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Biomedical subjects

R Sutton

Publications and source records attributed to R Sutton.

At least 55 records · Page 3Linked to original sources
PubMed1990

HLA DR, DP, DQ induction in human islet beta cells by the cytokine combination IFN-gamma + TNF-alpha.

Human islet beta cells do not express HLA Class II normally, yet, in the diabetic pancreas, beta cells are selectively positive for Class II and this may facilitate their recognition by T cells. It has been demonstrated that human beta cells can be induced to express Class II when cultured with IFN-gamma + TNF-alpha or IFN-gamma + TNF-beta. To assess whether or not they can be induced to express the products of the Class II subregions, DR, DP and DQ, human islet cultures from 10 pancreas were supplemented with the combination of IFN-gamma + TNF-alpha using MoAbs specific for DR, DP and DQ products, and antibodies to insulin and glucagon. The combination IFN-gamma + TNF-alpha (100-1000 U/ml each) was able to induce the expression of the three subregions in both beta and alpha cells. The induction of subregion expression followed the hierarchy DR greater than DQ greater than or equal to DP. The capability of beta cells to express all three Class II subregions supports the possibility that these cells can present their self antigens to T cells.

Gene Expression Regulation↗
PubMed1989

The specificity of rejection and the absence of susceptibility of pancreatic islet beta cells to nonspecific immune destruction in mixed strain islets grafted beneath the renal capsule in the rat.

The specificity of rejection of isolated pancreatic islets was examined in the rat using a quantitative model in which syngeneic (DA) or a mixture of syngeneic and allogeneic (DA and LEW or PVG) islets were implanted beneath the capsule of the kidney of nondiabetic normal rats (DA). 3 wk after transplantation total insulin extraction assays of the kidney with its islet implant together with immunohistological examination of the site of transplantation for evidence of syngeneic or allogeneic tissue demonstrated the total destruction of allogeneic islets without any evidence of damage to syngeneic islets either distant or in immediate proximity to allogeneic islets. Pancreatic islets, and especially beta cells, appear to be particularly vulnerable to the effector arm of both autoimmune and alloimmune responses, a vulnerability that has been attributed to the cytotoxic effects of lymphokines, notably IL-1, released in both autoimmune and alloimmune responses. The experiments reported here demonstrate not only the exquisite specificity of the allograft reaction but are not compatible with a hypothesis that B cells within an intact islet are nonspecifically susceptible to destruction by lymphokines.

Animals↗
PubMed1989

Tilting towards a diagnosis in recurrent unexplained syncope.

71 patients with recurrent syncope which remained unexplained after standard clinical and electrophysiological investigation underwent 60 degree head-up tilt. This procedure reproduced symptoms with vasovagal syncope in 53 (74%), 40 of whom had bradycardia, some with prolonged asystole, during syncope. The other 13 patients had predominant vasodepression with hypotension. Mean time to syncope after tilt was 25 min. Patients with conduction tissue disease and age-matched control subjects had a 15% and 7% incidence of tilt syncope, respectively. Temporary dual-chamber pacing aborted syncope in 85% of subjects, and improved cardiac index and systemic blood pressure during tilt. Long-term results indicate that selected patients may benefit from permanent dual-chamber pacing. Head-up tilt is useful in the investigation of unexplained syncope because symptoms are reproduced in front of a medical witness.

Aged↗
PubMed1989

Symptomatology and quality of life in patients with rate-responsive pacemakers: a double-blind, randomized, crossover study.

Although the hemodynamic advantages of rate-responsive (RR) pacing are well established, the symptomatic benefits remain controversial and the effects on the quality of life have not been assessed. Sixteen patients with RR pacemakers and a mean age of 56 (range 22-77) years were involved in a double-blind crossover study to assess their exercise capacity (treadmill testing), symptomatology, and quality of life (structured questionnaires). Pacemakers were implanted because of symptomatic heart block or sick sinus syndrome. Ventricular demand pacemakers were randomly programmed into the constant rate (VVI) or RR pacing modes for four-week study periods. All patients exercised longer in the RR mode than in the VVI mode (570 +/- 29 vs. 437 +/- 17 s, p less than 0.001). Statistically significant improvements in "shortness of breath" and "energy during daily activities" as measured by a 10-point scale were reported in the RR pacing mode by the patients and were also observed by their close relatives. Symptoms such as "chest pain" and "palpitations" were not worsened during RR pacing. Nondisease-specific "quality of life" was studied in 11 patients using the Nottingham Health Profile which showed a trend for an improved quality of life in five of the six dimensions of perceived health, although none of the changes were statistically significant. This study suggests that RR pacing should be recommended in selected patients on symptomatic grounds.

Adult↗
PubMed1989

Localisation of islet amyloid peptide in lipofuscin bodies and secretory granules of human B-cells and in islets of type-2 diabetic subjects.

Islet amyloid peptide (or diabetes-associated peptide), the major component of pancreatic islet amyloid found in type-2 diabetes, has been identified by electron-microscopic immunocytochemistry in pancreatic B-cells from five non-diabetic human subjects, and in islets from five type-2 diabetic patients. The greatest density of immunoreactivity for islet amyloid peptide was found in electron-dense regions of some lysosomal or lipofuscin bodies. The peptide was also localised by quantification of immunogold in the secretory granules of B-cells, and was present in cytoplasmic lamellar bodies. Acid phosphatase activity was also demonstrated in these organelles. Immunoreactivity for insulin was found in some lysosomes. These results suggest that islet amyloid peptide is a constituent of normal pancreatic B-cells, and accumulates in lipofuscin bodies where it is presumably partially degraded. In islets from type-2 diabetic subjects, amyloid fibrils and lipofuscin bodies in B-cells showed immunoreactivity for the amyloid peptide. Abnormal processing of the peptide within B-cells could lead to the formation of islet amyloid in type-2 diabetes.

Adolescent↗
PubMed1989

The effect of hyperglycaemia on pancreatic islets transplanted into rats beneath the kidney capsule.

The effect of hyperglycaemia on islet transplantation in the rat has been examined in two ways, using syngeneic transplantation of 400 islets to the kidney capsule and subsequent measurement of kidney insulin content as a measurement of B-cell survival. Firstly, islets were transplanted into either diabetic or normal rats, then 6 months later the composite kidney/islet graft was transplanted into a normal rat. The insulin content was measured after a further 6 months and was found to be significantly reduced in islets exposed to hyperglycaemia in the primary recipient. These findings are interpreted as showing that long-term exposure of islets to hyperglycaemia results in B-cell loss. In the second experiment 400 islets were transplanted into either a long-term (6 months) diabetic or a normal rat. Two weeks later the composite kidney/islet graft was transplanted into a normal rat. The insulin content was measured after a further 6 months and no significant difference was found, whether the primary recipient was diabetic or not. These results are interpreted as showing that islet graft implantation is not impaired in long-term diabetic rats.

Animals↗
PubMed1989

The hypoglycaemic and insulinotropic activity of Tinospora crispa: studies with human and rat islets and HIT-T15 B cells.

In Malaysia, Tinospora crispa extract is taken orally by Type 2 (non-insulin-dependent) diabetic patients to treat hyperglycaemia. We have evaluated the claimed hypoglycaemic property by adding aqueous extract to the drinking water of normal and alloxan-diabetic rats. After one week, fasting blood glucose levels were significantly (p less than 0.01) lower and serum insulin levels were significantly (p less than 0.01) higher in treated diabetic animals (10.4 +/- 1.0 mmol/l and 12.8 +/- 1.1 muU/ml respectively) compared to untreated diabetic controls (17.4 +/- 1.7 mmol/l and 8.0 +/- 0.7 muU/ml respectively). The insulinotropic action of T. crispa was further investigated in vitro using isolated human or rat islets of Langerhans and HIT-T15 cells. In static incubations with rat islets and HIT-T15 B cells, the extract induced a dosage dependent stimulation and potentiation of basal and glucose-stimulated insulin secretion respectively. This insulinotropic effect was also evident in perifused human and rat islets and HIT-T5 B-cells. The observations that (i) in all three models insulin secretory rates rapidly returned to basal levels on removal of the extract and (ii) in rat islets, a second challenge with T. crispa induced an additional, stimulated response, are all consistent with physiological release of insulin by B cells. Moreover, the rate of HIT-T15 glucose utilisation was not affected by incubation with T. crispa, suggesting that the cells were viable throughout. These are the first studies to provide biochemical evidence which substantiates the traditional claims for an oral hypoglycaemic effect of Tinospora crispa, and which also show that the hypoglycaemic effect is associated with increased insulin secretion.

Animals↗
PubMed1989

The ATP- and tolbutamide-sensitivity of the ATP-sensitive K-channel from human pancreatic B cells.

The ATP- and sulphonylurea-sensitivity of the ATP-sensitive K-channel was measured in human pancreatic B cells. In inside-out patches, half-maximal inhibition of channel activity was produced by 10 mumol/l ATP (with 2 mM Mg2+) and ATP-inhibition was partially antagonised by ADP. A significantly lower sensitivity to ATP was found in whole-cell recordings. Tolbutamide inhibited whole-cell ATP-sensitive K-currents half-maximally at 18 mumol/l; the sensitivity to tolbutamide was somewhat less in the inside-out patch. Ca-activated K-channels were unaffected by tolbutamide (10 mmol/l). These results resemble those found for rodent B cells and suggest that sulphonylureas exert their therapeutic effects in Type 2 (non-insulin dependent) diabetes by inhibition of the ATP-sensitive K-channel.

Adenosine Triphosphate↗
PubMed1989

Functional assessment of colonic interposition with 99Tcm-labeled milk.

A prospective study was performed to evaluate the use of radionuclide imaging in the assessment of patients who have undergone esophageal reconstruction. Dynamic radionuclide imaging was performed on ten patients aged 11 months to 11 years who had undergone colon interposition via the normal esophageal route for esophageal atresia. Patients were considered clinically unsatisfactory if at the time of imaging feeding was troubled, or if weight gain had fallen to below the third centile before operation and remained below after operation. Each patient underwent erect imaging with a small milk feed labeled with 10 to 20 MBq (250 to 500 muCi) 99Tcm DTPA adjusted according to body surface area; supine studies were subsequently performed on five patients. All five clinically unsatisfactory patients showed conduit emptying delayed beyond 45 minutes and/or spontaneous reflux, significantly different from the clinically satisfactory patients (X2 = 6.4, P less than .02). Conduit complications were subsequently identified in three of the five clinically unsatisfactory patients. Radionuclide imaging with radiolabeled milk was found to be well tolerated, and obtained results that were clinically useful. These results suggest that dynamic radionuclide imaging can be more widely applied in the assessment of esophageal substitutes.

Alanine↗
PubMed1989

Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus.

The 37-amino acid peptide called amylin is a major component of the islet amyloid deposited in the pancreases of persons with type 2 diabetes mellitus. We report the isolation of a partial cDNA clone and a phage lambda genomic clone of the coding region of the amylin gene. The DNA sequence encodes a protein sequence identical to that of amylin isolated from the amyloid found in the diabetic pancreas and shows that amylin is likely to be synthesized as a precursor peptide, now named proamylin. We have demonstrated that the amylin gene is present on chromosome 12 and that it is probably transcribed in the islets of Langerhans. The sequences of the genes for amylin and the calcitonin gene-related peptides (CGRPs) show strong similarity, especially over their 5' coding regions, where both peptides have a conserved intramolecular disulfide bridge, and also over their 3' coding regions, where the presence of a glycine codon strongly suggests that the carboxyl-terminal residue of amylin, like that of CGRP, is amidated. To examine the functional relevance of these posttranslational modifications, the biological activity of amylin synthesized with or without the disulfide bridge and/or amidation was measured. It was found that both features are necessary for full biological activity, thereby confirming the functional importance of those regions of the molecule whose sequences are conserved at both protein and genetic levels.

Amino Acid Sequence↗
PubMed1989

Pancreatic islet transplantation.

Successful transplantation of the endocrine pancreas in Type I diabetes with complete correction of the glucose metabolic abnormalities may prevent progression or development of the microangiopathic complications of the disease. This could be achieved by transplantation of the whole pancreas as a vascularized graft (the only available clinical approach at present), transplantation of isolated islets or of fetal pancreas. Since transplantation of the pancreas as a vascularized graft is associated with a significant peri-operative morbidity and requires immunosuppression to prevent rejection it is unlikely to be applicable at a relatively early stage of the disease, before microangiopathic complications become irreversible. For this reason transplantation of pancreatic islets or fetal pancreas is the only approach likely to be acceptable. Transplantation of isolated islets in the rodent does correct experimental diabetes, but recurrence of disease is seen in the spontaneous diabetes of the Biobreeding (BB) rat and the non-obese diabetic (NOD) mouse. Furthermore suppression of rejection of allogenic islets has proved difficult. In large mammals, including man, the lack of a technique to prepare isolated islets in a relatively pure form has been a further obstacle to development. Recently this problem has been overcome, allowing separation of islets in relatively large numbers with adequate purity, bringing closer the time when clinical trials might be considered. However, rejection and disease recurrence are likely to remain major obstacles, although experimental work suggests that both can be overcome.

Animals↗
PubMed1989

Physical growth velocity during conservative treatment and following subsequent surgical treatment for primary vesicoureteric reflux.

Physical growth was studied in 6 males and 16 females during 1 year of antimicrobial prophylaxis and during the 2 years following subsequent surgical treatment for severe primary vesicoureteric reflux. Surgery was performed between the ages of 2 and 8 because of either repeated breakthrough infection or persistence of grade III or IV reflux. Height and weight velocities were calculated as yearly rates and then converted into interquartile ratios (IQRs). Neither the mean centile height nor weight attained varied significantly between that at entry, after 1 year of medical treatment and at 2 years after surgery. However, the mean IQR for height velocity (+/- sem) rose significantly from -0.61 (+/- 0.45) during antimicrobial prophylaxis to 0.54 (+/- 0.25) following surgery. Similarly, the mean IQR for weight velocity rose significantly from -0.63 (+/- 0.50) during medical treatment to 0.47 (+/- 0.24) following surgery. These results suggest that surgical treatment is preferable to continued medical treatment in patients with severe primary vesicoureteric reflux who fail to respond to a trial of antimicrobial prophylaxis.

Anti-Infective Agents, Urinary↗
PubMed1989

Atrial natriuretic peptide response to rapid atrial pacing in cardiac-denervated dogs.

The effects of rapid atrial pacing on central hemodynamics, plasma hormones, and renal function were investigated in eight control and nine cardiac-denervated dogs under chloralose anesthesia. Pacing at approximately 250 ppm for 60 min caused similar increases in pulmonary wedge and right atrial pressures, systemic vascular resistance, and plasma atrial natriuretic peptide (ANP) in both groups. In control dogs, pacing produced a fall in both plasma vasopressin (AVP) and plasma renin activity (PRA) and a rise in urine flow rate associated with an increase in free water but not sodium clearance. In contrast, in cardiac-denervated dogs, both plasma AVP and PRA increased during pacing; urine flow rate did not change, and marked sodium retention occurred. This study supports the concept that the increase in urine flow during rapid atrial pacing is mediated by inhibition of renin and AVP secretion through intact cardiac nerves. The secretion of ANP is unaffected by cardiac denervation. The natriuretic and vasodilator actions of high plasma ANP concentrations during rapid atrial pacing can be inhibited either by neurally mediated cardiorenal effects in normal animals or by stimulation of the renin-angiotensin system after cardiac denervation.

Animals↗