rate while fractional fluid reabsorption remained steady. In contrast, fractional sodium and potassium reabsorption were increased. 4. These data suggest that kappa-opioid agonists alter renal handling of both water and electrolytes. This appears to be mediated by two separate mechanisms: increased fluid loss largely reflects altered glomerular events while the fall in electrolyte excretion results from altered tubular handling.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Effect of vasoactive intestinal peptide, bombesin and substance P on fluid secretion by isolated rat pancreatic ducts.
1. We have used micropuncture techniques to study the regulation of fluid secretion by interlobular ducts isolated from the pancreas of copper-deficient rats. 2. Ducts isolated from different strains of Wistar rats exhibited quantitative differences in basal fluid secretion; however, secretion rates measured in the presence of secretin were similar. 3. Vasoactive intestinal peptide had no effect on fluid transport. 4. Bombesin stimulated fluid secretion, and this effect was abolished by removal of extracellular bicarbonate. 5. Substance P inhibited basal secretion, and that stimulated by bombesin and secretin. These inhibitory effects were partially reversed by spantide. 6. Substance P also inhibited fluid secretion stimulated by dibutyryl cyclic AMP and forskolin. This places the site of inhibition mediated by substance P at a point in the secretory mechanism distal to the generation of cyclic AMP. 7. We conclude that rat pancreatic duct cells possess receptors for bombesin and substance P, in addition to 'secretin-preferring' receptors. Since VIP had no effect on fluid transport, it is unlikely that 'VIP-preferring' receptors are present on rat duct cells.
Animals↗
Catheter ablation of the atrioventricular junction in patients with refractory atrial arrhythmias.
Twelve patients with refractory symptomatic atrial arrhythmias were evaluated for closed chest ablation and permanent pacemaker implantation. This was successful in nine of the 11 patients in whom ablation was attempted. Two of these nine patients required two separate ablative procedures. Three patients underwent open surgical ablation. Electrical ablation had failed in two of these patients and had not been undertaken in the remaining patient (inadequate His recording). The mean His amplitude and delivered energy levels were not significantly different between the two groups. Complications occurred in three patients and were minor. Because ventricular arrhythmias and late sudden death are recognised complications in a minority of patients undergoing closed chest ablation of the A-V junction it should be restricted to patients with symptomatic atrial arrhythmias who have failed maximal medical treatment.
Adult↗
Kappa-opioid-induced changes in renal water and electrolyte management and endocrine secretion.
1. Subcutaneous injection of the kappa-opioid agonist U50,488 into conscious, saline-loaded rats was associated with a diuresis, antinatriuresis and antikaliuresis which lasted for up to 3 h. Plasma renin activity and corticosterone levels were elevated but plasma vasopressin (AVP) and aldosterone levels were unaltered in similarly treated rats. 2. U50,488 administration to adrenal demeddulated rats was not associated with a diuresis but produced an antinatriuresis, though sodium excretion rates were higher in demedullated than in sham-operated animals. Plasma AVP and corticosterone levels were not affected by demeddulation or subsequent U50,488 treatment. Sham-operated, U50-488-treated rats showed the expected increase in plasma corticosterone levels. 3. U50,488 administration resulted in an antidiuresis and an antinatriuresis in AVP-deficient Brattleboro DI rats. 4. When coupled with fasting stress U50,488 administration resulted in similar but attenuated renal responses compared with those observed in unfasted rats. Basal plasma corticosterone levels were elevated in fasted animals and were further increased by U50,488. 5. Both water and electrolyte handling by the kidney are altered by U50,488. The diuretic effects of U50,488 were reversed by adrenal demedullation and in the absence of endogenous AVP, but the antinatriuretic actions were not altered, suggesting that the effects upon renal water and electrolyte excretion may be mediated by separate mechanisms.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Blood pressure and renal function in a novel vasopressin-deficient, genetically hypertensive rat strain.
1. Hereditary hypothalamic diabetes insipidus was introduced into the New Zealand genetically hypertensive (NZGH) rat and its normotensive substrain (NZN) by cross-breeding males with female Brattleboro diabetes insipidus (DI) rats. 2. Selective breeding of the resultant DI/hypertensive (DI/H) rats on the basis of maximum systolic blood pressure and vasopressin deficiency produced animals in the F6 generation with blood pressures at 10 weeks of age higher than in DI/normotensive rats (DI/N), but much lower than in age-matched NZGH animals. Age-matched NZN and DI/N rats had comparable blood pressures. 3. Fluid turnover was far greater in DI/N and DI/H rats than in NZN and NZGH rats. Although comparable in DI/N and NZN rats, water balance (intake-urinary loss) was reduced in DI/H rats by comparison with NZGH rats. 4. Sodium balance was lower in DI/N rats compared with NZN rats but did not differ between DI/H and NZGH animals. Both DI groups had lower potassium balances. 5. Basal plasma vasopressin was elevated in NZGH rats compared with NZN rats, while vasopressin was undetectable in DI animals. Plasma aldosterone levels did not differ between groups, but corticosterone was lower in DI/N and DI/H rats by comparison with NZN and NZGH rats. 6. Replacement of vasopressin to achieve physiological plasma hormone levels restored normal fluid management in DI animals and was associated with a modest increase in systolic blood pressure in DI/N animals, compared with sham-treated rats. A much larger increase in blood pressure was observed in AVP-treated DI/H animals, but blood pressure remained below that in NZGH rats. 7. It is apparent that vasopressin may contribute to the hypertension of the NZGH rat and that it may be required from an early age. The mode of this contribution is unclear, but abnormal renal responses have been identified.
Aldosterone↗
Renal and blood pressure changes in response to vasopressin antagonism in the New Zealand genetically hypertensive rat.
The effects of a mixed pressor and antidiuretic vasopressin antagonist on blood pressure and renal function have been investigated in New Zealand genetically hypertensive and normotensive rats. Vasopressin antagonism was associated with a diuresis, compensatory polydipsia and kaliuresis in both normotensive and hypertensive animals. Hypertensive animals alone exhibited a natriuresis and a fall in systolic blood pressure, which was associated with a reduction in water balance and plasma sodium compared with antagonist-treated normotensive animals. The data suggest that vasopressin may exert a long-term influence on blood pressure through renally rather than vascularly mediated effects.
Animals↗
Neurohypophysial hormone influence on renal function in the New Zealand genetically hypertensive rat.
The acute effects of physiological levels of AVP and oxytocin administration on renal water and sodium handling have been investigated in New Zealand genetically hypertensive and normotensive rats. AVP infusion was associated with an antidiuresis in both normotensive and hypertensive rats and while normotensive rats also displayed a dose-related natriuresis, this was attenuated in hypertensive rats. Oxytocin administration had no effect on urine flow or sodium excretion in normotensive rats, but was associated with an antidiuresis in hypertensive rats. Combined hormone infusion produced a greater reduction in urine flow than following AVP alone in both normotensive and hypertensive groups and was associated with a potentiation of the natriuretic action of AVP in the hypertensive animals. The data suggest that the contribution of oxytocin to renal sodium excretion in hypertensive rats may be suppressed. A compensatory increase in basal AVP secretion in hypertensive rats may overcome their apparent renal insensitivity to AVP, to maintain appropriate sodium excretion. This intriguing disturbance in neurohypophysial function may reflect or possibly contribute to the hypertension of these animals.
Animals↗
Oxygen and the retinal blood vessels.
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Animals↗
Contractile proteins in ocular tissues. Their role in health and disease.
Various cytoskeletal and contractile filamentous systems are located within non-muscular eukaryotic cells including microtubules, intermediate filaments, myosin filaments, and actin microfilaments. Microtubules are a major component of cilia, flagella, axons, and the mitotic spindles, but apart from these more specialized roles they are cytoskeletal structures and are involved in the directional movement of organelles within the cytoplasm. Intermediate filaments are structurally and biochemically similar to neurofilaments and although they are present in most cells they are particularly prominent in mesenchymal cells. Their function is not fully understood but they probably have a supportive role and constrain organelles including the nucleus in position within the cell. The contractile proteins, actin and myosin, in their most complex forms are found as a variety of filamentous structures which are involved in such diverse processes as motility, adhesion, phagocytosis, endocytosis, and cytokinesis. In this study the distribution of cytoskeletal an contractile elements in the non-muscular tissues of the human and the rabbit eye were investigated both in vivo and in vitro using electron microscopy and indirect immunofluorescence. Particular emphasis was placed on the role of cytoplasmic filaments in normal tissue function and their possible significance in various pathological conditions.
Actins↗
Ophthalmological Societies of the United Kingdom. Centenary Meeting, April 1980. The presidential address.
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History, 19th Century↗
Allergic granulomatous nodules of the eyelid and conjunctiva. The XXXV Edward Jackson Memorial Lecture.
We studied the clinical and pathologic features of 22 cases of granulomas of the conjunctiva or eyelids. All cases showed the histologic features of the Splendore-Hoeppli phenomenon, that is, a giant cell and eosinophil granulomatous reaction to an antigen-antibody precipitate originally described in relation to parasites or fungi. In four of seven typical cases selected for detailed description unidentified nematodes were found to be the cause of the condition. In light of these findings together with a review of similar "allergic granulomas" reported both in ocular tissues and elsewhere in the body, we considered the cause in the remaining cases. All 22 cases may have been caused by nematodes, as seems, probable in 14 of them, or the causative antigens may have been of widely different kinds. Although in our cases all ocular granulomas had an identical histology, this study did not resolve the problem of those cases where no causative agent was found. Thorough investigation of such cases in the future and the demonstration of their cause may elucidate the wider problem of nonocular allergic granulomas.
Adolescent↗