Graduate Student Literature Review: Mitochondrial response to heat stress and its implications on dairy cattle bioenergetics, metabolism, and production.

The dairy industry depends upon the cow's successful lactation for economic profitability. Heat stress compromises the economic sustainability of the dairy industry by reducing milk production and increasing the risk of metabolic and pathogenic disease. Heat stress alters metabolic adaptations, such as nutrient mobilization and partitioning, that support the energetic demands of lactation. Metabolically inflexible cows are unable to enlist the necessary homeorhetic shifts that provide the needed nutrients and energy for milk synthesis, thereby impairing lactation performance. Mitochondria provide the energetic foundation that enable a myriad of metabolically demanding processes, such as lactation. Changes in an animal's energy requirements are met at the cellular level through alterations in mitochondrial density and bioenergetic capacity. Mitochondria also act as central stress modulators and coordinate tissues' energetic responses to stress by integrating endocrine signals, through mito-nuclear communication, into the cellular stress response. In vitro heat insults affect mitochondria through a compromise in mitochondrial integrity, which is linked to a decrease in mitochondrial function. However, limited evidence exists linking the in vivo metabolic effects of heat stress with parameters of mitochondrial behavior and function in lactating animals. This review summarizes the literature describing the cellular and subcellular effects of heat stress, with a focus on the effect of heat stress on mitochondrial bioenergetics and cellular dysfunction in livestock. Implications for lactation performance and metabolic health are also discussed.

Graduate Student Literature Review: Mitochondrial adaptations across lactation and their molecular regulation in dairy cattle.

As milk production in dairy cattle continues to increase, so do the energetic and nutrient demands on the dairy cow. Difficulties making the necessary metabolic adjustments for lactation can impair lactation performance and increase the risk of metabolic disorders. The physiological adaptations to lactation involve the mammary gland and extramammary tissues that coordinately enhance the availability of precursors for milk synthesis. Changes in whole-body metabolism and nutrient partitioning are accomplished, in part, through the bioenergetic and biosynthetic capacity of the mitochondria, providing energy and diverting important substrates, such as AA and fatty acids, to the mammary gland in support of lactation. With increased oxidative capacity and ATP production, reactive oxygen species production in mitochondria may be altered. Imbalances between oxidant production and antioxidant activity can lead to oxidative damage to cellular structures and contribute to disease. Thus, mitochondria are tasked with meeting the energy needs of the cell and minimizing oxidative stress. Mitochondrial function is regulated in concert with cellular metabolism by the nucleus. With only a small number of genes present within the mitochondrial genome, many genes regulating mitochondrial function are housed in nuclear DNA. This review describes the involvement of mitochondria in coordinating tissue-specific metabolic adaptations across lactation in dairy cattle and the current state of knowledge regarding mitochondrial-nuclear signaling pathways that regulate mitochondrial proliferation and function in response to shifting cellular energy need.

An expert panel process to evaluate habitat restoration actions in the Columbia River estuary.

We describe a process for evaluating proposed ecosystem restoration projects intended to improve survival of juvenile salmon in the Columbia River estuary (CRE). Changes in the Columbia River basin (northwestern USA), including hydropower development, have contributed to the listing of 13 salmon stocks as endangered or threatened under the U.S. Endangered Species Act. Habitat restoration in the CRE, from Bonneville Dam to the ocean, is part of a basin-wide, legally mandated effort to mitigate federal hydropower impacts on salmon survival. An Expert Regional Technical Group (ERTG) was established in 2009 to improve and implement a process for assessing and assigning "survival benefit units" (SBUs) to restoration actions. The SBU concept assumes site-specific restoration projects will increase juvenile salmon survival during migration through the 234 km CRE. Assigned SBUs are used to inform selection of restoration projects and gauge mitigation progress. The ERTG standardized the SBU assessment process to improve its scientific integrity, repeatability, and transparency. In lieu of experimental data to quantify the survival benefits of individual restoration actions, the ERTG adopted a conceptual model composed of three assessment criteria-certainty of success, fish opportunity improvements, and habitat capacity improvements-to evaluate restoration projects. Based on these criteria, an algorithm assigned SBUs by integrating potential fish density as an indicator of salmon performance. Between 2009 and 2014, the ERTG assessed SBUs for 55 proposed projects involving a total of 181 restoration actions located across 8 of 9 reaches of the CRE, largely relying on information provided in a project template based on the conceptual model, presentations, discussions with project sponsors, and site visits. Most projects restored tidal inundation to emergent wetlands, improved riparian function, and removed invasive vegetation. The scientific relationship of geomorphic and salmonid responses to restoration actions remains the foremost concern. Although not designed to establish a broad strategy for estuary restoration, the scoring process has adaptively influenced the types, designs, and locations of restoration proposals. The ERTG process may be a useful model for others who have unique ecosystem restoration goals and share some of our common challenges.

Magnetocardiography of direct currents: S-T segment and baseline shifts during experimental myocardial infarction.

Magnetocardiograms with a bandwidth of 0 to 40 hertz were recorded from intact dogs undergoing myocardial infarction. This was done with a superconducting magnetometer in a magnetically shielded room. The purpose was to look for the steady currents of injury from the heart which supposedly produce much of the S-T segment shifts during infarction. These heart currents cannot be measured with surface electrodes because of direct-current interference from other sources, such as from the contact potential between electrode and skin. The magnetocardiograms showed both S-T segment shifts and direct currents as a result of infarction. However, they also showed that the S-T segment shifts were not produced by the direct currents. It is unlikely that these direct currents originated from the infarcted area, and their exact origin is not yet known.

Life History Trade-offs within the Context of Mitochondrial Hormesis.

Evolutionary biologists have been interested in the negative interactions among life history traits for nearly a century, but the mechanisms that would create this negative interaction remain poorly understood. One variable that has emerged as a likely link between reproductive effort and longevity is oxidative stress. Specifically, it has been proposed that reproduction generates free radicals that cause oxidative stress and, in turn, oxidative stress damages cellular components and accelerates senescence. We propose that there is limited support for the hypothesis because reactive oxygen species (ROS), the free radicals implicated in oxidative damage, are not consistently harmful. With this review, we define the hormetic response of mitochondria to ROS, termed mitochondrial hormesis, and describe how to test for a mitohormetic response. We interpret existing data using our model and propose that experimental manipulations will further improve our knowledge of this response. Finally, we postulate how the mitohormetic response curve applies to variation in animal performance and longevity.

Comparison of cardiac output responses to 2,4-dinitrophenol-induced hypermetabolism and muscular work.

Both electrically induced exercise and infusion of 2,4-dinitrophenol (DNP) increased oxygen consumption and tissue metabolism in chloralose-anesthetized dogs. Cardiac output increased with oxygen consumption at the same rate in both experimental conditions. The increase in cardiac output induced by exercise was, as expected, accompanied by increases in both lactate-to-pyruvate ratio and "excess lactate" in arterial blood. However, these parameters did not increase after DNP infusion until the rate of oxygen consumption had increased four- to fivefold, perhaps due to facilitation of mitochondrial electron transport by DNP. Anaerobic tissue metabolism therefore probably did not contribute significantly to increased cardiac output during the mild-to-moderate tissue hypermetabolism induced by DNP. The increased cardiac output may have been the result of metabolic changes common to both exercise and DNP infusion; muscular activity alone may not have been the primary determinant of the cardiac output response during exercise.

Renin-angiotensin system inhibition in conscious sodium-depleted dogs. Effects on systemic and coronary hemodynamics.

The role of the renin-angiotensin system in the regulation of the systemic and coronary circulations during sodium depletion was studied in conscious normotensive dogs by i.v. administration of teprotide (0.5 mg/kg), an angiotensin-converting enzyme inhibitor, and saralasin (0.05-5 mug/kg per min), an angiotensin-receptor antagonist. Sodium depletion was produced by administering a low sodium diet and furosemide for 5 days. Administration of both teprotide and saralasin lowered systemic arterial blood pressure and total peripheral vascular resistance. Simultaneously, cardiac output increased, but left ventricular end-diastolic pressure, dP/dt, and dP/dt/P did not change significantly. Furthermore, both agents reduced diastolic coronary vascular resistance and increased coronary blood flow, but did not affect myocardial oxygen consumption, left ventricular work, or myocardial efficiency. These systemic and coronary vasodilator effects of teprotide and saralasin, however, were not observed in normal dogs on a regular sodium diet; in this group, the only effect noted was a slight increase in arterial pressure during saralasin infusion. Arterial plasma concentration of norepinephrine did not differ between normal and sodiumdepleted dogs, nor did it change significantly after teprotide administration. These results suggest that, during salt depletion, angiotensin II exerts an active vasoconstrictor action on the systemic and coronary vessels, but has no significant effects on myocardial contractility or energetics. It also appears likely that the increase in cardiac output observed in sodiumdepleted dogs after angiotensin inhibition was caused, at least in part, by the decrease in systemic arterial pressure.

Conditioning effects of chronic infusions of dobutamine. Comparison with exercise training.

We studied the conditioning effects of chronic infusion of dobutamine and exercise training in three groups of chronically instrumented dogs. One group was infused with normal saline, a second group was infused with dobutamine (40 mug/kg per min), and the third group was exercised on a treadmill at 4 mph, up a 10 degrees incline. Each group was either infused or exercised for 2 h a day, 5 d a week for 5 consecutive wk. Resting heart rate and arterial blood lactate concentration, measured at weekly intervals, decreased progressively in the dobutamine and exercise groups, but not in the group that received normal saline infusion. Cardiovascular responses to submaximal treadmill exercise were not changed by 5 wk of normal saline infusion. However, the increases in heart rate, cardiac output, mean aortic blood pressure, arterial blood lactate, plasma renin activity, and norepinephrine concentration during exercise were significantly smaller after 5 wk of conditioning with either dobutamine or exercise training. After conditioning, the increases in arteriovenous oxygen difference during exercise were larger in the latter two groups, but the increases in total body oxygen consumption did not differ before and after conditioning. To assess ventricular function, we intravenously infused methoxamine both before and after conditioning. The slope of the line that related systolic aortic blood pressure and mean left atrial pressure increased in the animals conditioned with either dobutamine or exercise, indicating enhanced myocardial contractility. Left ventricular blood flow was lower in these two groups of animals than it was in the normal saline group. Left ventricular weight did not differ among the three groups. Our results show that chronic infusion of dobutamine produced cardiovascular and metabolic conditioning effects like those produced by exercise training, and further suggest that sympathetic stimulation during exercise plays a role in physical conditioning.

Experimental myocardial infarction. II. Acute depression and subsequent recovery of left ventricular function: serial measurements in intact conscious dogs.

Acute myocardial infarction causes depression of left ventricular function, but the capacity of the ventricle to recover from such an injury remains unknown. This problem was explored by measuring left ventricular function in eight intact conscious dogs before, 1 hr after, and again 6-8 days after myocardial infarction. Acute myocardial infarction was produced using a technique which entails gradual inflation over an average period of 1 hr of a balloon cuff previously implanted around the left anterior descending coronary artery. Occurrence of anterior wall infarction was detected electrocardiographically and later confirmed by postmortem examination. Left ventricular function was evaluated from the relationship between left ventricular developed pressure (left ventricular peak systolic pressure minus left ventricular end-diastolic pressure) and left ventricular end-diastolic pressure during transient aortic occlusion with a balloon catheter. Left ventricular function curves were obtained by plotting left ventricular-developed pressure at increasing left ventricular end-diastolic pressures up to 50 mm Hg. Acute myocardial infarction caused marked depression of left ventricular function measured 1 hr after onset of infarction, but 1 wk later all eight animals showed improvement with return of function toward the control levels. A small but significant descending limb was noted at left ventricular end-diastolic pressures above 35 mm Hg. Quantitatively, the descending limb was similar before, 1 hr after, and 1 wk after myocardial infarction. Hemodynamic data revealed evidence of left ventricular failure in all animals, but variability in individual hemodynamic parameters was noted. The data indicate that the marked depression of left ventricular function observed immediately after experimental acute myocardial infarction undergoes considerable resolution within 1 wk, but that functional recovery remains incomplete.

Experimental myocardial infarction. IV. Reduction of left ventricular compliance in the healing phase.

Compliance of the infarcted left ventricle was studied in dogs 3-5 days after occlusion of the left anterior descending coronary artery. Compliance was assessed from postmortem pressure-volume curves and from pressure-length measurements (mercury-in-silastic segment length gauges) made both in vivo and postmortem. Postmortem pressure-volume curves showed reduced compliance compared to sham-operated animals. Postmortem pressure-length curves of infarcted and adjacent normal myocardium indicated that the diminished total compliance could be attributed to an increase in stiffness of the infarcted area. This was confirmed by in vivo end-diastolic pressure-length changes produced by transient aortic occlusion. The infarcted area was akinetic, showing neither contraction nor aneurysmal bulging. In addition, anesthetized dogs with infarcts, when compared with sham-operated animals, had similar left ventricular end-diastolic volumes (indicator dilution method), but higher left ventricular end-diastolic pressures. Taken with previous observations, which show that systolic aneurysmal bulging is uniformly present at the onset of ischemia, these results indicate that stiffening of the ischemic myocardium occurs during the first 5 days after infarction, and show that elevation of left ventricular filling pressure does not necessarily signify ventricular dilatation. The results also suggest a mechanism whereby ventricular performance may improve during recovery from acute myocardial infarction.

Experimental myocardial infarction. 8. Chronotropic augmentation of cardiac function in left ventricular failure of acute and healing stages in intact conscious dogs.

The hemodynamic effects of tachycardia induced by atrial pacing were investigated in left ventricular failure of acute and healing experimental myocardial infarction in 20 intact, conscious dogs. Myocardial infarction was produced by gradual inflation of a balloon cuff device implanted around the left anterior descending coronary artery 10-15 days prior to the study. 1 hr after acute myocardial infarction, atrial pacing at a rate of 180 beats/min decreased left ventricular end-diastolic pressure from 19 to 8 mm Hg and left atrial pressure from 17 to 12 mm Hg, without change in cardiac output. In the healing phase of myocardial infarction 1 wk later, atrial pacing decreased left ventricular end-diastolic pressure from 17 to 9 mm Hg and increased the cardiac output by 37%. This was accompanied by evidence of peripheral vasodilation. In two dogs with healing anterior wall myocardial infarction, left ventricular failure was enhanced by partial occlusion of the circumflex coronary artery. Both the dogs developed pulmonary edema. Pacing improved left ventricular performance and relieved pulmonary edema in both animals. In six animals propranolol was given after acute infarction, and left ventricular function deteriorated further. However the pacing-induced augmentation of cardiac function was unaltered and, hence, is not mediated by sympathetics.The results show that the spontaneous heart rate in left ventricular failure of experimental canine myocardial infarction may be less than optimal and that maximal cardiac function may be achieved at higher heart rates.

Experimental myocardial infarction. VI. Efficacy and toxicity of digitalis in acute and healing phase in intact conscious dogs.

Use of digitalis in myocardial infarction is controversial. To determine the efficacy and toxic threshold, serial infusions of 3 mug/kg per min of acetyl-strophanthidin were given to six intact conscious dogs 24 hr before and 1 hr, 2 days, and 7 days after myocardial infarction induced by inflation of a balloon cuff implanted on the left anterior descending coronary artery. Within 1 hr after myocardial infarction, heart rate increased by 28%. Left ventricular end-diastolic pressure increased from 7 to 20 mm Hg, and stroke volume decreased by 25%. At this time acetylstrophanthidin caused no beneficial hemodynamic change, 1 wk later, the heart rate and left ventricular end-diastolic pressure had declined toward normal but remained elevated. At this time, acetylstrophanthidin lowered left ventricular end-diastolic pressure by 25%, and increased the stroke volume and cardiac output by 25% and 21% respectively, without any change in heart rate or aortic pressure. Tolerance to acetylstrophanthidin, defined as appearance of ventricular tachycardia, declined the 1st hr after myocardial infarction by 24% (P<0.05) from the control level of 43 +/-4 mug/kg (SEM), but subsequently returned to control.Thus, immediately after myocardial infarction, tolerance to acetylstrophanthidin was reduced, and left ventricular failure was not ameliorated. 1 wk later in the healing phase of myocardial infarction, tolerance to acetylstrophanthidin returned to normal and left ventricular performance was improved by this drug. The study suggests a limited therapeutic role for digitalis in the treatment of left ventricular failure in the acute phase immediately after myocardial infarction, but beneficial effects may occur in the healing phase 1 wk later.

Insulin infusion in conscious dogs. Effects on systemic and coronary hemodynamics, regional blood flows, and plasma catecholamines.

Cardiovascular actions of insulin were studied by intravenous infusions of insulin (4 and 8 mU/kg per min) in normal conscious dogs. This resulted in increases in cardiac output, heart rate, and left ventricular derivative of pressure with respect to time (dP/dt) and dP/dt/P, as blood glucose was reduced. The inotropic and chronotropic effects of insulin were not related to hypoglycemia, as they persisted even when blood glucose was restored to control values or when it was prevented from falling by a simultaneous infusion of glucose. These cardiac effects were accompanied by increases in plasma catecholamines, and were abolished by propranolol pretreatment. Both plasma epinephrine and norepinephrine increased during insulin hypoglycemia, but only norepinephrine increased during insulin infusion when euglycemia was maintained. Mean arterial blood pressure did not change significantly during insulin hypoglycemia, but rose if euglycemia was maintained, probably due to the selective increase in norepinephrine in the latter condition. A pressor response also occurred in propranolol-pretreated dogs during insulin hypoglycemia, but was abolished when the animals also had been pretreated with phentolamine, indicating that the vasoconstrictor action of insulin was mediated via alpha adrenergic receptors. Insulin infusion increased left ventricular work and myocardial blood flow in dogs with and without hypoglycemia. Myocardial blood flow, however, did not change significantly during insulin infusion in dogs pretreated with propranolol. As propranolol also diminished the inotropic response, it appears that the increase in myocardial blood flow caused by insulin in the normal dog is causally related to the increased myocardial metabolic demand. Insulin also produced vasomotor effects on other vascular beds. In skeletal muscle, blood flow was increased under all study conditions, except during insulin hypoglycemia after propranolol-pretreatment when unopposed alpha-mediated vasoconstriction was present. The persistent increase in flow during both alpha and beta adrenergic blockade suggests that insulin has a direct dilator effect on skeletal muscle vasculature. In the adrenal gland, flow was increased except during euglycemia, when no rise in plasma epinephrine was observed, suggesting coupling between adrenal flow and catecholamine release. In the splanchnic bed, flow was decreased during euglycemia, when plasma norepinephrine rose, and during beta adrenergic blockade with propranolol, when unopposed alpha-mediated vasoconstriction also predominated. A similar pattern was found in the kidney, except that renal blood flow also fell after combined alpha and beta adrenergic blockade. The results show that the vasomotor effects on regional flows are mediated both via adrenergic mechanisms, and in the case of skeletal muscle and kidney, via mechanisms unrelated to sympathetic stimulation.

A new hypothesis based on suicide substrate inhibitor studies for the mechanism of action of aromatase.

Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes. We report here that 1,4-androstadiene 3,17-dione (Ki 0.32 microM; kinact 0.91 X 10(-3)/sec) and testolactone (Ki 35 microM; kinact 0.36 X 10(-3)/sec) also cause a similar loss of aromatase activity. The mechanism which explains the unexpected loss of activity caused by these five inhibitors is neither established nor apparent from current theories of the enzyme mechanism of action of aromatase. We propose an inactivation mechanism based on a new hypothesis for estrogen biosynthesis in which the third enzyme oxidation carried out by aromatase results in the formation of an enzyme-bound intermediate. This intermediate is released as an aromatized product via a facile elimination reaction which simultaneously regenerates the unaltered active enzyme. Various structural modifications made in these five inhibitors are hypothesized to redirect this elimination reaction so that the steroid intermediate remains covalently attached to the enzyme instead of being released as an aromatized product.

Role of converting enzyme inhibitors in the treatment of heart failure.

Treatment with angiotensin-converting enzyme inhibitors has proved to be effective in relieving symptoms of congestive heart failure. With recognition of the high mortality rate that accompanies heart failure, the question has arisen whether angiotensin-converting enzyme inhibitors may also improve survival. Early trials of the vasodilator combination hydralazine plus nitrates (V-HeFT trial) showed a strong trend toward a reduction in mortality, and a subsequent trial of the angiotensin-converting enzyme inhibitor enalapril in a population of patients with end-stage heart failure (CONSENSUS trial) showed a highly significant reduction in the mortality. The SOLVD trial was begun in 1986 to determine whether enalapril could reduce morbidity and mortality in patients with mild to moderate congestive failure (primarily New York Heart Association classes II and III), as well as in asymptomatic patients with a low ejection fraction. This report presents the results in patients with symptoms of congestive failure who were studied in the SOLVD treatment trial. A total of 2,569 patients were recruited into the trial, with an average follow-up period of 41.4 months. There was a 16% reduction in mortality in the enalapril-treated group compared with that of patients receiving placebo (p = 0.0036), as well as a 26% reduction in the combined end point of death plus hospital admission for congestive failure (p < 0.0001). Compared with placebo, enalapril significantly reduced the incidence of death due to progressive heart failure but apparently had no effect on sudden death. The results clearly indicate that the angiotensin-converting enzyme inhibitor enalapril can reduce both morbidity and mortality in symptomatic congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracoronary nifedipine in human beings: magnitude and time course of changes in left ventricular contraction/relaxation and coronary sinus blood flow.

Eight patients, all men, having at least 75% stenosis of the proximal, middle or both segments of the left anterior descending coronary artery, underwent intracoronary drug studies at the time of cardiac catheterization after saphenous vein bypass grafting. Nifedipine, 0.1 mg dissolved in saline solution, was infused into a left anterior descending graft that was the primary blood supply to each patient's anterior left ventricular wall and septum. High fidelity left ventricular pressure and its first derivative, dP/dt, and aortic pressure were sampled synchronously with coronary sinus blood flow by the thermodilution technique. The time constant of isovolumic pressure decay (T) was derived. In five patients, percent systolic shortening and mean shortening velocity were determined from myocardial markers implanted into the midwall of the myocardium at the time of cardiac surgery. In response to nifedipine, left ventricular systolic pressure decreased and end-diastolic pressure increased up to 60 seconds. Both positive and negative dP/dt also decreased up to 60 seconds, whereas coronary sinus blood flow increased up to 5 minutes. T was increased at 1 minute but returned to baseline by 3 minutes. Percent systolic shortening and mean shortening velocity were decreased at 1 minute but returned to control level by 3 minutes. Thus, although both left ventricular systolic and diastolic function were depressed by intracoronary administration of nifedipine, coronary sinus blood flow was augmented and remained increased long after changes in left ventricular contraction and relaxation had subsided. These temporal differences are consistent with animal studies showing a differential depressant effect of nifedipine on calcium uptake in smooth muscle and cardiac muscle.

Short-term effects of naloxone on hemodynamics and baroreflex function in conscious dogs with pacing-induced congestive heart failure.

OBJECTIVES: The purpose of this study was to determine the effects of naloxone on systemic hemodynamics and reflex function in dogs with congestive heart failure induced by rapid pacing. BACKGROUND: We have shown previously that naloxone, an opiate receptor antagonist, improves cardiac output, aortic blood pressure, systolic performance and the baroreflex function in conscious dogs with chronic right-sided congestive heart failure. However, whether endogenous opioids also play a role n mediating the reduction of myocardial and baroreflex function in animals with left heart failure remains controversial. METHODS: We administered naloxone (1 mg/kg body weight) and normal saline solution to 15 dogs with pacing-induced congestive heart failure (225 beats/min for 8 weeks) and 11 control dogs. In addition to systemic hemodynamic measurements, the slope of pressure-area relation obtained from echocardiography with intravenous bolus injection of phenylephrine was taken as a load-independent index of myocardial contractility. Baroreflex function was estimated by the slope of the regression line relating systolic aortic pressure and RR interval. RESULTS: Plasma beta-endorphin levels were elevated in dogs with congestive heart failure. Naloxone administration increased heart rate, mean aortic pressure, first derivative of left ventricular pressure, cardiac output and myocardial contractility in pacing-induced congestive heart failure. These changes correlated significantly with basal plasma beta-endorphin levels and were accompanied by increases in plasma beta-endorphin and catecholamines after naloxone administration. However, unlike the hemodynamic and cardiac effects of naloxone, baroreflex function did not change after naloxone in dogs with congestive heart failure. CONCLUSIONS: The increase in basal plasma beta-endorphin suggests that the endogenous opiate system is activated in left-sided congestive heart failure. Because naloxone improves the systemic hemodynamics and myocardial contractile function under this condition, the endogenous opioids appear to play an important role in mediating the myocardial depression that occurs in heart failure. However, the endogenous opiate system has no apparent effect on the regulation of baroreflex control in heart failure induced by rapid pacing.

The heart in sickle cell anemia.

Sickle cell anemia is a lifelong debilitating disease often required multiple, frequent hospital admissions. Multiple organ systems become damaged, but the heart, although demonstrating abnormalities, is relatively spared. With increasing life span of these patients, cardiac dysfunction may become more prominent. Recent noninvasive and pathologic studies have given new information on the effect of this disease on the heart. This article reviews the current knowledge of cardiac involvement in sickle cell anemia.

Evaluation of an upper hive entrance for control of Aethina tumida (Coleoptera: Nitidulidae) in colonies of honey bees (Hymenoptera: Apidae).

This investigation was conducted to test whether an upper hive entrance may result in reduced Aethina tumida Murray (Coleoptera: Nitidulidae) population buildup in newly established honey bee, Apis mellifera L., colonies over an 8-mo period. The upper hive entrance consisted of a 3.5-cm-i.d. polyvinyl chloride pipe positioned 20 cm above the hive bottom. Sixteen bee colonies were established using five-frame nucleus hives with a 0.9-kg (2-1b) package of bees with queen. Eight colonies were placed in each apiary, and each colony received one of two treatments: 1) conventional hive lower entrance and 2) modified upper hive entrance. This investigation was conducted in two distant apiaries where A. tumida had been a major problem to local beekeepers for a minimum of 2 yr. Results showed no overall differences between treatment effects on A. tumida counts over the test period, but there was a reduction in bee brood measured in colonies having an upper hive entrance. We conclude that the upper pipe entrance is not recommended in areas where A. tumida are well established and have become problematic. The expected reduction of brood in colonies as a result of using an upper hive entrance will lead to less productive units for honey production and pollination activities. Other control measures will be necessary to maintain tolerable levels of A. tumida in honey bee colonies at high pest densities.

Bivalent binding and signaling characteristics of Leridistim, a novel chimeric dual agonist of interleukin-3 and granulocyte colony-stimulating factor receptors.

Leridistim is a member of a novel family of engineered chimeric cytokines, myelopoietins, that contain agonists of both interleukin-3 (IL-3) receptors (IL-3R) and granulocyte colony-stimulating factor (G-CSF) receptors (G-CSFR). To more clearly understand Leridistim's function at the molecular level, binding to both IL-3R and G-CSFR and subsequent signaling characteristics have been delineated. The affinity of Leridistim for the human G-CSFR was found to be comparable to that of native G-CSF (IC(50) = 0.96 nM and 1.0 nM, respectively). Both Leridistim and G-CSF induced receptor tyrosine phosphorylation to a similar maximal level. Compared with native recombinant human IL-3 (rhIL-3), Leridistim was found to possess higher affinity for the IL-3R alpha chain (IL-3Ralpha) (IC(50) = 85 nM and 162 nM, respectively). However, the increase in Leridistim binding affinity to the functional, high-affinity heterodimeric IL-3Ralphabeta(c) receptor is lower than that observed with rhIL-3 (85 nM and 14 nM vs 162 nM and 3.5 nM, respectively). Leridistim induced tyrosine phosphorylation of beta(c) to a level comparable to native IL-3, and the level of JAK2 tyrosine phosphorylation in cells expressing both IL-3R and G-CSFR was comparable to that observed with IL-3 or G-CSF alone. The ability of Leridistim to interact with IL-3R and G-CSFR simultaneously was demonstrated using surface plasmon resonance analysis. These studies were extended to demonstrate that Leridistim exhibited a higher affinity for the IL-3R on cells that express both the IL-3Ralphabeta(c) and the G-CSFR (IC(50) = 2 nM) compared with cells that contain the IL-3Ralphabeta(c) alone (IC(50) = 14 nM). Leridistim binds to both IL-3R and G-CSFR simultaneously and has been shown to activate both receptors. The bivalent avidity may explain the unique biologic effects and unexpected potency of Leridistim in hematopoietic cells compared with rhIL-3 or G-CSF alone or in combination.