Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of peripheral indices of serotonergic function were examined in endurance-trained (ET) and sedentary males using the blood platelet as a model of the serotonergic neurone. The aim of the study was to investigate possible involvement and adaptation of the central serotonergic system in exercise-induced fatigue. The [3H] paroxetine-defined density of platelet serotonin transporters, platelet serotonin content and the plasma concentration of amino acids were determined in 10 ET and eight sedentary males. The mean (standard deviation) density of the serotonin transporter in the platelet membranes of the ET subjects was greater [1237 (182) fmol mg protein-1] than that of the sedentary subjects [910 (119) fmol mg protein-1; P = 0.013]. No difference (P = 0.51) could be seen between the median (range) platelet serotonin content of the ET subjects [0.98 (0.37-3.04) nmol platelet-10] and that of the sedentary subjects [0.82 (0.18-1.49) nmol platelet-10]. The platelet poor plasma concentrations of tryptophan and tyrosine were lower in the ET subjects (P = 0.028 and 0.015, respectively). The present study suggests that the platelet membrane of the ET subjects has a greater density of the serotonin transporter and that this is inversely related to the circulating concentration of the serotonin precursor, tryptophan. It remains to be resolved whether the increase in serotonin transporter density in the platelet membrane of ET subjects is reflected centrally and whether the ET platelet population may be sufficiently different from that of sedentary individuals to alter serotonin transporter density.
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PMID:Platelet serotonin transporter density and related parameters in endurance-trained and sedentary male subjects. 964 35

There is some evidence that the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) may be involved in the pathogenesis of seasonal affective disorder (SAD). Short-term tryptophan (TRP) depletion was carried out in 18 drug-free remitted patients who met DSM-IV criteria for SAD. Behavioral effects were measured with the Hamilton Depression Rating Scale (HDRS) both 24 h before and 24 h after TRP depletion. Some of the patients showed behavioral responses such as lowered mood, feelings of guilt, loss of interest, agitation, loss of energy, fatigue, social withdrawal, increased appetite, and carbohydrate craving. It was the aim of our study to investigate whether the genotypes of the serotonin transporter gene were associated with symptoms of transient depressive relapse after TRP depletion. In addition, we matched the SAD patients with healthy control subjects to see if alleles and genotypes of the serotonin transporter gene were associated with SAD. High molecular weight DNA was isolated from peripheral blood leukocytes using standard methods. For the 5-HTT receptor gene, a 17-bp repetitive element of intron 2 was genotyped (variable number tandem repeat, VNTR). Alterations in HDRS scores after TRP depletion showed no significant association with alleles or genotypes of the 5-HTT gene, although heterozygotes showed a trend toward increased HDRS scores. The serotonin transporter is known to play a critical role in the termination of serotonergic neurotransmission by sodium-dependent uptake of 5-HT into the presynaptic neuron. The present study in a small group of SAD patients was unable to demonstrate that the 5-HTT gene plays a role in the pathogenesis of SAD or in short-term depressive relapse after TRP depletion.
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PMID:Behavioral effects of tryptophan depletion in seasonal affective disorder associated with the serotonin transporter gene? 1033 77

The purpose of this report is to study serotonin reuptake of the brain in a severely overtrained athlete by using single-photon emission computed tomography (SPECT). A 26-year-old team athlete increased his training volume (by 200 %) and intensity markedly in a new high-level team. After two months, he started to feel continuous fatigue. He had tinnitus in his left ear, he felt disturbing palpitation and had pollacisuria. After four months, he started to suffer from insomnia. He still continued to play for another three months, after which he was unable to play. He could only sleep for 3 to 4 hours per night. Only minor abnormalities could be found in extensive physical and laboratory examinations. The athlete had a severe overtraining state. In the brain SPECT scans, using the specific radioligand for serotonin transporter imaging ( (123)I labelled 2beta-carbomethoxy-3beta-[4-iodophenyl]-nortropane), low activity areas were detected in the midbrain, anterior gingulus, and left frontal and temporo-occipital lobes. In a psychiatric examination, the patient was found to have signs of major depression, which he hardly recognized himself. We conclude, that that the severe overtraining state could have been related to decreased serotonin reuptake in the brain and signs of major depression.
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PMID:Abnormal serotonin reuptake in an overtrained, insomnic and depressed team athlete. 1498

Pulmonary arterial hypertension (PAH) is a syndrome of dyspnea, fatigue, chest pain and syncope defined by an increase in pulmonary vascular resistance (PVR) of unknown cause. The pathobiology of PAH remains incompletely understood. The gene of the idiopathic form of PAH (IPAH) has been located on chromosome 2, and shown to present mutations of a sequence that encodes for a transforming growth factor receptor, bone morphogenenetic protein receptor 2 (BMPR2). Severe pulmonary hypertension is associated with an increased expression of the angiogenic factor, angiopoietin-1, which shuts off the expression of BMPR1A, a transmembrane protein necessary for BMPR2 signalling, and thereby causes pulmonary artery smooth muscle cell proliferation. Additional biological abnormalities have been identified at all pulmonary arterial wall compartments of PAH patients. The endothelium produces an excess of endo-thelin, a potent vasoconstrictor and mitogenic mediator, while synthesis and release of antagonistic prostacyclin and nitric oxide is decreased. Pulmonary vascular smooth muscle cells present with an increased expression of a serotonin transporter, allowing for vasoconstrictive and mitogenic effects of increased circulating serotonin, and also show an increased expression of voltage-dependent potassium channels, which also promotes vasoreactivity and proliferation. The adventitial matrix bound metalloprotases appear to be activated in relation to increased serine elastase, leading to increased production of tenascin, a potent mitogen. While none of these abnormalities isolately explains PAH, their identification has already led to efficient therapeutic interventions, including the administration of prostacyclin derivatives and anti-endothelin compounds.
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PMID:Pathobiology of pulmonary arterial hypertension. 1561 96

The aim of the study was to evaluate the kinetic parameters of a specific serotonin transporter (SERT) and serotonin uptake in a mentally healthy subset of patients with fibromyalgia. Platelets were obtained from 40 patients and 38 healthy controls. SERT expression and functionality were evaluated through the measurement of [3H]paroxetine binding and the [3H]serotonin uptake itself. The values of maximal membrane binding capacity (Bmax) were statistically lower in the patients than in the healthy volunteers, whereas the dissociation constant (Kd) did not show any statistically significant variations. Moreover, a decrease in the maximal uptake rate of SERT (Vmax) was demonstrated in the platelets of patients, whereas the Michaelis constant (Km) did not show any statistically significant variations. Symptom severity score (tiredness, tender points index and Fibromyalgia Impact Questionnaire) were negatively correlated with Bmax and with Vmax, and positively correlated with Km. A change in SERT seems to occur in fibromyalgic patients, and it seems to be related to the severity of fibromyalgic symptoms.
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PMID:Alteration of serotonin transporter density and activity in fibromyalgia. 1679 74

In vivo molecular imaging has become a key technology for pathophysiological science and drug development. We are mostly utilizing PET(positron emission tomography) as a first-choice modality, because of its ultra-high sensitivity for molecules, adequate temporal and spatial resolution, and especially broad spectrum of target molecules. In vivo molecular imaging could bring the high-quality information about: 1. Molecular diagnosis for living patients with symptoms 2. Closer approach for etiology and differential diagnosis 3. Direct follow-up of key molecules as disease markers 4. Pharmacokinetics/Pharmacodynamics in primates/human 5. Dose finding information for individuals, corresponding to SNPs 6. Direct evidence for accumulation in non-target organs related to adverse effects 7. Drug effects with surrogate markers 8. Early decision of dropout substances (drug candidates) Here, the examples are shown as beta-amyloid imaging for Alzheimer's and mild cognitive impairment, serotonin transporter imaging for chronic fatigue, and dopaminergic components imaging for evaluation of drug for autistic spectrum disorder. In 2005, RIKEN and National Institute of Radiological Science were selected as the key centers for development of All-Japan research network to further promote mutual international and multi -disciplinary collaboration on in vivo molecular imaging.
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PMID:[Molecular imaging for drug development]. 1730 84

During treatment with selective serotonin reuptake inhibitors, some patients experience adverse events whereas others do not. Assessment of predictors for selective serotonin reuptake inhibitors-induced adverse events would be useful for the identification of patients likely to develop these events. This study evaluates the association between adverse events during selective serotonin reuptake inhibitor treatment and two polymorphisms in the serotonin transporter (5-HTTLPR and STin2) gene. We included 214 patients meeting Diagnostic and statistical manual of mental disorder-IV criteria for major depression and using an selective serotonin reuptake inhibitor for at least 6 weeks. Blood samples or buccal swabs were taken to determine 5-HTTLPR and STin2 genotype. Information on adverse events was gathered through interviews and general practitioners' files. The association between serotonin transporter genotype and adverse events was assessed by use of logistic regression. Patients with the 5-HTTLPR s/s or s/l genotype appeared to have an increased risk of adverse events, especially general adverse events (dermatologic reactions, weight change and fatigue); odds ratio 1.77 (95% confidence interval 0.80-3.92) for the s/s genotype, odds ratio 2.37 (95% confidence interval 1.13-4.96) for the s/l genotype. For STin2, results were inconsistent and observed associations were weak and statistically nonsignificant. Our findings indicate that patients with the 5-HTTLPR s/s or s/l genotype have an increased risk of developing adverse events during selective serotonin reuptake inhibitor treatment.
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PMID:Serotonin transporter polymorphisms and the occurrence of adverse events during treatment with selective serotonin reuptake inhibitors. 1741 39

Chronic fatigue syndrome (CFS) is an idiopathic illness characterized by persistent fatigue, which could be caused by a variety of etiologic factors including viral infection, abnormal production of cytokines and abnormal acylcarnitine metabolism. Recent studies suggest that CFS is closely associated with attenuation of central synaptic transmission mediated by neurotransmitters such as serotonin and glutamate. Attenuation of serotonin neurotransmission can be caused by increased expression of serotonin transporter, which results either from viral infection and subsequent production of interferon--alpha or from abnormal promoter for serotonin transporter gene. Other neurotransmitter systems may be also involved in CFS mediated by abnormal acylcarnitine metabolism and autoantibodies for neurotransmitter receptors. In this review, we focus recent data on CFS in terms of neurotransmitters.
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PMID:[Chronic fatigue syndrome and neurotransmitters]. 1756 89

Depression and fatigue are frequent side effects of interferon-alpha (IFN-alpha) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The 'low IL-6' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size = 0.7 at week 24; F = 9.4, d.f. = 436, P = 0.002). The 'high transcription' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size = 0.2 at week 24; F = 4.5, d.f. = 436, P = 0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F = 1.2, d.f. = 430, P = 0.2; 5-HTT: F = 0.5, d.f. = 430, P = 0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F = 5.0, d.f. = 434, P = 0.02): the 'protective' effect of the 5-HTTLPR polymorphism was evident only in the presence of the 'low IL-6' genotype (F = 5.4, d.f. = 64, P = 0.02), not in the presence of the 'high IL-6' genotype (F = 2.2, d.f. = 369, P = 0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.
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PMID:Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. 1845 77

Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 microg/kg) was administered through nasal spray followed by mood, nicotine reward (e.g. 'liking') and perception (e.g. 'feel effects') measures, physiological responses, sensory processing (prepulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine versus placebo spray choice procedure. For the dopamine D4 receptor [DRD4 variable number of tandem repeats (VNTR)], presence of the 7-repeat allele was associated with greater aversive responses to nicotine (decreases in 'vigor', positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased 'feel effects' and greater startle response, but in men only. Other genetic associations were also observed in men but not women, such as greater 'feel effects' and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T single nucleotide polymorphism) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3' VNTR (SLC6A3), and the mu opioid receptor A118G single nucleotide polymorphism (mu opioid receptor polymorphism 1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine before the onset of dependence and may do so differentially between men and women.
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PMID:Gene and gene by sex associations with initial sensitivity to nicotine in nonsmokers. 1869 Jan 17


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