Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is some evidence to suggest that certain neurotransmitter receptors, such as adrenergic and serotonergic receptors and receptor-linked signaling systems, may be altered in depression. Serotonin(2A) and alpha(2)-adrenergic receptors are linked to the phosphoinositide (PI) signaling system in platelets and brain. To examine if the PI signaling system is altered in depression, we studied thrombin- and sodium fluoride-stimulated inositol phosphate(1) (IP(1)) formation before and during desipramine (DMI) treatment in platelets of depressed patients and normal control subjects. We determined thrombin- and sodium fluoride-stimulated IP(1) formation in platelets obtained from hospitalized depressed patients during a drug-free baseline period and after 6 weeks of DMI treatment, and drug-free non-hospitalized normal control subjects. Depressed subjects were diagnosed according to DSM-IV criteria, and severity of illness was assessed with the Hamilton Depression Rating Scale. We observed that thrombin-stimulated IP(1) formation in platelets of depressed patients was significantly higher compared with that of normal control subjects. There were no significant differences in sodium fluoride-stimulated IP(1) formation between depressed patients and normal control subjects. We also did not find any significant effect of treatment with DMI on either thrombin- or sodium fluoride-stimulated IP(1) formation in platelets of depressed patients, which continued to be significantly higher after 6 weeks of treatment with DMI, compared with normal control values. Our studies found a hyperactive PI signaling system in platelets of depressed patients. This hyperactive system may be related either to an increased number of thrombin receptors or to a generalized overstimulation of this pathway; however, since we did not observe any differences in sodium fluoride-stimulated IP(1) formation, it appears that, although the sites distal to the receptors may be altered, this abnormality is probably not related to the abnormalities in G proteins.
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PMID:Hyperactive phosphoinositide signaling pathway in platelets of depressed patients: effect of desipramine treatment. 1174 Sep 72

By promoting atherosclerosis and thrombosis, a blood-clotting diathesis could contribute to excess cardiovascular morbidity and mortality in patients with systemic hypertension and/or obstructive sleep apnoea. Since psychological states affect haemostatic activity, we wondered about the contribution of behavioural factors to a hypercoagulable state in subjects with increased risk of cardiovascular disease. To tease apart the potential additive nature of cardiovascular disease risk, we examined four patient groups - hypertensives and normotensives, with and without sleep apnoea. The procoagulant molecules thrombin-antithrombin III complex, fibrin D-dimer and von Willebrand factor antigen were measured in 88 subjects (mean age 47 years; range 32-64 years) who underwent full polysomnography. Subjects completed the Center for Epidemiological Studies - Depression (CES-D) Scale, the Cook-Medley (CM) Hostility Scale, and the Profile of Mood States (POMS). Sleep apnoea, hypertension status, age, body mass index and psychological variables (CES-D, CM Stress, and POMS Vigour-Activity) together explained 29% of the variance in D-dimer, a marker of fibrin turnover ( r (2)=0.29, P =0.001). CES-D, CM Stress and POMS Vigour-Activity explained 17% of this variance even after controlling for sleep apnoea, hypertension status, age and body mass index (Delta r (2)=0.17, P =0.001). Thrombin-antithrombin III complex and von Willebrand factor were not significantly related to psychological variables, but this may reflect limited statistical power. Thus psychological factors are independently associated with D-dimer and explain as much of its variance as do traditional correlates (hypertension, sleep apnoea, age and body mass index). These results may provide a rationale for linking behavioural aspects with cardiovascular events.
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PMID:Independent contribution of psychological factors to fibrin turnover in subjects with sleep apnoea and/or systemic hypertension. 1224 29

Although heterotrimeric guanine nucleotide-binding regulatory (G) proteins have been implicated in the pathophysiology of mental illnesses (especially mood disorders), direct evidence has been scarce. This study was designed to reveal possible abnormalities of receptor-coupled G protein function in platelets in patients with psychiatric disorders such as depression and schizophrenia. The functional status of alpha(2A)-adrenergic receptor-coupled G(i2) and thrombin receptor-coupled G proteins (G(i2)+G(q)) was determined by the increase in high-affinity GTPase activity in response to epinephrine and thrombin, respectively, in platelet membranes from 18 patients with mood disorders (15 unipolar and three bipolar subtype), 13 schizophrenic patients, four neurotic patients and 29 healthy control subjects. Neither alpha(2A)-adrenergic receptor-coupled G(i2) nor thrombin receptor-coupled G(q) was functionally altered in platelets from psychiatric patients compared with control subjects. No significant correlation was observed between these biochemical measures in platelets and severity of psychopathological symptoms. The functional coupling efficiency of G proteins with receptors appears intact, at least between alpha(2A)-adrenergic receptors and G(i2), and between thrombin receptors and G(q), in platelets from patients with psychiatric disorders.
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PMID:Epinephrine- and thrombin-stimulated high-affinity GTPase activity in platelet membranes from patients with psychiatric disorders. 1242 57

Complex disturbances in hemostasis characterise chronic renal insufficiency. Defect of primary hemostasis is a common cause of bleeding complications. The hemodialysis procedure (HD), by itself, influences platelet function (the key part of primary hemostasis) which is compromised after the procedure. Many functional defects of thrombocytes have been described in end stage renal failure (ESRF) patients; one of them is adhesion defect where the pivotal role plays the complex of glycoprotein Ib (GP Ib) and IX. The aim of the study was to determine the extent of activation, reactivity of platelets and expression of GP Ib in ESRF patients. The flow cytometry method was used, and thrombin was used for stimulation of thrombocytes. Membrane expression of GP Ib and selectin P was assessed in 14 hemodialysed patients before and after stimulation with thrombin, before and after HD and in 10 healthy persons. The patient group had lower expression of GP Ib on resting platelets and significantly lower expression of selectin P after stimulation with thrombin when compared to the control group. After HD, thrombocytes had much lower expression of GP Ib; however there was no difference in expression of selectin P when compared to the state before HD. A lower reduction of GP Ib expression after stimulation with thrombin was observed after and before HD. On the basis of the results the following conclusions may be drawn: hemo-dialysed ESRF patients have lower expression of platelet GP Ib and reactivity of thrombocytes; the HD results in further depression in expression of GP Ib and reactivity of thrombocytes. It is plausible that nitric oxide (NO) released during HD modulates the expression of selectin P, but it remains to be confirmed.
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PMID:[Influence of hemodialysis on expression of glycoprotein lb platelets reactivity in patients with the end stage renal failure]. 1263 21

Tissue factor (TF) and lipopolysaccharide (LPS) are frequently used to induce disseminated intravascular coagulation (DIC) in experimental animal models. Although the pathophysiology of DIC may differ depending on which agent is used for induction, previous studies on models of DIC have not distinguished which DIC-inducing agent was used. In the present paper, we evaluate the characteristics of TF-induced and LPS-induced DIC using two types of DIC models, with special reference to selected hemostatic parameters and pathological findings within the kidney. Male Wistar rats were administered TF (3.75 U/kg; sustained infusion for 4 h) or LPS (30 mg/kg; sustained infusion for 4 h) via the tail vein, and blood sampling was performed at 0, 1, 3, 4, 5, 7, 9, 11, and 28 h. Judging from changes in the levels of thrombin-antithrombin complex, fibrinogen levels, and platelet counts, it is reasonable to conclude that the severity of both types of experimental DIC is similar with regard to hemostatic activation and consumption coagulopathy. A marked elevation in the level of D-dimer was noted without any organ dysfunction or much fibrin deposition in the kidney upon administration of TF. However, a markedly prolonged period of elevation in plasminogen activator inhibitor activity, a prolonged depression in antithrombin III activity, severe organ failure, and a markedly prolonged period of fibrin deposition in the kidney was observed following LPS administration. A modest number of the rats from the TF-induced DIC model died during the experimental period, whereas a large number of rats died during LPS-induced DIC, especially after 9 h. Since the time course of the pathophysiology differed remarkably among the TF-induced and LPS-induced DIC models in rats, we recommend that TF-induced and LPS-induced DIC be approached as distinct models in order to determine the implications of their experimental and clinical use.
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PMID:Pathophysiology of disseminated intravascular coagulation (DIC) progresses at a different rate in tissue factor-induced and lipopolysaccharide-induced DIC models in rats. 1269 43

Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation, leading to widespread deposition of fibrin in the circulation. Recent knowledge on important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with DIC. Thrombin generation proceeds via the (extrinsic) tissue factor/activated factor VII route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin and the protein C and protein S system. Also, impaired fibrin degradation, due to high circulating levels of plasminogen activator inhibitor type-I, contributes to enhanced intravascular fibrin deposition. Strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, by means of the administration of antithrombin concentrate or (activated) protein C.
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PMID:Therapeutic intervention in disseminated intravascular coagulation: have we made any progress in the last millennium? 1291 85

Clinical depression has been proposed to be an independent risk factor for cardiovascular disease. While it is suggested that selective serotonin reuptake inhibitors (SSRIs) reduce the risk of acute cardiovascular problems of depressed patients, the effect of SSRIs on platelets, the only blood cells committed to serotonin (5-HT) transport, remains largely unknown. The goal of this pilot study was to measure the 5-HT levels in platelets of untreated and SSRI-treated depressed patients and normal subjects and to determine whether the interaction of SSRIs with platelets can explain their possible cardiovascular benefit in patients with depression. Platelet 5-HT was determined by an immunocytochemical assay and high-pressure liquid chromatography with electrochemical detection (HPLC-ECD). In normal control subjects without cardiovascular disease, 78 +/- 8% of platelets were 5-HT-positive (n = 14). Depression caused a significant reduction in platelet 5-HT to 46 +/- 21% in untreated patients (n = 13) and 22 +/- 13% in SSRI-treated patients (n = 14). As a class, all selective serotonin reuptake inhibitors significantly reduced the 5-HT concentration in patient platelets. An inverse relationship of 5-HT level and dose of medication might be suggested. These results correlated well with 5-HT data from HPLC (r = 0.8509, p < 0.001). SSRIs did not affect platelet aggregation and dense granule release in response to thrombin, but significantly reduced ADP-induced platelet aggregation and dense granule release in both patient and normal control samples. The active inhibition of platelet aggregation by SSRIs might explain their cardiovascular benefit.
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PMID:The influence of selective serotonin reuptake inhibitors on human platelet serotonin. 1469 77

Thromboembolism is a frequent complication of paroxysmal nocturnal hemoglobinuria (PNH) and contributes significantly to patient morbidity and mortality. A number of mechanisms have been proposed to explain the increased incidence of this complication of PNH. Increased platelet activation with platelet microparticle formation and depression of cell surface-mediated fibrinolysis has been demonstrated in patients with PNH. We have studied two patients with hemolytic PNH who had recurrent and refractory venous thromboembolic events despite therapeutic anticoagulation. Plasma samples from both patients demonstrated marked hemostatic activation as determined by elevated plasma thrombin-antithrombin complexes (TAT) and D-dimers. Plasma samples from both patients were also shown to contain markedly elevated levels of circulating tissue factor (TF), which was shown to be predominantly derived from monocytes and macrophages. In one patient, a successful allogeneic bone marrow transplant resulted in a reduction in hemostatic activation associated with a marked decrease in circulating tissue factor to near normal levels. We propose that thrombosis in PNH results from increased tissue factor expression by complement injured CD55- and CD59-deficient monocytes and macrophages.
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PMID:Thrombosis in patients with paroxysmal noctural hemoglobinuria is associated with markedly elevated plasma levels of leukocyte-derived tissue factor. 1469 69

Sepsis almost invariably leads to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation, may deplete platelets and coagulation factors, which may in turn cause bleeding. Recent insights into important pathogenetic mechanisms that may lead to DIC have resulted in novel preventive and therapeutic approaches to patients with sepsis and a derangement of coagulation. Thrombin generation proceeds via the (extrinsic) tissue factor/factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin III and the protein C system. Also, impaired fibrin degradation, due to high circulating levels of PAI-1, contributes to enhanced intravascular fibrin deposition. Supportive strategies aimed at the inhibition of coagulation activation may be justified on theoretical grounds and have been found to be beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, by means of the administration of antithrombin concentrate or recombinant human activated protein C.
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PMID:Sepsis and disseminated intravascular coagulation. 1476 Feb 11

A variety of clinical conditions may cause systemic activation of coagulation, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). DIC consists of a widespread systemic activation of coagulation, resulting in diffuse fibrin deposition in small and midsize vessels. There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation, may result in depletion of platelets and coagulation factors, which may cause bleeding. Recent understanding of important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with sepsis and a derangement of coagulation. Thrombin generation proceeds via the (extrinsic) tissue factor/factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin III and the protein C system. Also, impaired fibrin degradation, due to high circulating levels of the fibrinolytic inhibitor plasminogen activator inhibitor, type 1 (PAI-1), contributes to enhanced intravascular fibrin deposition. Interestingly, an extensive cross-talk between activation of inflammation and coagulation exists, where inflammatory mediators (such as cytokines) not only activate the coagulation system, but vice versa activated coagulation proteases and protease inhibitors may modulate inflammation through specific cell receptors. Supportive strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, for example by means of the administration of recombinant human activated protein C.
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PMID:New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology. 1500 Mar 46


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