| 1. |
- Erhardt, Sophie, et al.
(författare)
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Connecting Inflammation with Glutamate Agonism in Suicidality
- 2013
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group: Open Access Hybrid Model Option A. - 0893-133X .- 1740-634X. ; 38:5, s. 743-752
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Tidskriftsartikel (refereegranskat)abstract
- The NMDA-receptor antagonist ketamine has proven efficient in reducing symptoms of suicidality, although the mechanisms explaining this effect have not been detailed in psychiatric patients. Recent evidence points towards a low-grade inflammation in brains of suicide victims. Inflammation leads to production of quinolinic acid (QUIN) and kynurenic acid (KYNA), an agonist and antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, respectively. We here measured QUIN and KYNA in the cerebrospinal fluid (CSF) of 64 medication-free suicide attempters and 36 controls, using gas chromatography mass spectrometry and high-performance liquid chromatography. We assessed the patients clinically using the Suicide Intent Scale and the Montgomery Asberg Depression Rating Scale (MADRS). We found that QUIN, but not KYNA, was significantly elevated in the CSF of suicide attempters (Pandlt;0.001). As predicted, the increase in QUIN was associated with higher levels of CSF interleukin-6. Moreover, QUIN levels correlated with the total scores on Suicide Intent Scale. There was a significant decrease of QUIN in patients who came for follow-up lumbar punctures within 6 months after the suicide attempt. In summary, we here present clinical evidence of increased QUIN in the CSF of suicide attempters. An increased QUIN/KYNA quotient speaks in favor of an overall NMDA-receptor stimulation. The correlation between QUIN and the Suicide Intent Scale indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality. Our findings have important implications for the detection and specific treatment of suicidal patients, and might explain the observed remedial effects of ketamine. Neuropsychopharmacology (2013) 38, 743-752; doi:10.1038/npp.2012.248; published online 9 January 2013
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| 2. |
- Feldwisch, Joachim, et al.
(författare)
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Design of an optimized scaffold for affibody molecules.
- 2010
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 398:2, s. 232-247
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules are non-immunoglobulin-derived affinity proteins based on a three-helical bundle protein domain. Here, we describe the design process of an optimized Affibody molecule scaffold with improved properties and a surface distinctly different from that of the parental scaffold. The improvement was achieved by applying an iterative process of amino acid substitutions in the context of the human epidermal growth factor receptor 2 (HER2)-specific Affibody molecule Z(HER2:342). Replacements in the N-terminal region, loop 1, helix 2 and helix 3 were guided by extensive structural modeling using the available structures of the parent Z domain and Affibody molecules. The effect of several single substitutions was analyzed followed by combination of up to 11 different substitutions. The two amino acid substitutions N23T and S33K accounted for the most dramatic improvements, including increased thermal stability with elevated melting temperatures of up to +12 degrees C. The optimized scaffold contains 11 amino acid substitutions in the nonbinding surface and is characterized by improved thermal and chemical stability, as well as increased hydrophilicity, and enables generation of identical Affibody molecules both by chemical peptide synthesis and by recombinant bacterial expression. A HER2-specific Affibody tracer, [MMA-DOTA-Cys61]-Z(HER2:2891)-Cys (ABY-025), was produced by conjugating MMA-DOTA (maleimide-monoamide-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to the peptide produced either chemically or in Escherichia coli. ABY-025 showed high affinity and specificity for HER2 (equilibrium dissociation constant, K(D), of 76 pM) and detected HER2 in tissue sections of SKOV-3 xenograft and human breast tumors. The HER2-binding capacity was fully retained after three cycles of heating to 90 degrees C followed by cooling to room temperature. Furthermore, the binding surfaces of five Affibody molecules targeting other proteins (tumor necrosis factor alpha, insulin, Taq polymerase, epidermal growth factor receptor or platelet-derived growth factor receptor beta) were grafted onto the optimized scaffold, resulting in molecules with improved thermal stability and a more hydrophilic nonbinding surface.
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| 3. |
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| 4. |
- Lindqvist, Daniel, et al.
(författare)
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Cerebrospinal fluid inflammatory markers in Parkinson's disease - Associations with depression, fatigue, and cognitive impairment.
- 2013
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Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 33:Jul.,31, s. 183-189
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Tidskriftsartikel (refereegranskat)abstract
- Neuroinflammation may be involved in the pathophysiology of Parkinson's disease (PD) and specifically in non-motor symptoms such as depression, fatigue and cognitive impairment. The aim of this study was to measure inflammatory markers in cerebrospinal fluid (CSF) samples from PD patients and a reference group, and to investigate correlations between non-motor symptoms and inflammation. We quantified C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, eotaxin, interferon gamma-induced protein-10, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein 1-β in CSF samples from PD patients (N=87) and the reference group (N=33). Sixteen of the PD patients had a dementia diagnosis (PDD). We assessed symptoms of fatigue, depression, anxiety and cognitive function using the Functional Assessment of Chronic Illness Therapy-Fatigue, the Hospital Anxiety and Depression Scale, and the Mini Mental State Examination, respectively. There were no significant differences in mean levels of inflammatory markers between PD patients and the reference group. After controlling for age, gender and somatic illness, patients with PDD had significantly higher levels of CRP compared to non-demented PD patients (p=0.032) and the reference group (p=0.026). Increased levels of inflammatory markers in CSF were significantly associated with more severe symptoms of depression, anxiety, fatigue, and cognition in the entire PD group. After controlling for PD duration, age, gender, somatic illness and dementia diagnosis, high CRP levels were significantly associated with more severe symptoms of depression (p=0.010) and fatigue (p=0.008), and high MCP-1 levels were significantly associated with more severe symptoms of depression (p=0.032). Our results indicate that non-motor features of PD such as depression, fatigue, and cognitive impairment are associated with higher CSF levels of inflammatory markers.
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| 5. |
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| 6. |
- Lindqvist, Daniel, et al.
(författare)
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CSF biomarkers in suicide attempters - a principal component analysis.
- 2011
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Ingår i: Acta Psychiatrica Scandinavica. - : Wiley. - 1600-0447 .- 0001-690X. ; 124, s. 52-61
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Tidskriftsartikel (refereegranskat)abstract
- Lindqvist D, Janelidze S, Erhardt S, Träskman-Bendz L, Engström G, Brundin L. CSF biomarkers in suicide attempters - a principal component analysis. Objective: The objective of the present study was to identify biological patterns (factors) among 20 cerebrospinal fluid (CSF) biomarkers in suicide attempters and subsequently analyse their association with suicidal behaviour. Method: We measured kynurenic acid, orexin, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol, chemokines, matrix metalloproteases and cytokines in the CSF of 124 drug-free suicide attempters. Patients were evaluated for suicidality and psychiatric symptoms using well-defined psychiatric rating scales and followed-up regarding future suicide. We used principal component analysis to identify factors among the biological substances. Results: Four factors were extracted from the 20 biomarkers, explaining 52.4% of the total variance. Factors 1 and 2 were characterized by high loadings of chemokines and cytokines respectively. They were both associated with severe depressive symptoms. Factor 2 was also associated with a high suicidal intent. Factor 4 was characterized by strong loadings of the monoamine metabolites 5-HIAA and HVA, as well as orexin and interleukin-6. High scores on this factor were found in patients who performed a violent suicide attempt and in patients who subsequently completed suicide. Conclusion: Our results suggest that specific combinations of CSF biomarkers may discriminate between types of suicidal behaviour and indicate increased risk for future suicide.
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| 7. |
- Lindqvist, Daniel, et al.
(författare)
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Non-motor symptoms in patients with Parkinson's disease - correlations with inflammatory cytokines in serum.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's Disease (PD) is the second most common neurodegenerative disorder of the central nervous system. Motor symptoms are the focus of pharmacotherapy, yet non-motor features of the disease (e.g. fatigue, mood disturbances, sleep disturbances and symptoms of anxiety) are both common and disabling for the patient. The pathophysiological mechanisms behind the non-motor symptoms in PD are yet to be untangled. The main objective of this study was to investigate associations between pro-inflammatory substances and non-motor symptoms in patients with PD.
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| 8. |
- Lindqvist, Daniel, et al.
(författare)
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Peripheral antioxidant markers are associated with total hippocampal and CA3/dentate gyrus volume in MDD and healthy controls-preliminary findings.
- 2014
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Ingår i: Psychiatry Research. - : Elsevier BV. - 1872-7123 .- 0925-4927. ; 224:3, s. 168-174
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Tidskriftsartikel (refereegranskat)abstract
- Several psychiatric disorders, including major depressive disorder (MDD), are associated with increased blood markers of oxidative stress. The relevance of this to the oxidation-sensitive hippocampus (HC) is unknown. We investigated the relationship between peripheral oxidative stress markers and HC volume in unmedicated individuals with MDD (n=16) and healthy controls (n=19). To conserve power, our primary analysis was carried out in the combined group of subjects, and secondary analyses examined each group separately. Oxidative stress markers (oxidized glutathione (GSSG)) and antioxidants (reduced glutathione (GSH), glutathione peroxidase (Gpx), and Vitamin C) were assessed, and a "total net antioxidant score" was calculated. 4-T MRI estimated total HC volume and HC subfield (CA1, CA1-CA2 transition zone, subiculum and CA3/dentate gyrus [CA3&DG]) volumes. Across groups, the antioxidant score was significantly and positively correlated with total HC volume and CA3&DG subfield volume (normalized to total intracranial volume), adjusting for age and sex. Similar relationships were observed in each individual group but missed statistical significance, likely due to type II errors, with the exception of a significant correlation between the antioxidant score and CA3&DG volume in the MDD group. These preliminary data are consistent with oxidative stress being associated with smaller total HC and CA3&DG subfield volumes.
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| 9. |
- Lindqvist, Daniel, et al.
(författare)
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Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress.
- 2014
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Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 42:Jun 12, s. 81-88
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Tidskriftsartikel (refereegranskat)abstract
- Chronic inflammation may be involved in combat-related post-traumatic stress disorder (PTSD) and may help explain comorbid physical diseases. However, the extent to which combat exposure per se, depression, or early life trauma, all of which are associated with combat PTSD, may confound the relationship between PTSD and inflammation is unclear.
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| 10. |
- Lindqvist, Daniel
(författare)
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Redefining suicidal behaviour – Rating scales and biomarkers
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Risk assessment of suicidal behaviour is one of the most important tasks in clinical psychiatry and a major determinant of subsequent care and treatment selections. To date, suicide risk assessment is based solely on clinical evaluations, which inevitably leads to subjective interpretations and decisions by the psychiatrist. In order to find more robust instruments in the evaluation of suicidality it is important to search for objective correlates of different aspects of suicidal behavior. The main aim of the present thesis was to investigate neurobiological and clinical characteristics in a group of suicide attempters in order to gain a further understanding of the mechanisms underlying suicidal behavior. The patients, who were all treated at a psychiatric ward of the Lund University Hospital after a suicide attempt, participated in a research program including clinical and biochemical investigations, as well as expert and self -ratings. While free of psychotropic medications, the patients underwent lumbar punctures and Dexamethasone Suppression Tests (DST). Diagnostic interviews and ratings of different aspects of psychopathology were carried out at the psychiatric ward. A subset of the patients participated in a clinical follow-up approximately 12 years after the suicide attempt, this time in an outpatient setting. Salivary samples were collected in conjunction with the follow-up. Biomarkers from the stress-, immune-, and the monoaminergic systems were analyzed in cerebrospinal fluid (CSF), saliva and blood, and subsequently analyzed in relation to different aspects of suicidal behaviour and psychiatric symptoms. The most salient findings were that: 1. Low post-DST cortisol levels were associated with high suicidal intent among patients with Major Depressive Disorder (MDD). 2. Low salivary cortisol levels were found in suicide attempters approximately years after the index suicide attempt. Low salivary cortisol was associated with repetition of suicidal behaviour and severe psychiatric symptoms. 3. Suicide attempters had significantly higher CSF levels of pro- inflammatory cytokine Interleukin (IL)-6 compared to healthy individuals, and the highest levels were found in violent suicide attempters and patients with MDD. 4. Levels of CSF-Kynurenic acid (Kyna), an end-metabolite of tryptophan through the kynurenine-pathway, did not significantly differ between suicide attempters and controls. High Kyna levels were, however, associated with high IL-6 levels and a diagnosis of MDD. 5. By using Principal component analysis (PCA) we found that a combination of IL-6, 5-Hydroxyindoleacetic acid (serotonin metabolite), and Homovanillic acid (dopamine metabolite) was associated with severe suicidal behaviour and risk for future completed suicide. We found that suicide attempters display elevated levels of the proinflammatory cytokine IL-6 in CSF. We therefore suggest that neuroinflammation may be involved in the pathophysiology of suicidal behaviour. The results from the PCA further confirm that IL-6 seems to play an important role for suicidal behaviour, an effect perhaps mediated via the monoaminergic system. In addition, our results suggest that low Hypothalamic-Pituitary-Adrenal (HPA)- axis activity is associated with more severe forms of suicidal behaviour in our sample of patients. This might be due to long-term stress resulting in an “HPA- axis burnout”. We propose a neurobiological model for suicidal behaviour linking long-term stress with HPA-axis burnout, which in turn might lead to a shift towards immune activation. We further suggest a dynamic relationship between the immune system and monoamines, where an acute immune response may result in increased monoamine turnover whereas long-lasting, low-grade inflammation, in contrast, may lead to a monoamine depletion. Our findings may in the long run have important clinical implications. For example, we are planning to start a treatment study in which suicidal patients will receive anti-inflammatory agents added to their regular medicine. We hope that this combination will improve their psychiatric symptoms and that this will show in blood and CSF samples. Another potential clinical implication is the use of biomarkers in psychiatry. Suicide risk assessment is one clinical situation in which biomarkers would be useful as a tool in the clinical evaluation. Indeed, inflammatory markers such as IL-6 are candidates for this purpose, although further studies are warranted in order to identify biomarkers with sufficient sensitivity and specificity to be used in the clinic.
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| 11. |
- Serafini, Gianluca, et al.
(författare)
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The Role of Neuropeptides in Suicidal Behavior: A Systematic Review
- 2013
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Ingår i: BioMed Research International. - : Hindawi Limited. - 2314-6133 .- 2314-6141. ; 2013
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Forskningsöversikt (refereegranskat)abstract
- There is a growing evidence that neuropeptides may be involved in the pathophysiology of suicidal behavior. A critical review of the literature was conducted to investigate the association between neuropeptides and suicidal behavior. Only articles from peer-reviewed journals were selected for the inclusion in the present review. Twenty-six articles were assessed for eligibility but only 22 studies were included. Most studies have documented an association between suicidality and some neuropeptides such as corticotropin-releasing factor (CRF), VGF, cholecystokinin, substance P, and neuropeptide Y (NPY), which have been demonstrated to act as key neuromodulators of emotional processing. Significant differences in neuropeptides levels have been found in those who have attempted or completed suicide compared with healthy controls or those dying from other causes. Despite cross-sectional associations between neuropeptides levels and suicidal behavior, causality may not be inferred. The implications of the mentioned studies were discussed in this review paper.
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| 12. |
- Uhlén, Fredrik, et al.
(författare)
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New diamond nanofabrication process for hard x-ray zone plates
- 2011
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Ingår i: Journal of Vacuum Science & Technology B. - : American Vacuum Society. - 1071-1023 .- 1520-8567. ; 29:6, s. 06FG03-1-06FG03-4
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Tidskriftsartikel (refereegranskat)abstract
- The authors report on a new tungsten-hardmask-based diamond dry-etch process for fabricating diamond zone plate lenses with a high aspect ratio. The tungsten hardmask is structured by electron-beam lithography, together with Cl2/O2 and SF6/O2 reactive ion etching in a trilayer resist-chromium-tungsten stack. The underlying diamond is then etched in an O2 plasma. The authors demonstrate excellent-quality diamond gratings with half-pitch down to 80 nm and a height of 2.6 μm, as well as zone plates with a 75 μm diameter and 100 nm outermost zone width. The diffraction efficiency of the zone plates is measured to 14.5% at an 8 keV x-ray energy, and the imaging properties were investigated in a scanning microscope arrangement showing sub-100-nm resolution. The imaging and thermal properties of these lenses make them suitable for use with high-brightness x-ray free-electron laser sources.
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