Ray E. Gleason

Concurrent Morning Increase in Platelet Aggregability and the Risk of Myocardial Infarction and Sudden Cardiac Death

Abstract We have previously reported that the frequencies of myocardial infarction and of sudden cardiac death are highest during the period from 6 a.m. to noon. Since platelet aggregation may have a role in triggering these disorders, we measured platelet activity at 3-hour intervals for 24 hours in 15 healthy men. In vitro platelet responsiveness to either adenosine diphosphate (ADP) or epinephrine was lower at 6 a.m. (before the subjects arose) than at 9 a.m. (60 minutes after they arose). The lowest concentration of these agents required to produce biphasic platelet aggregation decreased (i.e., aggregability increased) from a mean ±SEM of 4.7±0.6 to 3.7±0.6 μM (P<0.01) for ADP and from 3.7±0.8 to 1.8±0.5 μM (P<0.01) for epinephrine. The period from 6 to 9 a.m. was the only interval in the 24-hour period during which platelet aggregability increased significantly. We subsequently studied 10 subjects on alternate mornings after they arose at the normal time and after delayed arising. The morning increas...

Clinical Consequences of Acquired Transfusional Iron Overload in Adults

We assessed the clinical sequelae of transfusional iron overload in 15 nonthalassemic adults (40 to 71 years of age) with anemias requiring transfusions. Iron loading had been present for less than four years in 14 patients. The number of units of blood transfused ranged from 60 to 210 (mean, 120). Liver-biopsy specimens in 10 patients contained seven to 26 times the normal amount of iron and typically showed focal portal fibrosis. Left ventricular cardiac function was impaired in only the most heavily transfused patients or in those with coexisting coronary-artery disease, All patients had glucose intolerance associated with significantly reduced insulin output, compared with controls (P < 0.01). Pituitary reserve of ACTH was limited in 10 of 12 patients, and that of gonadotropin in five of 13. We conclude that widespread subclinical organ dysfunction can result from transfusional iron overload developing in adulthood. The pattern of organ involvement resembles that encountered in idiopathic hemochromatosis.

Pre-Type I Diabetes: Linear Loss of Beta Cell Response to Intravenous Glucose

Twenty-one intravenous (i.v.) glucose tolerance tests were performed on nine subjects before the onset of overt type I diabetes mellitus. Islet cell antibodies (6 of 9 subjects) and elevated levels of la-positive T-lymphocytes (3 of 3 subjects studied) were detected during the prediabetic period. Elevations of fasting blood glucose and peak glucose during oral glucose tolerance tests were not observed until the year before onset of clinically overt diabetes. During the prediabetic period, there was a progressive loss of early-phase insulin release to i. v. glucose (rate of decline, 20–40 μU/ml insulin release/yr; correlation coefficient, 0.9).

A randomized, placebo-controlled, double-blind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata

Thirty-eight premenopausal women with uterine leiomyomata were enrolled in a randomized, double-blind, placebo-controlled study evaluating the efficacy of depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, in decreasing uterine volume. Eighteen women received intramuscular (IM) depot LA 3.75 mg every 4 weeks for 24 weeks (group A); 20 women received IM placebo with the same injection schedule (group B). Group A patients had a mean reduction in pretreatment uterine volume from 505 +/- 93 cu cm (mean +/- standard error of the mean) to 305 +/- 57 cu cm after 12 weeks (P less than 0.05 versus pretreatment) and 307 +/- 57 cu cm after 24 weeks of therapy (P less than 0.05 versus therapy (P less than 0.05 versus pretreatment). At 3 months after cessation of therapy, the mean uterine volume in group A had increased to 446 +/- 92 cu cm (P less than 0.05 versus week 24). Group B patients had no significant change in uterine volume over the 24-week treatment period. These results suggest that depot LA therapy may significantly decrease uterine volume in patients with leiomyomata, but that regrowth of uterine size occurs shortly after cessation of therapy.

Reproducibility and Comparative Analysis of Repeated Intravenous and Oral Glucose Tolerance Tests

We have developed a methodology for measuring the reproducibility of the oral glucose tolerance test (OGTT) and the intravenous glucose tolerance test (IVGTT) in normal subjects and in offspring of conjugal diabetic parents. Both groups of subjects revealed more striking correlations of several parameters of blood glucose and insulin secretion between two IVGTTs than between two OGTTs. Employing arbitrary criteria, we calculated a “reproducibility index” as a quantitative measure of blood glucose variability in each subject. No significant difference was found in the reproducibility of OGTT versus IVGTT, nor in normals versus the offspring. Only about 50 per cent of the tests in normals and in the offspring could be considered to be “reproducible.” The offspring revealed greater correlations of several parameters, particularly insulin secretion, between the two IVGTTs and between the two OGTTs as compared with the normal group. However, the blood glucose variations tended to be considerably greater in the offspring from one to the other test.

Differential Sensitivity to β-Cell Secretagogues in “Early,” Type I Diabetes Mellitus

The insulin secretory response to various β-cell secretagogues was studied in four children (ages 11,11, 12, and 10 yr) in “early” stages or remission of type I diabetes mellitus. One child was an anti-islet antibody positive monozygotic twin of a type I diabetic subject, two children had impaired glucose tolerance and elevated levels of la-positive T-cells, and the fourth was in remission (off insulin) of type I diabetes 6 mo after immunotherapy. The peak first-phase (0–10 min) insulin increment after intravenous (i.v.) glucose was negligible in each patient, whereas the peak responses to i.v. glucagon, tolbutamide, arginine, and oral glucose ranged between 10% and 43% of median responses in normal control subjects. The rank order of response to a variety of secretagogues was remarkably similar in all four subjects: i.v. arginine > i.v. glucagon > oral glucose > i.v. tolbutamide > i.v. glucose. These studies indicate that a “functional” β-cell defect, namely a complete loss of response to i.v. glucose and a partial loss to other secretagogues, exists in type I diabetic patients before complete β-cell destruction. This alteration in β-cell responsiveness probably underlies our prior observation of slowly progressive loss of i.v.-glucose-induced insulin release in islet cell antibody-positive siblings of type I diabetic subjects.

Non-modulation as an intermediate phenotype in essential hypertension.

Non-modulation is a trait characterized by abnormal angiotensin-mediated control of aldosterone release and the renal blood supply. To determine whether non-modulation defines a specific subgroup of the hypertensive population and its utility as an intermediate phenotype, we have studied the distribution of this quantitative trait, whether its features are reproducible on repeated testing, and whether there is concordance of its multiple features. Essential hypertensive patients (224) and normotensive subjects (119) received an infusion of angiotensin II (Ang II) at 3 ng.kg-1.min-1 for 30-45 minutes. p-Aminohippurate (PAH) clearance was assessed as an index of renal plasma flow while the subjects were on a 200 meq sodium diet; plasma aldosterone levels were measured while the subjects were on a 10 meq sodium diet. In 54 subjects, diuretic-induced volume depletion superimposed on a low salt diet was substituted for the Ang II infusion. The results of each study were submitted to maximum likelihood analysis to assess bimodality. In response to both diuretic-induced volume depletion (p < 0.000023) and Ang II infusion (p < 0.0009), aldosterone responses were bimodally distributed in the essential hypertensive but not in the normotensive subjects, suggesting that this trait identifies a discrete subgroup. In the 59 subjects who had both an adrenal and renal study, 50 (85%) were concordant. Finally, in 27 subjects studied two to six times over a span of 1-60 months, the intraclass correlations of the adrenal, PAH, or both responses were highly significant (p values between 0.001 and 0.00007), indicating high reproducibility of results on repeated testing.(ABSTRACT TRUNCATED AT 250 WORDS)

A Model of Glucose-insulin Homeostasis in Man that Incorporates the Heterogeneous Fast Pool Theory of Pancreatic Insulin Release

Current physiologic knowledge about glucose-insulin homeostasis in liver, brain, pancreas, kidney, peripheral tissues, and central vascular organs has been synthesized to form a whole-system mathematical model of glucose metabolism in normal, ideal man. In addition to data of other workers, results from more than 100 intravenous glucose tolerance tests, including variable dosage, variable duration of infusion, and double pulse studies, were used to determine model structure and parameters. Model and clinical testing have focused particularly on the fast phase of insulin response to vascular glucose. The model incorporates blood circulation and equilibration of substances between vascular and interstitial spaces, and it assumes constant fractional clearance of insulin by liver and kidney. Studies using a double pulse of glucose suggest that the time derivative of glucose level is not the sole or predominant influence on fast phase insulin release, but that preinfusion glucose level and/or previous glucose exposure of the pancreas are also important. Variable dosage glucose studies suggest that the amount of insulin released during the fast phase rather than the insulin release rate is regulated by the glucose level. A two-pool, heterogeneous threshold mechanism for beta cell response to glucose is presented that is compatible with the clinical results.

Temporal relationship of glycosylated haemoglobin concentrations to glucose control in diabetics.

SummaryTo examine the temporal relationship between Hb AIc values and various indices of blood glucose control, 38 diabetic and 28 nondiabetic youth counsellors employed at two summer camps for diabetic children took part in an eight-week study. Each week fasting determinations were made of Hb AI, Hb AIc, serum cholesterol, triglyceride and growth hormone and plasma glucose. Total daily urine glucose excretion was measured approximately two times per week, capillary glucose values were measured fasting and at 11 a. m. and 3 p. m. on two days per week, and urine glucose was measured semi-quantitatively four times per day. As Hb AI was correlated highly with Hb AIc (r = 0.997), it was used as the primary index of glycosylated haemoglobin. The mean values of Hb AI, serum cholesterol and triglycerides and fasting plasma glucose were all significantly elevated in the diabetic group but only Hb AI values provided total separation of the two groups. Within the diabetic group the Week 8 Hb AI values showed a significant correlation with the Week 8 mean capillary glucose concentrations, the proportion of urine tests showing 2% and 0% glycosuria, and mean serum triglycerides. Correlations of Week 8 Hb AI with the mean values of these glycaemic parameters for each week of the study demonstrated low order correlations with the glycaemic measures of Week 1, and a progressive increase in the degree of correlation reaching a plateau with the glycaemic measures of Week 4 to 8. Similar correlation analysis using the Hb AI values from Week 4 confirmed these findings. Therefore, while Hb AI provides an index of the control of diabetes, it appears to be more acutely responsive to blood glucose alteration than generally recognized.

The effect of operative technique and uterine size on blood loss during myomectomy: a prospective randomized study * †

OBJECTIVES To compare operative blood loss between two accepted blood loss-reducing techniques used during myomectomy and to evaluate the effect of preoperatively determined uterine volume on blood loss. DESIGN Subjects were stratified by ultrasound-determined uterine volume < 600 cm3 (n = 11) and > or = 600 cm3 (n = 10) and then randomized into treatment groups. The same radiologist, surgeons, and anesthetic induction technique were involved in every case. In the pharmacologic technique, diluted vasopressin (20 U in 20 mL normal saline) was injected into the serosa and/or myometrium overlying the fibroid(s) before the uterine incision(s). In the mechanical technique, a penrose drain tourniquet was passed through defects created in the broad ligaments at the level of the internal os and secured posteriorly, occluding the uterine vessels. In addition, vascular clamps were placed on the infundibulopelvic ligaments, occluding anastomotic blood flow through the ovarian vessels. RESULTS There was no difference in operative blood loss, operating time, preoperative and intraoperative mean arterial blood pressures, postoperative febrile morbidity, preoperative and postoperative hematocrits, transfusion rates, and length of hospital stay between groups. Blood loss was significantly greater for uteri with ultrasound-determined volumes > or 600 cm3 (627 +/- 175 mL, mean +/- SEM) than for those < 600 cm3 (228 +/- 49 mL). For all subjects, blood lost while operating on the uterus (mean, 379 mL; range, 35 to 1,968 mL) was positively correlated with the total weight of the fibroids resected and with time spent operating on the uterus. Total blood loss (mean, 418 mL; range, 42 to 1,968 mL) was also positively correlated with the time spent operating on the uterus and with total operating time. CONCLUSIONS There were no demonstrable differences in blood loss, morbidity, or transfusion requirements between subjects undergoing myomectomy using pharmacologic vasoconstriction and mechanical vascular occlusion techniques. Blood loss during myomectomy is primarily incurred while operating on the uterus and is correlated with preoperative uterine size, total weight of fibroids removed, and operating time.