Biomedical subjects
Publications and source records attributed to D Brady.
The dense interconnections that characterize neural networks are most readily implemented using optical signal processing. Optoelectronic 'neurons' fabricated from semiconducting materials can be connected by holographic images recorded in photorefractive crystals. Processes such as learning can be demonstrated using holographic optical neural networks.
The binding and biologic potencies as well as kinetics of action of human biosynthetic proinsulin (HPro) were studied in primary cultures of rat hepatocytes. HPro had 3% (on a molar basis) of the potency of porcine insulin for displacing (125I)-TyrA14-insulin from receptors. Maximally effective concentrations of insulin and HPro caused similar stimulations of 14C-glucose incorporation into glycogen and glycogen synthase activity. However, the dose response curve for HPro stimulation of glycogen synthase was shifted far to the right (EC50 = 4.1 +/- 1.1 nM) of that for insulin (.09 +/- .01). The relative biologic potency of HPro was approximately 3%. Biologically equivalent maximal doses of insulin (8.3 nM) and HPro (53.2 nM) stimulated glycogen synthase activity with similar time courses; half maximal between 15-30 min with maximal effects at 60 min. Deactivation of glycogen synthase upon removal of the hormone was very rapid for both hormones. The relative binding and biologic potencies of HPro compared to insulin in liver (approximately 3%) were similar to values previously seen in adipocytes. This fact, together with the similarity of kinetics of action, suggest that the in vivo hepatoselectivity of HPro is not a property of the target cell itself.
Recent studies from our laboratory have shown that the rate at which insulin activates glucose disposal in vivo is much slower in obese subjects compared with lean controls. To determine if this was caused by an abnormality in activation of insulin-stimulated glucose transport at the cellular level, we measured the rate at which insulin stimulated glucose transport in human adipocytes from obese volunteers. Basal rates of 3-O-methylglucose transport in the absence of insulin were lower (0.20 +/- 0.04 vs. 0.40 +/- 0.11 pmol.10(-5) cells.10 s-1, P less than .25) in adipocytes from obese subjects (n = 10) than in lean control subjects (n = 5), but this did not achieve statistical significance. Maximal insulin-stimulated (4300 pM insulin) glucose transport rates were significantly decreased in obesity (2.81 +/- 0.81 vs. 1.15 +/- 0.20 pmol.10(-5) cells.10 s-1, P less than .005). It took longer for adipocytes from obese subjects to achieve half-maximal activation of insulin-stimulated glucose transport than those from lean subjects (15 +/- 2 vs. 9.4 +/- 1.2 min, P less than .05). The slower overall rates of activation of maximal insulin-stimulated glucose transport observed in adipocytes from obese subjects mirror the slower rates of stimulation of glucose disposal in vivo, which suggests that the in vivo findings are caused by a cellular abnormality in insulin action at a step beyond the binding of insulin to its receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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The binding and biologic potencies of human biosynthetic proinsulin (HPro) were determined in isolated rat adipocytes. At both 16 degrees C and 37 degrees C, proinsulin was found to have 3% (on a molar basis) the potency of porcine insulin for displacing bound [(125I)TyrA14]-insulin from insulin receptors. Human biosynthetic proinsulin also had 3% of the molar potency of insulin for stimulation of deoxyglucose transport (EC50 = 8.8 +/- 0.05 X 10(-11) M for insulin and 2.9 +/- 0.55 nM for HPro). However, both hormones produced the same maximal effect on glucose transport. In order to determine if the delay in onset and persistence of proinsulin action seen in vivo was due to any differences at the cellular level, the time course of HPro action on glucose transport was determined. Biologically equivalent submaximal concentrations of insulin (0.166 nM) and HPro (4.44 nM) gave identical time courses for stimulation of deoxyglucose transport at 37 degrees C with half-maximal effects at 4 min and full effects by 30 min. Maximally stimulating concentrations of insulin (1.66 nM) and HPro (22.2 nM) also had superimposable time courses. Deactivation of stimulated glucose transport was determined by incubating equivalent concentrations of insulin (0.166 and 1.66 nM) and HPro (4.44 and 22.2 nM) until full stimulation was achieved, washing cells free of unbound hormone, and initiating dissociation and deactivation by resuspension in hormone-free buffer. Both the absolute activities of transport and rates of deactivation were the same for insulin and HPro. At the submaximal concentrations, 50% of the hormones' effects were lost by 20 min, while 50 min was required after maximal stimulation for 50% deactivation.(ABSTRACT TRUNCATED AT 250 WORDS)
Mouse monoclonal antibodies (Mac 002 and Mac 003) raised against recombinant human Interleukin-2 (rec IL-2), were developed for use as assay and purification reagents. In the Immunoradiometric assay, (IRMA), 125I-Mac 002 is used as tracer, with sheep polyclonal anti-rec IL-2 on the solid phase. This reliably measures rec IL-2 in the range 3-1000 ng/ml. The assay measures natural IL-2 with a lower sensitivity. For some samples of IL-2, the amount detected by IRMA is greater than expected from the biological assays, presumably because there are IL-2 molecules with antigenic, but not biological activity. This is a possible source of variation in the specific activities observed in different preparations of of IL-2. In the purification reagent, Mac 003 is immobilised on sepharose CL-4B to purify recombinant IL-2 from less than 1% in an E. Coli extract, to greater than 90% purity, in a single step with greater than 80% yield.
The purpose of this report was to examine the influence of nephropathy and sodium balance on the orthostatic blood pressure and renin (PRA) responses of diabetic patients with orthostatic hypotension (OH). Four groups of similar age were studied: non-diabetic controls (n = 7), diabetics free of OH and other diabetic complications (n = 7), diabetics with OH but no nephropathy (n = 6), and diabetics with OH and nephropathy (24-hr urine protein greater than 400 mg, n = 6). In the diabetics with OH, mean systolic BP fell 49 and 47 mmHg on standing in the groups without and with nephropathy respectively. NaE (expressed as % predicted by leanness index) differed significantly between the groups and was 100 +/- 2 in the controls, 109 +/- 3 in the diabetics free of complications, 102 +/- 2 in the diabetics with OH free of nephropathy, and 121 +/- 6 in diabetics with OH and nephropathy (p less than 0.05 compared to diabetics with OH and no nephropathy). Both supine (r = 0.68, p less than 0.02) and upright (r = 0.78, p less than 0.005) mean arterial pressure correlated with NaE in diabetics with OH but not in the other groups. Upright PRA was greatest in diabetics with OH but no nephropathy and lowest in diabetics with OH and nephropathy. These findings suggest that the presence of nephropathy markedly influences sodium balance in diabetics with OH and has a substantial influence on orthostatic BP and PRA responses.
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The objective of this study was to examine total exchangeable sodium, plasma-blood volume, and the status of the renin-angiotensin system in hypertensive diabetic patients with established nephropathy. We also evaluated hypertensive patients with diabetes who were free of clinically apparent nephropathy or other diabetic complications. Total exchangeable sodium (by 24Na dilution) was expressed as percentage predicted. Subjects were studied as inpatients receiving unrestricted sodium intake and in stable metabolic control. Total exchangeable sodium was 100 +/- 2% in controls (n = 42), higher (p less than 0.01) at 108 +/- 2% in normotensive patients with diabetes (n = 30), and higher still (p less than 0.005) in hypertensive patients with diabetic nephropathy (n = 16) 118 +/- 4% (p less than 0.05 vs normotensive diabetics). The value correlated with blood pressure only in diabetics with nephropathy (r = 0.61, p less than 0.01). Plasma renin activity, and blood and plasma volumes were similar in nephropathic diabetics and controls. Hypertensive patients with maturity-onset (type II) diabetes free of nephropathy (n = 18) were compared with nondiabetic controls (n = 16) and normotensive patients with type II diabetes (n = 18) of similar age. Total exchangeable sodium in the controls was 100 +/- 3%, higher (p less than 0.01) in normotensive diabetics at 109 +/- 2%, but not significantly elevated in hypertensive diabetics at 106 +/- 2%. Again, blood and plasma volumes did not differ among the groups. Plasma renin activity was suppressed (p less than 0.01) to a comparable degree in both normotensive and hypertensive patients with type II diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)