New Trends in the Treatment of Angina Pectoris

Traditionally when considering the pharmacologic basis of therapy in angina pectoris, attention is focussed on alterations of coronary blood flow. Yet the diseased coronary arteries in these patients often do not appear to be capable of responding to vasodilatory drugs. Since the pain of myocardial ischemia is relieved by a number of interventions without an increase in coronary blood flow, the concept herein considered is that angina pector is best viewed as an unfavorable relation between myocardial oxygen requirements and availability. Thus, the clinical value of the major antianginal agents is thought to be based importantly upon their actions to reduce myocardial oxygen consumption rather than to increase coronary blood flow.Sublingual nitroglycerin possesses a powerful dilator effect on veins which reduces venous return and thereby the size of the heart and intra-myocardial tension; thus myocardial oxygen requirements are diminished.The beta-adrenergic receptor blocking drug, propranolol (Inderal®), inhibits sympathetic stimulation of the heart at rest and during exercise. Thus, myocardial oxygen requirements are diminished by the reduction in heart rate and diminished contractility. As a result of this latter action, cardiac output is reduced and thereby arterial pressure and intramyocardial tension is lowered. In patients with advanced heart disease and borderline cardiac compensation, propranolol is hazardous because it removes the availability of one of the important reserve mechanisms for maintaining cardiac compensation—the sympathetic support of the failing heart.The introduction of electrical stimulation of the carotid sinus nerves as a means of therapy in patients with angina pectoris has provided a powerful tool for the treatment of patients with refractory ischemic pain.     

Clinical Experiences with Assisted Circulation

Of primary importance in the clinical application of mechanical support for the failing circulation are the selection of patients and definition of criteria for assessing the therapeutic results. Experimental and clinical observations suggest that serial measurements of arteriovenous oxygen difference are a reliable rough measurement of the adequacy of the existing cardiac output to meet the oxygen requirements of the tissues. Patients with a decreasing cardiac output may profit from assisted circulation. Thirteen such patients are presented, all of whom were in intractable heart failure. Seven “medical” patients underwent common femoral vein-to-artery perfusion with an oxygenator for an average of 135 minutes. Of these, one patient who had already had two cardiac arrests died, six patients showed striking clinical and biochemical improvement for hours to days, and two patients were discharged from the hospital. Of particular interest were five in whom the indication for assisted circulation was irreversible cardiac arrest. Three patients were resuscitated, and one, who had neurological signs usually accepted as those of anoxic cerebral damage for 45 minutes, recovered completely.     

Oxygen consumption during septic shock. Effects of inotropic drugs

Septic shock may be defined as a clinical entity wherein a patient has an inadequate peripheral metabolism in the presence of circulating bacteria. The demands for metabolic requirements of the tissues and hence for oxygen transport to these tissues are then markedly high. The average response to increased metabolism in such patients is a percentage increase in cardiac output that is comparable to the percentage increase in oxygen consumption while oxygen extraction rate does not change or even decreases in severe or/and advanced septic shock. This emphasizes the high priority placed by the body on the ability to increase blood flow from the heart in the presence of increased metabolic demands due to sepsis. Concerning the myocardium, oxygen consumption is low in hyper- and hypodynamic states of septic shock, probably and partially due to marked arterial vasodilatation. However, in hypodynamic states, the lower value of perfusion pressure may account for a decrease in myocardial oxygen supply, especially in subendocardial areas and may be responsible for myocardial ischaemia, more especially as myocardial oxygen extraction as well as systemic oxygen extraction is impaired. The goal of therapeutics is to improve oxygen availability through: (1) maintenance of haemoglobin levels and (2) increases in stroke volume using inotropic drugs since these drugs may produce a rise in myocardial oxygen supply higher than their drug-induced increase in oxygen requirements in hypodynamic states of septic shock.     

Ketone metabolism in the failing heart

The high energy demands of the heart are met primarily by the mitochondrial oxidation of fatty acids and glucose. However, in heart failure there is a decrease in cardiac mitochondrial oxidative metabolism and glucose oxidation that can lead to an energy starved heart. Ketone bodies are readily oxidized by the heart, and can provide an additional source of energy for the failing heart. Ketone oxidation is increased in the failing heart, which may be an adaptive response to lessen the severity of heart failure. While ketone have been widely touted as a “thrifty fuel”, increasing ketone oxidation in the heart does not increase cardiac efficiency (cardiac work/oxygen consumed), but rather does provide an additional fuel source for the failing heart. Increasing ketone supply to the heart and increasing mitochondrial ketone oxidation increases mitochondrial tricarboxylic acid cycle activity. In support of this, increasing circulating ketone by iv infusion of ketone bodies acutely improves heart function in heart failure patients. Chronically, treatment with sodium glucose co-transporter 2 inhibitors, which decreases the severity of heart failure, also increases ketone body supply to the heart. While ketogenic diets increase circulating ketone levels, minimal benefit on cardiac function in heart failure has been observed, possibly due to the fact that these dietary regimens also markedly increase circulating fatty acids. Recent studies, however, have suggested that administration of ketone ester cocktails may improve cardiac function in heart failure. Combined, emerging data suggests that increasing cardiac ketone oxidation may be a therapeutic strategy to treat heart failure.     

Oxygen Transport in Acute Pulmonary Oedema and in Acute Exacerbations of Chronic Bronchitis

When breathing air, the average arterial oxygen tension in eight patients with acute pulmonary oedema was significantly higher than in eight other patients suffering from an acute exacerbation of chronic bronchitis, but the mixed venous oxygen tension was very similar in both groups. This largely arose from the smaller arteriovenous difference of oxygen content in the bronchitic cases, presumably due to their higher cardiac output, associated with raised arterial CO₂ tensions. Oxygen therapy (60-90% for pulmonary oedema, 30% for the bronchitics) raised the mixed venous oxygen tensions to a similar level in both groups. We suggest that the major need for oxygen therapy lies in patients who maintain their oxygen consumption but show a reduction in mixed venous tension when breathing air. Although partial correction of arterial hypoxaemia is adequate in chronic bronchitis—in which the cardiac output is maintained—high concentrations of oxygen are necessary in pulmonary oedema, in which the cardiac output is low.     

Yield Trends Are Insufficient to Double Global Crop Production by 2050

Several studies have shown that global crop production needs to double by 2050 to meet the projected demands from rising population, diet shifts, and increasing biofuels consumption. Boosting crop yields to meet these rising demands, rather than clearing more land for agriculture has been highlighted as a preferred solution to meet this goal. However, we first need to understand how crop yields are changing globally, and whether we are on track to double production by 2050. Using ∼2.5 million agricultural statistics, collected for ∼13,500 political units across the world, we track four key global crops—maize, rice, wheat, and soybean—that currently produce nearly two-thirds of global agricultural calories. We find that yields in these top four crops are increasing at 1.6%, 1.0%, 0.9%, and 1.3% per year, non-compounding rates, respectively, which is less than the 2.4% per year rate required to double global production by 2050. At these rates global production in these crops would increase by ∼67%, ∼42%, ∼38%, and ∼55%, respectively, which is far below what is needed to meet projected demands in 2050. We present detailed maps to identify where rates must be increased to boost crop production and meet rising demands.     

The molecular basis of myocardial hypertrophy and heart failure

Heart failure (HF) is the inability of the heart to cope with the metabolic demands of the periphery. It is the common end-stage of many frequent cardiac diseases and is characterized by relentless progression. Mechanisms of progression include renal sodium and water retention, neurohumoral activation and alterations of the protein composition (gene programme) of the heart itself. In this review, we explain the often confusing terminology in the subject, briefly touch upon the peripheral mechanisms of HF, and then focus on the changes in the gene programme of the failing heart and the molecular mechanisms leading to them. Understanding the basic processes underlying HF will help uninitiated readers to gain insight into recent novel approaches to its treatment.     

Peritoneal Dialysis in Chronic Renal Failure

The long-term results of intermittent peritoneal dialysis in long-term treatment of renal disease have yet to equal those of intermittent hemodialysis. However, further exploration and refinement of this technique is justified.Performed in acute stages of disease, both peritoneal dialysis and hemodialysis relieve the symptoms of uremia and specifically “buy time” for the patient so that proper medical or surgical therapy may be instituted. In acute situations, peritoneal dialysis is the procedure of choice, and is an important adjunct to more conventional treatment for chronic renal disease. It may be useful sometimes even in chronically hemodialyzed patients—for example, when the hemodialysis cannula for one reason or another is inaccessible because of clots, replacement, or infection. It is especially valuable when the hemorrhagic complications of uremia contraindicate hemodialysis treatment.Its use in chronic uremia remains sharply limited in time, but for brief periods chronic peritoneal dialysis appears to be a reasonably satisfactory means of prolonging life while awaiting homotransplant or decision for maintenance hemodialysis therapy.     

Long-Term Responses to Loss of Renal Mass: Control Mechanisms: The Role of Renal “Work” in Compensatory Kidney Growth

In a series of studies designed to test the role of renal “work” in compensatory kidney growth we examined the relationship between absolute sodium reabsorption—which constitutes the bulk of renal energy expenditure, and growth of the remaining kidney at various intervals after contralateral nephrectomy.The increase in weight of the remaining kidney preceded the rise in sodium reabsorption and these two processes took place at different rates between 24 hours and 21 days after uninephrectomy.Absolute sodium reabsorption did not change during the first hours after contralateral nephrectomy, at a time when biochemical alterations are known to occur.The rate of [¹⁴C] choline incorporation into renal phospholipid, an early biochemical indicator of compensatory kidney growth, increased significantly one hour after contralateral nephrectomy but remained unchanged after sham-nephrectomy, regardless of the magnitude or direction of the concomitant change in absolute sodium reabsorption (“kidney work”).These results indicate that renal work expended in the reabsorption of glomerular filtrate is neither the initiating, nor the primary controlling factor, of the compensatory kidney growth that follows unilateral nephrectomy.     

Gender Differences in Sleep Deprivation Effects on Risk and Inequality Aversion: Evidence from an Economic Experiment

Excessive working hours—even at night—are becoming increasingly common in our modern 24/7 society. The prefrontal cortex (PFC) is particularly vulnerable to the effects of sleep loss and, consequently, the specific behaviors subserved by the functional integrity of the PFC, such as risk-taking and pro-social behavior, may be affected significantly. This paper seeks to assess the effects of one night of sleep deprivation on subjects’ risk and social preferences, which are probably the most explored behavioral domains in the tradition of Experimental Economics. This novel cross-over study employs thirty-two university students (gender-balanced) participating to 2 counterbalanced laboratory sessions in which they perform standard risk and social preference elicitation protocols. One session was after one night of undisturbed sleep at home, and the other was after one night of sleep deprivation in the laboratory. Sleep deprivation causes increased sleepiness and decreased alertness in all subjects. After sleep loss males make riskier decisions compared to the rested condition, while females do the opposite. Females likewise show decreased inequity aversion after sleep deprivation. As for the relationship between cognitive ability and economic decisions, sleep deprived individuals with higher cognitive reflection show lower risk aversion and more altruistic behavior. These results show that one night of sleep deprivation alters economic behavior in a gender-sensitive way. Females’ reaction to sleep deprivation, characterized by reduced risky choices and increased egoism compared to males, may be related to intrinsic psychological gender differences, such as in the way men and women weigh up probabilities in their decision-making, and/or to the different neurofunctional substrate of their decision-making.     

Cell Lineages and the Logic of Proliferative Control

It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors (“chalones”) may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifying performance objectives—what, precisely, is being controlled, and to what degree—and go on to calculate how well different types of feedback configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE—the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue—fit with expectations for the best possible control. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules—such as whether a cell is a stem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator—may be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character.     

A Mathematical Model of the Metabolic and Perfusion Effects on Cortical Spreading Depression

Cortical spreading depression (CSD) is a slow-moving ionic and metabolic disturbance that propagates in cortical brain tissue. In addition to massive cellular depolarizations, CSD also involves significant changes in perfusion and metabolism—aspects of CSD that had not been modeled and are important to traumatic brain injury, subarachnoid hemorrhage, stroke, and migraine. In this study, we develop a mathematical model for CSD where we focus on modeling the features essential to understanding the implications of neurovascular coupling during CSD. In our model, the sodium-potassium–ATPase, mainly responsible for ionic homeostasis and active during CSD, operates at a rate that is dependent on the supply of oxygen. The supply of oxygen is determined by modeling blood flow through a lumped vascular tree with an effective local vessel radius that is controlled by the extracellular potassium concentration. We show that during CSD, the metabolic demands of the cortex exceed the physiological limits placed on oxygen delivery, regardless of vascular constriction or dilation. However, vasoconstriction and vasodilation play important roles in the propagation of CSD and its recovery. Our model replicates the qualitative and quantitative behavior of CSD—vasoconstriction, oxygen depletion, extracellular potassium elevation, prolonged depolarization—found in experimental studies. We predict faster, longer duration CSD in vivo than in vitro due to the contribution of the vasculature. Our results also help explain some of the variability of CSD between species and even within the same animal. These results have clinical and translational implications, as they allow for more precise in vitro, in vivo, and in silico exploration of a phenomenon broadly relevant to neurological disease.     

Metabolic Bone Disease Secondary to Renal and Intestinal Disorders

Metabolic bone disease occurring in renal or intestinal disorders has been reviewed with particular reference to etiological factors.Hyperparathyroidism is seen as a recurring cycle of renal damage—hyperphosphatemia—hypocalcemia—parathyroid stimulation—mobilization of bone calcium and phosphate—renal tubular phosphate rejection. In intestinal cases, the initial stimulus is presumably hypocalcemia.Osteomalacia is seen as resulting from phosphate depletion for the following reasons:1. Experimentally, rickets results from dietary phosphate restriction in rats.2. Such rickets is not prevented by the presence of normally adequate amounts of dietary vitamin D, and may therefore be termed “resistant” in the clinical sense.3. Osteomalacia or rickets in intestinal malabsorption and renal tubular disorders is associated with hypophosphatemia due to excessive fecal or urinary loss.4. Renal tubular rickets has been healed by oral phosphate loading in some studies.5. Acidosis may induce osteomalacic changes, experimentally and clinically (for example, in uretero-sigmoidostomy). Reversal of systemic acidosis with oral bicarbonate has resulted in phosphate retention and a rising serum phosphate in one such case.6. Preliminary data from analysis of full-thickness bone biopsy in two osteomalacic patients shows a significant reduction in calcium and phosphate content.7. Despite the hyperphosphatemia of azotemic renal failure, over-all phosphate depletion may be present in this situation also due to: • Diminished dietary phosphate in low protein diets • Nausea and vomiting • Occasional diarrhea • The use of oral phosphatebinding antacids • Perpetuation of urinary phosphate losses by reduction in proportion of tubular reabsorbed phosphate (secondary hyperparathyroidism) and possibly high filtered load per nephron • Repeated losses of phosphate to bath fluid during dialysis.     

Severe Metabolic Acidemia in Infants: Clinical and Therapeutic Aspects

A study of 10 infants in severe metabolic acidemia (pH below 7) led to the conclusion that the clinical signs—hyperventilation, coma or lethargy, peripheral vascular collapse, a significantly palpable liver, and abdominal distension—may all be directly related to the metabolic acidemia. In five of 10 infants, an initial erroneous diagnosis of congestive heart failure or pneumonia was made. Dramatic clinical improvement followed correction of the acidemia with rapid intravenous administration of sodium bicarbonate. This rapid administration of sodium bicarbonate was safe, provided hypocalcemia was recognized and treated in its early stages. In severe metabolic acidemia the measurement of blood bicarbonate alone does not reflect adequately the magnitude of the acid-base derangement and repeated measurements of hydrogen ion concentration, Pco₂ and bicarbonates are needed to evaluate and treat such infants correctly.     

The effect of adrenaline and high Ca2+ on the mechanical performance and oxygen consumption of the isolated perfused trout (Oncorhynchus mykiss) heart

In heart muscle from mammals, catecholamines frequently evoke an oxygen waste and reduce efficiency. It was examined if this also applies to fish in which heart muscle activity is often restricted by oxygen availability. In the isolated perfused heart from rainbow trout, adrenaline (0.5 microM) increased power output by approximately 97%, when afterload was adjusted to maximum both before and after adrenaline addition, and by approximately 68%, when afterload remained at the maximum obtained before adrenaline addition. Oxygen consumption was enhanced by a similar amount (approximately 70%) in both situations. Hence, efficiency, i.e. power output/oxygen consumption, increased significantly from 25 to 30% for the heart always exposed to maximal afterload, whereas it stayed unchanged at 24% for the heart exposed to control afterload only. Adrenaline increases the Ca2+ activity participating in activation, but doing this by elevating perfusate Ca2+ from 1.5 to 5 mM instead of applying adrenaline did not change the mechanical efficiency, although afterload was maximized. The results suggest that catecholamines enhance heart pump activity in the living trout without any oxygen waste. On the contrary, the oxygen budget may even improve when the peripheral resistance is increased by catecholamines.     

Mechanisms of actin disassembly

The actin cytoskeleton is constantly assembling and disassembling. Cells harness the energy of these turnover dynamics to drive cell motility and organize cytoplasm. Although much is known about how cells control actin polymerization, we do not understand how actin filaments depolymerize inside cells. I briefly describe how the combination of imaging actin filament dynamics in cells and using in vitro biochemistry progressively altered our views of actin depolymerization. I describe why I do not think that the prevailing model of actin filament turnover—cofilin-mediated actin filament severing—can account for actin filament disassembly detected in cells. Finally, I speculate that cells might be able to tune the mechanism of actin depolymerization to meet physiological demands and selectively control the stabilities of different actin arrays.     

Effect of indomethacin on modest pressure natriuresis in chloralose-anesthetized, non-laparotomized dogs

To determine if indomethacin (indo) would attenuate the effects of changed renal perfusion pressure on sodium excretion as reported by others, we performed clearance studies in chloralose-anesthetized dogs without the major stress of laparotomy. Mean renal arterial pressure was varied by a balloon-tipped catheter indwelling the aorta suprarenally. With pressure decreases to mean values above 85 mm Hg during isotonic saline infusion, sodium output decreased only by 10.7 +/- 2.4% per 10 mm Hg pressure decrease without indo pre-treatment but decreased by 22.0 +/- 3.8% per 10 mm Hg pressure decrease with indo pre-treatment. The greater, rather than lesser, pressure effect on excretory function after indo in these experiments with chloralose anesthesia suggest that renal prostaglandin (PG) activity does not mediate normally pressure natriuresis. Instead, the data suggest that, in the absence of major stress, the renal pressure effects on excretory function may become more sensitive after indo. In addition, we postulate that the normal acute pressure natriuresis may be modest and may average no more than 20% change for each 10 mm Hg change in mean pressure above 90 mm Hg when stress is minimal and when vasoactive preglomerular autoregulation is nearly perfect. This is a phenomenon which keeps intrarenal tissue pressure and urine output relatively constant with arterial pressure elevations.     

Long-term telemetry of heart rates and energy metabolic rate during the diurnal cycle in normothermic and torpid African blue-naped mousebirds (Urocolius macrourus)

Colies are one of the phylogenetically oldest groups among the modern birds; the earliest finds are from about 35 million years ago. In states of energy deficiency they can undergo torpor during the night when metabolic rate and body temperature are decreased drastically to save energy (up to 90%). Here, we report the first measurements of heart rate (HR) by long-term telemetry, in seven individuals of blue-naped mousebirds (Urocolius macrourus); simultaneously and continuously metabolic rate (MR) was determined. HR at night was about 20% below the range of expected values (246/310 bpm). Mean oxygen pulse (O₂ output/stroke) in normothermic birds was in a range of 0.019–0.020 ml O₂/stroke; during torpor nights this value decreased significantly to 0.0086. Mean cardiac output ranged from 724 to 1214 ml blood/kg per min; in torpid birds this value fell to 400 ml blood/kg per min. Cardiac regulation of metabolic demand within an activity phase (day or night) is mainly achieved by chronotropy. Inotropy contributes at most 25% to the differences in MR between day and night (ca. 40%). Entry into torpor is brought about mainly by changes in HR (decrease from 240 to 90 bpm); after torpor levels have been reached, there is an increase in HR (to 200 bpm) and a sharp decrease (−53%) in stroke volume. This regulation by inotropy is also characteristic of arousal from torpor.     

Effects of walking on ventilatory and cardiac function in intact and cardiac-impaired lobsters

Decapod crustaceans with normal heart function respond to the increased oxygen delivery requirements during walking with a step increase in heart and ventilation rate. In American lobsters, ventilation rate increased by the same amount during exercise at two walking speeds (2.4 and 8 m min(-1)); however, ventilation volume was significantly greater at the fastest walking speed (280 mL min(-1)) compared to animals at rest or walking at the slower speed (180 mL min(-1)). The heart responded in a similar manner to locomotion. Heart rate was elevated to the same level at the two different walking speeds, but cardiac stroke volume was greater, implying increased cardiac output, at the faster walking speed. The communication and compensation between the cardiac and ventilatory systems was revealed when the function of one was impaired. Ventilatory rate was significantly elevated when cardiac output was impaired by sectioning two of the alary ligaments and/or the regulatory nerves to the heart. When cardiac output was more severely impaired, ventilation rate was greater. Despite ventilatory compensation, anaerobic metabolism made a greater contribution to energy production with impaired heart function. Hemolymph lactate concentration was three to five times greater in impaired animals than controls. It is known that the ventilatory and cardiac systems of lobsters are coregulated. These data demonstrate that the performance of one system can respond to compensate for impaired function in the other.     

The Role of Latin America’s Land and Water Resources for Global Food Security: Environmental Trade-Offs of Future Food Production Pathways

One of humanity’s major challenges of the 21st century will be meeting future food demands on an increasingly resource constrained-planet. Global food production will have to rise by 70 percent between 2000 and 2050 to meet effective demand which poses major challenges to food production systems. Doing so without compromising environmental integrity is an even greater challenge. This study looks at the interdependencies between land and water resources, agricultural production and environmental outcomes in Latin America and the Caribbean (LAC), an area of growing importance in international agricultural markets. Special emphasis is given to the role of LAC’s agriculture for (a) global food security and (b) environmental sustainability. We use the International Model for Policy Analysis of Agricultural Commodities and Trade (IMPACT)—a global dynamic partial equilibrium model of the agricultural sector—to run different future production scenarios, and agricultural trade regimes out to 2050, and assess changes in related environmental indicators. Results indicate that further trade liberalization is crucial for improving food security globally, but that it would also lead to more environmental pressures in some regions across Latin America. Contrasting land expansion versus more intensified agriculture shows that productivity improvements are generally superior to agricultural land expansion, from an economic and environmental point of view. Finally, our analysis shows that there are trade-offs between environmental and food security goals for all agricultural development paths.