Glucocorticoid-induced protection in circulatory shock: role of reticuloendotheilial system function.

Experiments with rats indicate that: (i) hydrocortisone sodium succinate (HC) and methylprednisolone sodium succine (MP) enhance survival after hemorrhage; (ii) MP is approximately 10-times more potent than HC; (iii) both HC and MP are more efficacious if administered prior to hemorrhage; (iv) efficacy of postshock therapy with both steroids is not only time- but dose-dependent; and (v) HC and MP can ameliorate or completely prevent the early RES phagocytic depression observed in circulatory shock. Overall, these data could be used to suggest that: (i) the RES may play a pivotal role in the beneficial actions of synthetic adrenocorticosteroids in circulatory shock, and (ii) numerical RES phagocytic indices may be diagnostic and prognostic parameters in circulatory shock therapy.     

The severity of shock is associated with impaired rates of net alveolar fluid clearance in clinical acute lung injury

The rate of alveolar fluid clearance (AFC) is associated with mortality in clinical acute lung injury (ALI). Patients with ALI often develop circulatory shock, but how shock affects the rate of AFC is unknown. To determine the effect of circulatory shock on the rate of AFC in patients with ALI, the rate of net AFC was measured in 116 patients with ALI by serial sampling of pulmonary edema fluid. The primary outcome was the rate of AFC in patients with shock compared with those without shock. We also tested the effects of shock severity and bacteremia. Patients with ALI and shock (n = 86) had significantly slower rates of net AFC compared with those without shock (n = 30, P = 0.03), and AFC decreased significantly as the number of vasopressors increased. Patients with positive blood cultures (n = 21) had slower AFC compared with patients with negative blood cultures (n = 96, P = 0.023). In addition, the edema fluid-to-plasma protein ratio, an index of alveolar-capillary barrier permeability, was highest in patients requiring the most vasopressors (P < 0.05). Patients with ALI complicated by circulatory shock and bacteremia had slower rates of AFC compared with patients without shock or bacteremia. An impaired capacity to reabsorb alveolar edema fluid may contribute to high mortality among patients with sepsis-induced ALI. These findings also suggest that vasopressor use may be a marker of alveolar-capillary barrier permeability in ALI and provide justification for new therapies that enhance alveolar epithelial and endothelial barrier integrity in ALI, particularly in patients with shock.     

In vivo stress preconditioning

The heat shock or stress protein response is a highly conserved defense mechanism. Activation of the stress protein response by mild hyperthermia or by pharmacological agents allows cells to withstand a subsequent metabolic insult that would otherwise be lethal, a phenomenon referred as "thermotolerance" or "preconditioning." Heat shock response is characterized by increased expression of stress proteins that provide cellular protection, e.g., via increased chaperoning activity in all organisms, from bacteria to animals and humans. Indeed, there is experimental evidence that overexpression of specific heat shock proteins or heat shock factors produce protective effects similar to those observed after stress preconditioning. The purpose of this review is first to discuss the methods used to induce in vivo thermotolerance with mild hyperthermia or pharmacological agents. Then, as an example of the organ protection provided by in vivo stress preconditioning, the second part of this paper will examine how the induction of thermotolerance modulates the lung inflammatory response associated with acute lung injury, thus providing broad organ and tissue protection against oxidative stress associated this syndrome.     

Redox regulation of heat shock protein expression in aging and neurodegenerative disorders associated with oxidative stress: A nutritional approach

Summary. Oxidative stress has been implicated in mechanisms leading to neuronal cell injury in various pathological states of the brain. Alzheimers disease (AD) is a progressive disorder with cognitive and memory decline, speech loss, personality changes and synapse loss. Many approaches have been undertaken to understand AD, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to AD pathogenesis.Brains of AD patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress.Recently, the involvement of the heme oxygenase (HO) pathway in anti-degenerative mechanisms operating in AD has received considerable attention, as it has been demonstrated that the expression of HO is closely related to that of amyloid precursor protein (APP). HO induction occurs together with the induction of other HSPs during various physiopathological conditions. The vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, products of HO-catalyzed reaction, represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response.Increasing interest has been focused on identifying dietary compounds that can inhibit, retard or reverse the multi-stage pathophysiological events underlying AD pathology. Alzheimers disease, in fact, involves a chronic inflammatory response associated with both brain injury and -amyloid associated pathology. All of the above evidence suggests that stimulation of various repair pathways by mild stress has significant effects on delaying the onset of various age-associated alterations in cells, tissues and organisms. Spice and herbs contain phenolic substances with potent antioxidative and chemopreventive properties, and it is generally assumed that the phenol moiety is responsible for the antioxidant activity. In particular, curcumin, a powerful antioxidant derived from the curry spice turmeric, has emerged as a strong inducer of the heat shock response. In light of this finding, curcumin supplementation has been recently considered as an alternative, nutritional approach to reduce oxidative damage and amyloid pathology associated with AD. Here we review the importance of the heme oxygenase pathway in brain stress tolerance and its significance as an antidegenerative mechanism potentially important in AD pathogenesis. These findings have offered new perspectives in medicine and pharmacology, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms such as the heat shock response, through nutritional antioxidants or pharmacological compounds, represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistent with this notion, maintenance or recovery of the activity of vitagenes, such as the HO gene, conceivably may delay the aging process and decrease the occurrence of age-related neurodegenerative diseases.     

A pharmacological approach to thromboxane receptor antagonism

Thromboxane A2 (TxA2) appears to be an important mediator of ischemia and hypoxia. Despite its short half-life and the fact that it may not circulate in the blood until its values become quite high, TxA2 contributes to the pathogenesis of cardiopulmonary diseases (e.g., sudden death, myocardial ischemia, circulatory shock). It does so because it propagates its own formation by activating platelets and constricting blood vessels, thus activating more TxA2 and trapping it locally within an ischemic or hypoxic region. TxA2 concentrations in the extracellular fluid of lymph of ischemic regions may be much higher than that occurring in nonischemic, normally perfused regions. Specific and potent Tx receptor antagonists (TxRA) have recently become available for study. The TxRA are useful tools in the study of the pathophysiology of Tx-dependent disease processes and have been found to be effective in a variety of ischemic disorders including circulatory shock, myocardial ischemia, and sudden cardiopulmonary death. Moreover, inasmuch as early work indicates that these agents are both safe and effective in humans, Tx receptor antagonists may be employed as therapeutic agents in several cardiovascular disease states. Further investigation is necessary to clarify the role of TxRA as therapeutic agents.     

The role of lysosomes in circulatory shock

Lysosomes are sensitive to the stressful stimuli which develop in the shock states (i.e., ischemia, hypoxia, acidosis). As a result, lysosomal membranes become leaky and tissue lysosomes swell. These conditions are favorable for the leakage of lysosomal contents, largely acid hydrolases, into the cytoplasm of splanchnic cells, particularly in the liver and pancreas. These acid hydrolases are then transported primarily via the lymphatic system to the systematic circulatin where they are free to exert a variety of deleterious actions particularly as the RES becomes impaired in shock. Some of these effects include damage to the microcirculation promoting hypotension and reduced nutritive blood flow to certain tissues. These enzymes also contribute to production of toxic factors and impairment of mitochondrial function in circulatory shock.     

Insulin Secretion in Cardiogenic Shock

A nearly complete suppression of insulin secretion was observed in four patients in circulatory shock following acute myocardial infarction. This may be due to intense sympathetic activity and raised catecholamine excretion associated with shock.     

Evaluation of the mutagenic potential of yangambin and of the hydroalcoholic extract of Ocotea duckei by the Ames test

Ocotea duckei Vattimo is a plant popularly known as "louro-de-cheiro" found in the northeast of Brazil. Traditional medicinal uses of this plant are not known, but recent pharmacological studies with the isolated major constituent yangambin have shown various qualities: platelet activating factor (PAF) antagonist, protective effects against cardiovascular collapse and anaphylactic shock, anti-allergic properties, analgesic activity, and depressant effect in the central nervous system. In this work, the Ames test was used to evaluate the mutagenic potential of the hydroalcoholic extract of O. duckei leaves and of yangambin. Using TA97a, TA98, TA100, TA102 and TA1535 strains of Salmonella typhimurium, positive results were obtained only with the hydroalcoholic extract, with or without metabolic activation. Yangambin was not mutagenic, which is of interest due to its pharmacological properties.     

The pioneering use of systems analysis to study cardiac output regulation

This essay examines the historical significance of an APS classic paper that is freely available online: Guyton AC, Lindsey AW, and Kaufmann BN. Effect of mean circulatory filling pressure and other peripheral circulatory factors on cardiac output. Am J Physiol 180: 463-468, 1955 (http://ajplegacy.physiology.org/cgi/reprint/180/3/463).     

Therapy of pulmonary embolism

The therapeutic regimen in acute pulmonary embolism of different severity is discussed. Heparin is indicated in patients with only small and submassive embolism without impairment of the circulation. Fibrinolysis is the therapy of choice in submassive pulmonary embolism with circulatory insufficiency and massive embolism. In fulminant embolism with circulatory shock or cardiac arrest embolectomy should be performed. If the course of lung embolism is subacute, fibrinolysis may improve the late prognosis in respect to chronic pulmonary hypertension.     

Lack of effect of thyrotropin releasing hormone (TRH) in circulatory shock

Thyrotropin releasing hormone (TRH) has been reported to reverse hypotension induced by a variety of agents and thus it has been suggested to be of therapeutic value in circulatory shock. We have investigated TRH (2 mg/kg bolus plus 2 mg/kg/hr infusion) in both hemorrhagic (cats) and traumatic shock (rats). TRH induced a pressor effect of 23 +/- 8 mm Hg (p less than 0.05) in cats and 19 +/- 3 mm Hg (p less than 0.01) in rats during hypotension. However, this transient (10-15 min) response did not result in any sustained improvement in the cardiovascular status of the animals in either shock model when compared to the vehicle. In addition, TRH did not attenuate any of the biochemical indices of the severity of the shock state (i.e., plasma amino-nitrogen concentrations, or plasma cathepsin D and MDF activities) nor did it improve survival time in traumatic shock (2.8 +/- 0.4 vs. 2.0 +/- 0.2 hours). Furthermore, TRH resulted in a significant blunting of the maximum post-reinfusion superior mesenteric artery flow and enhanced beta-glucuronidase release from liver lysosomal preparations in vitro. These potentially detrimental effects in conjunction with the lack of any overt protective effect under the conditions existing in these two shock models, do not provide evidence that TRH is beneficial as a therapeutic agent in circulatory shock.     

Opioids and neuropeptides: mechanisms in circulatory shock

Endogenous opioid systems are activated in stressful situations such as circulatory shock. The opiate antagonist naloxone improves cardiovascular function in several models of shock caused by endotoxemia, hypovolemia, anaphylaxis, and spinal trauma. The ergotropic neuropeptide, thyrotropin-releasing hormone, in supraphysiological doses, also improves cardiovascular function in these shock models, but this effect does not result from action at the opiate receptor. For both these agents a central nervous system (CNS) site of action has been partially characterized. A variety of neuropeptides, including the opioids, seem capable of modulating autonomic function through their CNS actions. In addition, they may play a role in peripheral integration and transmission of autonomic nervous activity by actions at the ganglia and/or at nerve endings. Some neuropeptides also have direct autacoid effects on cells, including those of the microvasculature. This raises new questions concerning possible peripheral functions of neuropeptides during circulatory shock, and the nature of their interactions with other potential shock mediators such as monokines and arachidonic acid derivatives.     

A single injection of CM1021, a long half-life hepatocyte growth factor mimetic,increases liver mass in mice

Despite years of positive animal data, hepatocyte growth factor (HGF) has never been developed into a useful pharmaceutical, primarily due to its poor pharmacological properties. CM1021 is a fusion protein containing the K1 loop of HGF and the human IgG1 Fc region. The experiments described here demonstrate that CM1021 has the biological properties of HGF and the pharmacological properties of a monoclonal antibody. CM1021 stimulates scattering and branching morphogenesis in MDCK cells and stimulates liver growth in vivo. Unlike HGF, it is available via intraperitoneal injection and has an estimated half-life similar to an antibody.     

Hemorrhagic fever with renal syndrome: clinical aspects

Hemorrhagic fever with renal syndrome (HFRS) is an acute viral fever which typically progresses through five stages: an acute grippe, followed by hemorrhage and shock, acute renal insufficiency from tubulo-interstitial nephritis, and recovery. Death from circulatory or renal failure occurs in 5%-15% of cases. In mild or abortive forms of the disease, associated with viral strains enzootic in Scandinavia the illness is milder. Hemorrhage and shock occur with lower frequency and the fatality rate is less than 1%. Pathologic examination of HFRS cases from Asia discloses generalized congestion, hyperemia, and hemorrhage, with scattered foci of necrosis in numerous organs. Congestion and hemorrhage are most evident in the kidney medulla. Widespread microscopic evidence of capillary and vascular dysfunction is found, with endothelial cell swelling, perivascular edema, diapadesis of erythrocytes and mononuclear cell infiltration. Hemorrhage and inflammation in the renal interstitium and tubular epithelial degeneration characterize the kidney pathology. Limited data indicate pathogenic roles for cell destruction from viral infection as well as immune mediated mechanisms. No specific therapy is available.     

Convective heat transfer coefficients in the circulation

Convective heat transfer in the vessels of the circulatory system is investigated numerically. In the modeling, account is taken of the non-Newtonian rheological properties of blood and the presence of a cell-depleted plasma layer at the vessel wall. The latter is found to produce a remarkable enhancement of the heat transfer rate in the small vessels, while the effects due to the rheological behavior of blood are comparatively low. A comparison with experimental data available in the open literature is finally attempted.     

The simple β-carboline alkaloids

The simple β-carbolines are presented as a distinct group of alkaloids displaying structural modification of three basic ring systems. Their occurrence in plants is listed on a taxonomic basis and aspects of their metabolism, pharmacological properties and taxonomic significance are briefly summarized.     

Leadless pacing in a young patient with cardioinhibitory vasovagal syncope

Vasovagal syncope is characterized by vasodilatation and/or bradycardia and thereby a fall in arterial BP and global cerebral perfusion in response to a trigger. Although it is a benign condition, patients with frequent and traumatic episodes need treatment in order to improve quality of life. We describe the case of a 17-years-old boy suffering from cardioinhibitory syncope. At the end of a complete negative cardiac and neurological examination, a loop recorder was implanted. During the subsequent follow-up the ILR documented a 9-s pause. To improve the patient's compliance, and considering cardioinhibitory syncope as a temporary condition, a leadless pacemaker was eventually implanted.     

Insertion of the Impella 5.0 left ventricular assist device via right anterior mini-thoracotomy: a novel practical approach

The Impella 5.0 microaxial pump is a miniaturized left ventricular assist device commonly used for circulatory support in acute cardiogenic shock. The catheter-based pump is designed to be inserted either into a peripheral artery or directly into the ascending aorta. We report the first case in which the Impella 5.0 device was placed directly into the ascending aorta via a small right anterior thoracotomy in a patient following acute myocardial infarction complicated by cardiogenic shock.