Biomedical subjects
Publications and source records attributed to R Sutton.
Recurrent syncope is a distressing phenomenon and may be very difficult to treat where the cause remains obscure. A methodical approach to investigation will often be fruitful when proper emphasis is given to thorough clinical assessment and simple investigations. Where these are normal, head-up tilt testing will often diagnose 'malignant vasovagal syndrome'.
A retrospective review of 227 consecutive breast cancer patients who were 35 years of age or younger and who had been given doxorubicin-containing adjuvant chemotherapy was conducted to determine the frequency of pregnancy and its effect on the clinical course of the disease. Also, the status of the newborn was evaluated. There were 33 pregnancies in 25 patients (10 pregnancies were terminated, 2 patients had spontaneous abortions, and 19 patients gave birth to full-term offspring without fetal malformation). Two patients were still pregnant at the time of this report. The median interval between the completion of chemotherapy and pregnancy was 12 months. Eight patients who became pregnant experienced temporary amenorrhea during chemotherapy. Of the 25 patients who became pregnant, recurrent disease subsequently developed in 7 and 3 died. A patient's disease-free and overall survival status was not adversely effected by pregnancy. These data illustrate that in a sizeable fraction of patients 35 years of age or younger treated with adjuvant doxorubicin-containing therapy, ovarian function remained intact and subsequent pregnancy did not affect the disease-free or overall survival of the patients.
Vinblastine sulfate (VLB) suspended within a collagen matrix (CM) as a diffusion limiting drug delivery vehicle was examined in vitro, as well as in mouse subcutaneous and brain tumor models. Against RIF-1 and KHT subcutaneous tumors, there was enhancement of antitumor activity with intratumoral (i.t.) delivery of VLB when it was combined with CM and/or epinephrine (epi) provided as a vasoactive agent to limit diffusion of VLB away from the injection site. Furthermore, in pharmacokinetic studies an 3-fold enhancement of tumor exposure to drug (AUC) with the CM-formulation was observed relative to the administration of free VLB i.t. Craniotactic injection of VLB into mouse brain in doses from 0.2 to 2 mg/kg revealed that the CM association markedly reduced the acute toxicity of VLB in normal mouse brain. Furthermore, mice with stereotactically implanted KHT brain tumors treated with 0.2 mg/kg VLB in CM had less tumor present in the brain histologically compared to the free VLB and untreated control groups.
We report clinical and hemodynamic data in two cases of recurrent syncope. Both patients received permanent demand ventricular pacing (VVI) for unexplained syncope. Both patients experienced recurrent syncope after pacemaker implantation. They later underwent 60 degrees head-up tilt testing, initially noninvasively and then with hemodynamic profile. A vasovagal response to tilt occurred with bradycardia and was complicated by the onset of ventricular pacing and retrograde atrioventricular conduction (RAVC) with hemodynamic deterioration and rapid reproduction of syncope. Limited intracardiac electrophysiological study (EPS) excluded atrioventricular (AV) conduction disease, sinus node disease, and carotid sinus syndrome, and confirmed RAVC. Both patients were upgraded to dual chamber pacing, DDI mode, with 50/80 rate hysteresis. One patient was asymptomatic at repeat tilt testing; the other experienced continued symptoms due to the vasodepressor component of vasovagal syncope. Cardiac pacing alone is ineffective treatment for this phenomenon, and no proven therapy is presently available. Ventricular pacing applied to patients with unexplained syncope may lead to an increase in or continuation of symptoms rather than an amelioration. There is a need for full investigation of such patients, which must include tilt testing, to allow for the most accurate diagnosis possible and guide the most appropriate therapy.
The history of pacing to control the atrial arrhythmias of sinoatrial node disease (SND) is reviewed and is demonstrated to have become more physiological in recent years. The importance of atrial stimulation is emphasized especially in the context of the natural history of SND. The role of single and dual chamber rate responsive pacing for correction of chronotropic incompetence is outlined and guidelines are proposed for the management of the different types of SND presentation.
The influence of cardiac innervation on the renal response to volume expansion was investigated. Systemic hemodynamic, plasma hormone, and renal clearance measurements were made before, during, and after intravenous administration of 1,000 ml 0.9% saline over 10 min to six control and six cardiac-denervated, chloralose-anesthetized mongrel dogs. Volume expansion resulted in a two- to threefold rise in plasma atrial natriuretic peptide (ANP) concentrations and a 50% rise in glomerular filtration rate (GFR) in both groups. Plasma renin activity (PRA) and plasma arginine vasopressin remained higher throughout in cardiac-denervated compared with control dogs. The marked increases in urine flow rate and sodium and free water clearances seen in the controls were attenuated or abolished after cardiac denervation. These differences were due to the influence of higher PRA and vasopressin in these animals compared with the controls, rather than differences in hemodynamic responses operating via GFR or in direct humoral responses via ANP secretion.
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.
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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.
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.
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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.
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.
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.
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.