The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.
Subarachnoidal release of inflammatory cytokines (interleukin (IL)-1 , IL-6, and tumour necrosis factor (TNF)-) was characterised in 35 patients with subarachnoid haemorrhage (SAH) and control subjects and compared with development of complicating haemodynamic abnormalities in basal cerebral arteries and clinical outcome. Serial analysis allowed the observation of a subacute response profile of these key mediators of inflammation in the subarachnoidal space. This compartmentalised inflammatory host response was closely associated in time and extent with development of increased blood flow velocities in the basal cerebral vessels as recorded by transcranial Doppler sonography. Moreover, intrathecal secretion of inflammatory cytokines was significantly increased in patients with poor clinical outcome. Together, these findings suggest a role of excessive compartmentalised inflammatory host response in pathogenesis of cerebrovascular complications after SAH. (J Neurol Neurosurg Psychiatry 2001;70:534-537) Keywords: subarachnoid haemorrhage; inflammatory cytokines; cerebral blood flow; vasospasm; cerebral ischaemia Subarachnoid haemorrhage (SAH) most commonly occurs when an aneurysm in a basal cerebral artery ruptures. Among patients who survive this event, the leading cause of death and disability is subsequent constriction of the large cerebral arteries causing delayed cerebral ischaemia, the "second stroke". 1 2 Monitoring of cerebral blood flow velocities (CBFVs) in the large pial arteries identifies patients with SAH with raised risk for ischaemic complications. [3][4][5][6] In SAH, it has been shown in multiple studies that CBFVs on transcranial Doppler sonography are inversely related to vessel diameters on angiography. [3][4][5][6] The noninvasive character of this technique enables serial investigations of developing haemodynamic abnormalities in an individual patient.Earlier studies described inflammatory changes in SAH-that is, subarachnoidal and perivascular leucocytic infiltrates in the subarachnoidal space 7-9 in relation to development of cerebral vasospasms. 8 9 Moreover, the proinflammatory cytokines interleukin (IL)-1 , IL-6, and tumour necrosis factor (TNF)-that orchestrate the cascade of inflammatory host response to infection and tissue damage 10 11 have been detected in the CSF of patients with SAH. [12][13][14][15][16] These earlier findings suggest an inflammatory pathogenesis of vasospasms in SAH. In this study, we tested the hypothesis that the extent and pattern of secretion of key mediators of inflammation IL-1 , IL-6, and TNFare associated with development of haemodynamic abnormalities in basal cerebral arteries and with clinical outcome. Patients and methods PATIENTS AND CONTROL SUBJECTSThirty five patients (21 women and 14 men), aged between 23 and 76 (median 56) years with SAH caused by aneurysmal rupture and presenting within 48 hours after onset of first symptoms were studied. Hunt and Hess scores to classify disease severity were 1 in 9%, 2 in 11%, 3 in 32%, 4 in 29%, and...
This core set has been approved by the American College of Rheumatology (ACR) Board of Directors asProvisional. This signifies that the core set has been quantitatively validated using patient data, but it has not undergone validation based on an external data set. All ACR-approved core sets are expected to undergo intermittent updates.Objective. To validate a core set of outcome measures for the evaluation of response to treatment in patients with juvenile dermatomyositis (DM). Methods. In 2001, a preliminary consensus-derived core set for evaluating response to therapy in juvenile DM was established. In the present study, the core set was validated through an evidence-based, large-scale data collection that led to the enrollment of 294 patients from 36 countries. Consecutive patients with active disease were assessed at baseline and after 6 months. The validation procedures included assessment of feasibility, responsiveness, discriminant and construct ability, concordance in the evaluation of response to therapy between physicians and parents, redundancy, internal consistency, and ability to predict a therapeutic response. Results. The following clinical measures were found to be feasible, and to have good construct validity, discriminative ability, and internal consistency; furthermore, they were not redundant, proved responsive to clinically important changes in disease activity, and were associated strongly with treatment outcome and thus were included in the final core set: 1) physician's global assessment of disease activity, 2) muscle strength, 3) global disease activity measure, 4) parent's global assessment of patient's well-being, 5) functional ability, and 6) health-related quality of life. Conclusion. The members of the Paediatric Rheumatology International Trials Organisation, with the endorsement of the American College of Rheumatology and the European League Against Rheumatism, propose a core set of criteria for the evaluation of response to therapy that is scientifically and clinically relevant and statistically validated. The core set will help standardize the conduct and reporting of clinical trials and assist practitioners in deciding whether a child with juvenile DM has responded adequately to therapy.
The PVAS validity in children with systemic vasculitis was demonstrated. Like the BVAS, we anticipate that the PVAS will provide a robust tool to objectively define disease activity for clinical trials and future research.
Symptoms typical of RLS may be induced by risperidone treatment and should be differentiated from akathisia. Although polysomnography is not necessary, it may be helpful confirming the diagnosis.
The mutation epsilon1267delG might be frequent in European congenital myasthenic syndrome patients of Gypsy ethnic origin. In general, patients (epsilon1267delG) were characterized by the onset of symptoms in early infancy, the presence of ophthalmoparesis, positive response to anticholinesterase treatment, and the benign natural course of the disease.
Objective. Juvenile idiopathic arthritis (JIA) is an autoimmune disease of the young. The pathogenesis is not completely understood. Premature aging, associated thymic involution, and compensatory autoproliferation could play important roles in the pathogenesis of autoimmunity. We undertook this study to determine whether patients with JIA demonstrate premature immunosenescence.Methods. To test this hypothesis, we measured 3 indicators of aging: the percentages and total counts of peripheral blood naive T cells, the frequency of T cell receptor excision circles (TRECs) in naive T cells, and telomeric erosion and Ki-67 expression as estimates of the replicative history of homeostatic proliferation.Results. JIA patients showed an accelerated loss of CD4؉,CD45RA؉,CD62L؉ naive T cells with advancing age and a compensatory increase in the number of CD4؉,CD45RO؉ memory T cells. JIA patients demonstrated a significantly decreased frequency of TRECs in CD4؉,CD45RA؉ naive T cells compared with agematched healthy donors (P ؍ 0.002). TREC numbers correlated with age only in healthy donors (P ؍ 0.0001).Telomeric erosion in CD4؉,CD45RA؉ naive T cells was increased in JIA patients (P ؍ 0.01). The percentages of Ki-67-positive CD4؉,CD45RA؉ naive T cells were increased in JIA patients (P ؍ 0.001) and correlated with disease duration (P ؍ 0.003), which was also an independent factor contributing to telomeric erosion (P ؍ 0.04).Conclusion. Our findings suggest that ageinappropriate T cell senescence and disturbed T cell homeostasis may contribute to the development of JIA. In patients with JIA, dysfunction in the ability to reconstitute the T cell compartment should be considered when exploring new therapeutic strategies.
Low cholesterol concentrations and cholesterol-lowering therapies have been suggested to be associated with increased suicidality. This article examined the association of cholesterol, triglycerides, and body-mass index (BMI) with suicidal ideation and suicide attempts. Findings are based on a nationally representative community sample of n = 4,181 subjects (18-65 years) examined with a standardized diagnostic interview (CIDI) for (DSM-IV) mental disorders. Controlling for age and gender the study revealed a moderate positive association between cholesterol, triglycerides, BMI, and suicide attempts in subjects with depressive symptoms during the past 12 months (n = 1,205). The results of this study are compatible with two recent epidemiological cohort studies showing a positive association between cholesterol and completed suicide.
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