Carvedilol (Kredex) reduces infarct size in a canine model of acute myocardial infarction.

Carvedilol (Kredex) is a multiple action, antihypertensive agent that may also prove to be useful in the treatment of angina and congestive heart failure. Carvedilol combines in one molecule both beta-adrenoceptor blocking and vasodilating activities. Inasmuch as beta-adrenoceptor blocking agents are known to be cardioprotective and thereby reduce infarct size, it is logical to assume that carvedilol, likewise, would possess this desirable activity. Furthermore, the additional vasodilating activity of carvedilol could contribute to further reductions in infarct size by reducing myocardial work (and therefore myocardial oxygen demand) through reductions in both afterload and myocardial wall tension. As such, we have investigated the ability of carvedilol to reduce infarct size in a canine model of acute myocardial infarction. Carvedilol (1 mg/kg i.v.) or its vehicle, dimethylformamide, were administered 15 min before left circumflex coronary artery (LCX) occlusion. Following 1 h of LCX occlusion, dogs were reperfused through a critical stenosis and then allowed to recover for 24 h. Carvedilol-treated animals exhibited a 78% reduction in infarct size compared to vehicle controls, such that the percentage of the left ventricle infarcted was reduced significantly from 16.2 +/- 4.1% in control animals to 3.6 +/- 1.3% in animals treated with carvedilol (p = 0.017, n = 6). Stained tissue sections of the left ventricle were photographed, digitized and color-enhanced using an Image Analysis Computer System, and three-dimensional reconstruction of the left ventricle, including the infarcted areas, was performed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mitogen-stimulated lymphocyte proliferation and pituitary hormones in major depression

To assess cellular immune status and the hypothalamic-pituitary (HP) axis in patients with major depression, we examined peripheral blood mononuclear cells (PBMC) and measured the plasma levels of cortisol, adrenocorticotropin hormone (ACTH), growth hormone (GH), and prolactin (PRL). Twenty patients with major depression were compared with 20 control subjects matched for age, sex, and race. The dose-response curves for concanavalin-A (Con-A) and phytohemagglutinin (PHA) stimulation were not significantly different between the two groups. The patients had decreased Con-A-stimulated T-lymphocyte proliferation when compared to the control subjects, but only at the lowest suboptimal concentration of Con-A. None of the four concentrations of PHA-stimulated proliferation were different between the two groups, neither was PHA-induced interleukin-2 production. Within the patient group only, plasma prolactin (PRL) correlated significantly with stimulated lymphocyte proliferation using two optimal concentrations of PHA and one optimal concentration of Con-A, when the proliferation was expressed using the stimulation index.     

Hemodynamic effects of naloxone on hemorrhagic shock in the beagle

Naloxone reverses the hypotension in various types of hemorrhagic shock models. What has yet to be firmly established is the mechanism by which naloxone reverses the hypotension. In a canine hemorrhagic shock model, impedance cardiography and invasive methods were used to measure various cardiovascular parameters. All dogs (beagles, 10-15 kg) were bled to and maintained at a mean arterial blood pressure (MAP) of 60 mmHg for 90 min and were then given either naloxone (2 mg/kg; n = 6) or an equivalent volume of saline (n = 6) intravenously (IV). After another 90 min observation period, the shed blood was reinfused. No significant differences in the preshock and shock cardiodynamics were noted between the naloxone and the control animals. During the treatment period, MAP was significantly increased in the naloxone group. There was no increase in cardiac output (CO), stroke volume (SV), end diastolic volume (EDV), dP/dt max, dP/dt/P, or HI (the impedance contractility index) over control animals. The most significant parameter improvement was total peripheral resistance (TPR). The data suggest that naloxone in this hemorrhagic shock model improves hemodynamics primarily by increasing vascular resistance.     

Interferon induced increases in c-myc expression in a human breast carcinoma cell line.

Previous studies from our laboratory have indicated that interferon-gamma inhibits the growth of a human breast carcinoma cell line, MDA 468. We measured steady state levels of c-myc mRNA to determine if the antiproliferative effect of IFN-gamma was mediated by changes in the expression of this proto-oncogene. C-myc message levels increased after 24 hours of IFN treatment, peaked at 48 hours, but remained elevated through 96 hours of treatment. The increase in c-myc mRNA was observed with as little as 10 U/ml of IFN-gamma. The stability of mRNA was enhanced in interferon treated cells. These data suggest that IFN-gamma increased expression of c-myc mRNA, but decreased cell growth, and point out the complexities of the relationship of the expression of this protooncogene to cell growth.     

Urinary free cortisol output and disruptive behavior in children

Hostile, impulsive, and aggressive behaviors have been associated with decreased urinary free cortisol (UFC) output. This is the first study to assess 24-hour UFC output in disruptive behavior disorders. The UFC of 19 boys with attention deficit and/or conduct disorder was compared with that of 19 age, race, and IQ matched normal controls studied as inpatients. Continuous Performance Test scores showed greater impulsivity in the disruptive group. UFC output did not differ between groups. However, UFC and difficulty were positively correlated on the continuous performance test in the form of longer interstimulus intervals and longer reaction times.     

Pathophysiology of Intense Physical Conditioning in a Hot Climate. I. MECHANISMS OF POTASSIUM DEPLETION

Serial estimations of exchangeable (42)K showed that six volunteer subjects undergoing intensive physical conditioning in a hot climate sustained a mean deficit of 517 mEq. This deficit occurred despite a daily potassium intake of 100 mEq. Simultaneous values for lean body mass rose suggesting that potassium deficiency was not the result of catabolism. Although sweating was the major avenue by which the deficit occurred, daily excretion of potassium into the urine when each subject was maximally deficient ranged from 46 to 75 mEq and thus was inappropriately high for potassium-depleted subjects. Despite high intakes of sodium and excretion of corresponding quantities into the urine, Na/K ratios in sweat were low thus indicating unsuppressed activity of aldosterone on sweat glands. Moreover, excretion and secretion of aldosterone and in many instances, plasma renin activity, appeared to be high with respect to sodium intake.These findings suggest that intense physical work in the heat stimulates higher production of aldosterone than would occur in nonexercising subjects on similar sodium intakes. Similar to the phenomenon of mineralocorticoid escape, such overproduction of aldosterone in the presence of conditions permitting excretion of sodium into the urine could facilitate continued excretion of potassium by the kidney despite serious potassium depletion. As a consequence, the kidney played a role in the genesis of potassium depletion in these subjects.In contrast to subjects undergoing conditioning in the summer months, potassium depletion did not occur in 16 subjects during identical training under cooler environmental conditions.     

GMP-140 mediates adhesion of stimulated platelets to neutrophils.

In vivo, platelets associate with neutrophils at sites of hemorrhage or inflammation. In vitro, stimulated platelets bind to neutrophils in a Ca2(+)-dependent manner. GMP-140, an integral membrane glycoprotein found in secretory granules of platelets and endothelium, is rapidly translocated to the cell surface after cellular activation. It shares sequence similarity with two leukocyte adhesion molecules, ELAM-1 and a lymphocyte homing receptor. We have recently shown that neutrophils bind to purified GMP-140 in a Ca2(+)-dependent fashion, and that GMP-140 participates in adhesion of neutrophils to activated endothelium. In this study we demonstrate that GMP-140 also mediates adhesion of neutrophils to stimulated platelets. Fixed thrombin-activated human platelets, but not unstimulated platelets, formed rosettes around neutrophils in the presence of Ca2+. The binding of platelets to neutrophils was inhibited by a monoclonal antibody to GMP-140 and by purified GMP-140. By promoting close cell-cell contact, GMP-140 may recruit both platelets and neutrophils to sites of tissue injury as well as modulate the function of each cell type by the other.     

Intestinal absorption and jejunal morphology in duodenal ulcer patients

Summary and conclusions 1. Impaired intestinal absorption manifested by a subnormal carotene-loading test may be demonstrated in some patients with duodenal ulcer who have not undergone gastric resection.2. Subnormal carotene-loading tests may be found in some duodenal ulcer patients during the first few weeks after subtotal gastrectomy. In some cases, however, the abnormality revealed by this test tends to regress and the tests revert in time to normal.3. No consistent correlation could be demonstrated between the results of the carotene-loading test and the jejunal mucosal morphology in patients with duodenal ulcer. This may in part be explained by the possible existence of patchy rather than uniform jejunal changes.4. Two of 22 postgastrectomy duodenal ulcer patients had abnormal jejunal biopsies. Both of these patients exhibited significant weight loss and persistent diarrhea.5. The occurrence of subnormal carotene-loading tests in some ulcer patients before gastric resection raises the question that the operation may in some cases serve to unmask a latent malabsorption state.6. In ulcer patients in whom evidence for impaired absorption is detected prior to surgery, the use of the most conservative surgical procedure feasible should be considered.Deceased.     

HLA-B35 correlates with a favorable outcome following adjuvant administration of an HLA-matched allogeneic melanoma vaccine

This work presents survival data of 42 melanoma patients at high risk for disease recurrence who received an allogeneic melanoma vaccine composed of three cell lines, each matching at least one allele of the recipient's human leukocyte antigen (HLA)-A and -B loci. The 5-year overall survival (OS) rate and disease-free survival (DFS) compared favorably with the standard interferon-α regimen. Interestingly, patients bearing HLA-B35 had significantly better OS and DFS (OS of 100% and DFS of 90% for HLA-B35 vs 56% and 23%, for the non-B35 patients). In contrast, patients expressing HLA-B07 did not fare well with the vaccine. Although the data include a relatively small cohort of patients, it strongly hints toward a correlation between HLA types and potential benefit from anticancer immunotherapy.