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Biomedical subjects

J F Yale

Publications and source records attributed to J F Yale.

49 records · Page 3Linked to original sources
PubMed1986

Sensitivity of BB rat beta cells as determined by dose-responses to the cytotoxic effects of streptozotocin and alloxan.

BB rats of diabetes-prone lines develop a spontaneous Type 1 diabetic syndrome, with many immunological concomitants. No data are available as to the integrity of their islet beta cells prior to onset of the insulitis which proceeds to their selective destruction. We tested the effects of the beta-cytotoxins streptozotocin and alloxan on such rats, compared to Wistar and to non diabetes-prone BB control rats studied prior to usual age of diabetes onset. A dose-response of a single injection of the agents with respect to pancreatic insulin content 48 hr post-injection as well as to circulating insulin and glucose, weight, and lymphocyte counts was established. Clear dose-responses were found for pancreatic insulin content. Though less sensitive, plasma insulin and glucose values showed responses. Whereas some litters of diabetes-prone rats showed greater reductions of pancreatic insulin than controls after some doses of streptozotocin, overall results in 8-26 recipients of each dose showed no significant differences when compared with either BB or Wistar controls. With smaller numbers of diabetes-prone rats, the same was obtained for alloxan, though with fewer doses tested. The latter required the construction of an alloxan dose-response in normal Wistar rats. Thus, this study has not demonstrated a nonspecific increase in "fragility" of BB rat beta cells in response to these classical diabetogenic agents. This would be consistent with other data suggesting that the primary abnormality in the syndrome does not necessarily reside within the beta cell.

Alloxan↗
PubMed1986

Obliterative segmental sclerosis of pancreatic islets. A possible consequence of hypotensive shock in young BB rats.

During the conduct of a time-course study of peripheral blood T lymphocytes in BB rats, a hitherto unreported islet lesion was recognized in 8 of 17 glucose-tolerant rats which had been subjected to repetitive cardiac puncture in early life and sacrificed at 186-190 days of age. Some of the large islets contiguous to fibrous septa demonstrated variable degrees of obliterative sclerosis and reduction of islet cell mass, associated with evidence of remote peri- and intrainsular hemorrhage. In 3 rats, additional features included an active, proliferative replacement of islet substance by fibroblasts and histiocytes. These islet alterations are not characteristic of BB rats, nor have identical lesions been described in studies of experimental or human diabetes mellitus. Affected rats had sustained repetitive episodes of blood loss (from 15% to 28% of total blood volume each time) during the early phase of the study. It is possible, but not proved, that hypovolemic shock was induced in some of these animals. Ischemic necrosis of islets has been reported in premature and young infants succumbing to shock. It is posited that hypovolemic shock in the young animal may, as in the infant, result in islet cell ischemic necrosis, sufficient to produce, with time, the described islet morphologic features.

Animals↗
PubMed1985

Time course of the lymphopenia in BB rats. Relation to the onset of diabetes.

The spontaneously diabetic BB rat syndrome is associated with a marked lymphopenia, which affects all members of litters of diabetes-prone rats, and may be a necessary condition for the development of the disease. We assessed peripheral blood lymphocyte counts and subsets from birth to 66 days of age with a view to assessing the early time course. At birth, total numbers were decreased, as were total T-cells (monoclonal antibody W3/13+, with an even greater deficit in OX19+ cells), the helper/inducer subset (W3/25+), and the suppressor/cytotoxic subset (OX8+), but Ia+ (B, OX6+) cells were not reduced. There was a less-than-normal rise in these values with time, and a similar pattern was observed at 66 days. Rats followed thereafter to onset of diabetes showed no differences at 66 days that were predictive of subsequent diabetes development. Another set of rats studied at the same age and again at onset of diabetes showed no changes concurrent with diabetes onset. The data are consistent with a genetically determined defect in lymphocyte numbers that leads to a subnormal rise in circulating cells later in life, and may predispose to another unidentified factor responsible for precipitation of the beta cell cytotoxicity.

Age Factors↗
PubMed1985

Effects of cyclosporine on glucose tolerance in the rat.

In a study of prevention of spontaneous diabetes in BB rats by therapeutic doses of cyclosporine (10 mg/kg/day), the male control non-diabetes-prone rats showed glucose intolerance after a 0.25 g/kg glucose load by gavage, at 90 and 130 days of treatment. Non-BB male Wistar rats treated similarly showed glucose intolerance at 1 wk of treatment, with progressive worsening for 5 wk, then sustained up to 12 wk of treatment. Fasting euglycemia was maintained, but both pre- and postchallenge plasma insulin levels were significantly lower with cyclosporine at several time points. Total pancreatic insulin was decreased to one-third that of control after 5 wk. After withdrawal of cyclosporine, glucose tolerance returned to normal in 2 wk. Sprague-Dawley rats responded similarly and in both strains, an increase in the cyclosporine dose to 15 mg/kg/day augmented the glucose intolerance. These results demonstrate that therapeutic doses of this agent induce reversible glucose intolerance due, in part, to inhibition of insulin secretion and also possibly inhibition of synthesis, though a peripheral effect is not excluded. This hyperglycemic effect of cyclosporine has implications for its potential use in type I diabetes mellitus, transplantation, and other autoimmune disease.

Animals↗
PubMed1984

Catecholamine responses to hypocaloric diets and fasting in obese human subjects.

Catecholamines have multiple metabolic and fluid-electrolyte as well as cardiovascular effects, and their levels in plasma respond to alterations in nutrient and sodium intakes. Plasma norepinephrine, epinephrine, and dopamine were measured in 12 obese nondiabetic subjects before and after 400 kcal/day diets of either protein or glucose, followed by total fasting, and then by hypocaloric refeeding, each for 14-day periods. Measurements were made in the supine and upright posture and during and after 6-10 min of exhaustive exercise at 80% maximal VO2. Sodium intake varied with the nutrients ingested, being markedly decreased with the 400 kcal/day diets and fasting. Norepinephrine levels were higher in fasting than base line while subjects were lying or standing and after recovery from exercise. Those of epinephrine were elevated on standing. No differences were found after the 400 kcal/day diets, with protein and glucose yielding equivalent results. In contrast, refeeding was associated with lower norepinephrine levels than all other diets while subjects were lying or standing and after recovery from exercise. Peak levels of norepinephrine and epinephrine with exercise were indistinguishable among diets. Fasting was associated with lower systolic and diastolic blood pressures and lower responses to standing and exercise than base line, whereas upright heart rate was greater and that during exercise less than base line. Significant though less extensive changes occurred with the other diets. Thus both electrolyte status and nutrient intakes interact to determine net catecholamine responses, and the former seem to override the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Peroxovanadium compounds: biological actions and mechanism of insulin-mimesis.

When used alone, both vanadate and hydrogen peroxide (H2O2) are weakly insulin-mimetic, while in combination they are strongly synergistic due to the formation of aqueous peroxovanadium species pV(aq). Administration of these pV(aq) species leads to activation of the insulin receptor tyrosine kinase (IRK), autophosphorylation at tyrosine residues and inhibition of phosphotyrosine phosphatases (PTPs). We therefore undertook to synthesize a series of peroxovanadium (pV) compounds containing one or two peroxo anions, an oxo anion and an ancillary ligand in the inner co-ordination sphere of vanadium, whose properties and insulin-mimetic potencies could be assessed. These pV compounds were shown to be the most potent inhibitors of PTPs yet described. Their PTP inhibitory potency correlated with their capacity to stimulate IRK activity. Some pV compounds showed much greater potency as inhibitors of insulin receptor (IR) dephosphorylation than epidermal growth factor receptor (EGFR) dephosphorylation, implying relative specificity as PTP inhibitors. Replacement of vanadium with either molybdenum or tungsten resulted in equally potent inhibition of IR dephosphorylation. However IRK activation was reduced by greater than 80% suggesting that these compounds did not access intracellular PTPs. The insulin-like activity of these pV compounds were demonstrable in vivo. Intra venous (i.v.) administration of bpV(pic) and bpV(phen) resulted in the lowering of plasma glucose concentrations in normal rats in a dose dependent manner. The greater potency of bpV(pic) compared to bpV(phen) was explicable, in part, by the capacity of the former but not the latter to act on skeletal muscle as well as liver. Finally administration of bpV(phen) and insulin led to a synergism, where tyrosine phosphorylation of the IR beta-subunit increased by 20-fold and led to the appearance of four insulin-dependent in vivo substrates. The insulin-mimetic properties of the pV compounds raises the possibility for their use as insulin replacements in the management of diabetes mellitus.

Animals↗
PubMedDate not supplied

In vivo effects of peroxovanadium compounds in BB rats.

Peroxovanadium compounds, each containing an oxo ligand, one or two peroxo anions, and an ancillary ligand in the inner coordination sphere of vanadium, were synthesized, crystallized and characterized by 51V NMR as > 95% pure. They markedly decreased plasma glucose in insulin-deprived diabetic BB rats, with a nadir occurring between 60 and 100 min after intravenous, intraperitoneal or subcutaneous administration. Plasma glucose was reduced after oral administration in insulin-treated and in insulin-deprived BB rats. When compared to sodium orthovanadate, peroxovanadium compounds exhibited a markedly greater potency on a molar basis, and in relation to their toxicity. The in vivo potency can be predicted by the degree of phosphotyrosine phosphatase inhibition observed in vitro. These are the first agents other than insulin that can acutely and markedly reduce plasma glucose in hypoinsulinemic diabetic BB rats.

Animals↗
PubMedDate not supplied

Impact of a computer-based patient record system on data collection, knowledge organization, and reasoning.

OBJECTIVE: To assess the effects of a computer-based patient record system on human cognition. Computer-based patient record systems can be considered "cognitive artifacts," which shape the way in which health care workers obtain, organize, and reason with knowledge. DESIGN: Study 1 compared physicians' organization of clinical information in paper-based and computer-based patient records in a diabetes clinic. Study 2 extended the first study to include analysis of doctor-patient-computer interactions, which were recorded on video in their entirety. In Study 3, physicians' interactions with computer-based records were followed through interviews and automatic logging of cases entered in the computer-based patient record. RESULTS: Results indicate that exposure to the computer-based patient record was associated with changes in physicians' information gathering and reasoning strategies. Differences were found in the content and organization of information, with paper records having a narrative structure, while the computer-based records were organized into discrete items of information. The differences in knowledge organization had an effect on data gathering strategies, where the nature of doctor-patient dialogue was influenced by the structure of the computer-based patient record system. CONCLUSION: Technology has a profound influence in shaping cognitive behavior, and the potential effects of cognition on technology design needs to be explored.

Cognition↗