| 1. |
- Asherson, P., et al.
(författare)
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The effects of atomoxetine on emotional control in adults with ADHD : An integrated analysis of multicenter studies
- 2015
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Ingår i: European psychiatry. - : Cambridge University Press (CUP). - 0924-9338 .- 1778-3585. ; 30:4, s. 511-520
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate the effects of atomoxetine on emotional control in adults with ADHD. Methods: We performed an integrated analysis using individual patient data pooled from three Eli Lilly-sponsored studies. An integrated analysis can be viewed as a meta-analysis of individual patient-level data, rather than study-level summary data. Results: Two populations were identified: a large sample of patients with pre-treatment baseline data (the "overall population''; n = 2846); and a subset of these patients with placebo-controlled efficacy data from baseline to 10 or 12 weeks after initiating treatment (the "placebo-controlled population''; n = 829). At baseline, in the overall population, similar to 50% of ADHD patients had BRIEF-AS (Behavior Rating Inventory of Executive Function-Adult Version Self-Report) Emotional control subscores between 21 and 30, compared with similar to 10% of normative subjects in the BRIEF-A manual. At endpoint, in the placebo-controlled population, atomoxetine led to a small (effect size 0.19) but significant (P = 0.013) treatment effect for emotional control. The effect size was 0.32 in patients with BRIEF-AS Emotional control scores > 20 at baseline. Improvements in emotional control correlated with improvements in the core ADHD symptoms and quality-of-life. Discussion: As deficient emotional control is associated with impaired social, educational and occupational functioning over and above that explained by core ADHD symptoms alone, improvements in emotional control may be clinically relevant. Conclusion: At baseline, adults with ADHD were more likely to have impaired emotional control than normative subjects. In the adult ADHD patients, atomoxetine treatment was associated with improvements in emotional control, as well as in core ADHD symptoms and quality-of-life.
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| 2. |
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| 3. |
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| 4. |
- Min, Soyoung, et al.
(författare)
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Alternatively folded proteins with unexpected beneficial functions
- 2012
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Ingår i: Biochemical Society Transactions. - 0300-5127. ; 40, s. 746-751
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Tidskriftsartikel (refereegranskat)abstract
- HAMLET (human alpha-lactalbumin made lethal to tumour cells) and its related partially unfolded protein-fatty acid complexes are novel biomolecular nanoparticles that possess relatively selective cytotoxic activities towards tumour cells. One of the key characteristics is the requirement for the protein to be partially unfolded, hence endowing native proteins with additional functions in the alternatively folded states. Beginning with the history of its discovery and development, the cellular targets that appear to be strongly correlated with tumour cell death are introduced in the present article.
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| 5. |
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| 6. |
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| 7. |
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| 8. |
- Wegmann, F., et al.
(författare)
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Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens
- 2012
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Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 30:9
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Tidskriftsartikel (refereegranskat)abstract
- Protection against mucosally transmitted infections probably requires immunity at the site of pathogen entry(1), yet there are no mucosal adjuvant formulations licensed for human use. Polyethyleneimine (PEI) represents a family of organic polycations used as nucleic acid transfection reagents in vitro and DNA vaccine delivery vehicles in vivo(2,3). Here we show that diverse PEI forms have potent mucosal adjuvant activity for viral subunit glycoprotein antigens. A single intranasal administration of influenza hemagglutinin or herpes simplex virus type-2 (HSV-2) glycoprotein D with PEI elicited robust antibody-mediated protection from an otherwise lethal infection, and was superior to existing experimental mucosal adjuvants. PEI formed nanoscale complexes with antigen, which were taken up by antigen-presenting cells in vitro and in vivo, promoted dendritic cell trafficking to draining lymph nodes and induced non-proinflammatory cytokine responses. PEI adjuvanticity required release of host double-stranded DNA that triggered Irf3-dependent signaling. PEI therefore merits further investigation as a mucosal adjuvant for human use.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Casbarra, A, et al.
(författare)
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Conformational analysis of HAMLET, the folding variant of human alpha-lactalbumin associated with apoptosis
- 2004
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Ingår i: Protein Science. - : Wiley. - 1469-896X .- 0961-8368. ; 13:5, s. 1322-1330
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Tidskriftsartikel (refereegranskat)abstract
- A combination of hydrogen/deuterium (H/D) exchange and limited proteolysis experiments coupled to mass spectrometry analysis was used to depict the conformation in solution of HAMLET, the folding variant of human alpha-lactalbumin, complexed to oleic acid, that induces apoptosis in tumor and immature cells. Although near- and far-UV CD and fluorescence spectroscopy were not able to discriminate between HAMLET and apo-alpha-lactalbumin, H/D exchange experiments clearly showed that they correspond to two distinct conformational states, with HAMLET incorporating a greater number of deuterium atoms than the apo and holo forms. Complementary proteolysis experiments revealed that HAMLET and apo are both accessible to proteases in the P-domain but showed substantial differences in accessibility to proteases at specific sites. The overall results indicated that the conformational changes associated with the release of Ca2+ are not sufficient to induce the HAMLET conformation. Metal depletion might represent the first event to produce a partial unfolding in the beta-domain of a-lactalbumin, but some more unfolding is needed to generate the active conformation HAMLET, very likely allowing the protein to bind the C18:1 fatty acid moiety. On the basis of these data, a putative binding site of the oleic acid, which stabilizes the HAMLET conformation, is proposed.
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| 15. |
- Connell, H., et al.
(författare)
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Type 1 fimbrial expression enhances Escherichia coli virulence for the urinary tract
- 1996
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 93:18, s. 9827-9832
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 fimbriae are adhesion organelles expressed by many Gram-negative bacteria. They facilitate adherence to mucosal surfaces and inflammatory cells in vitro, but their contribution to virulence has not been defined. This study presents evidence that type 1 fimbriae increase the virulence of Escherichia coli for the urinary tract by promoting bacterial persistence and enhancing the inflammatory response to infection. In a clinical study, we observed that disease severity was greater in children infected with E. coli O1:K1:H7 isolates expressing type 1 fimbriae than in those infected with type 1 negative isolates of the same serotype. The E. coli O1:K1:H7 isolates had the same electrophoretic type, were hemolysin-negative, expressed P fimbriae, and carried the fim DNA sequences. When tested in a mouse urinary tract infection model, the type 1-positive E. coli O1:K1:H7 isolates survived in higher numbers, and induced a greater neutrophil influx into the urine, than O1:K1:H7 type 1-negative isolates. To confirm a role of type 1 fimbriae, a fimH null mutant (CNI016) was constructed from an O1:K1:H7 type 1-positive parent. E. coli CNI016 had reduced survival and inflammatogenicity in the mouse urinary tract infection model. E. coli CNI016 reconstituted with type 1 fimbriae (E. coli CN1018) had restored virulence similar to that of the wild- type parent strain. These results show that type 1 fimbriae in the genetic background of a uropathogenic strain contribute to the pathogenesis of E. coli in the urinary tract.
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| 16. |
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| 17. |
- Godaly, Gabriela, et al.
(författare)
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Neutrophil recruitment, chemokine receptors, and resistance to mucosal infection
- 2001
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Ingår i: Journal of Leukocyte Biology. - 1938-3673. ; 69:6, s. 899-906
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil migration to infected mucosal sites involves a series of complex interactions with molecules in the lamina propria and at the epithelial barrier. Much attention has focussed on the vascular compartment and endothelial cells, but less is known about the molecular determinants of neutrophil behavior in the periphery. We have studied urinary tract infections (UTIs) to determine the events that initiate neutrophil recruitment and interactions of the recruited neutrophils with the mucosal barrier. Bacteria activate a chemokine response in uroepithelial cells, and the chemokine repertoire depends on the bacterial virulence factors and on the specific signaling pathways that they activate. In addition, epithelial chemokine receptor expression is enhanced. Interleukin (IL)-8 and CXCR1 direct neutrophil migration across the epithelial barrier into the lumen. Indeed, mIL-8Rh knockout mice showed impaired transepithelial neutrophil migration, with tissue accumulation of neutrophils, and these mice developed renal scarring. They had a defective antibacterial defense and developed acute pyelonephritis with bacteremia. Low CXCR1 expression was also detected in children with acute pyelonephritis. These results demonstrate that chemokines and chemokine receptors are essential to orchestrate a functional antimicrobial defense of the urinary tract mucosa. Mutational inactivation of the IL-8R caused both acute disease and chronic tissue damage.
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| 18. |
- Godaly, Gabriela, et al.
(författare)
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Role of fimbriae-mediated adherence for neutrophil migration across Escherichia coli-infected epithelial cell layers
- 1998
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Ingår i: Molecular Microbiology. - : Wiley. - 1365-2958 .- 0950-382X. ; 30:4, s. 725-735
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Tidskriftsartikel (refereegranskat)abstract
- This study examined the role of P and type 1 fimbriae for neutrophil migration across Escherichia coli-infected uroepithelial cell layers in vitro and for neutrophil recruitment to the urinary tract in vivo. Recombinant E. coli K-12 strains differing in P or type 1 fimbrial expression were used to infect confluent epithelial layers on the underside of transwell inserts. Neutrophils were added to the upper well, and their passage across the epithelial cell layers was quantified. Infection with the P- and type 1-fimbriated recombinant E. coli strains stimulated neutrophil migration to the same extent as a fully virulent clinical E. coli isolate, but the isogenic non-fimbriated vector control strains had no stimulatory effect. The enhancement of neutrophil migration was adhesion dependent; it was inhibited by soluble receptor analogues blocking the binding of P fimbriae to the globoseries of glycosphingolipids or of type 1 fimbriae to mannosylated glycoprotein receptors. P- and type 1-fimbriated E. coli triggered higher interleukin (IL) 8 secretion and expression of functional IL-8 receptors than non-fimbriated controls, and the increase in neutrophil migration across infected cell layers was inhibited by anti-IL-8 antibodies. In a mouse infection model, P- or type 1-fimbriated E. coli stimulated higher chemokine (MIP-2) and neutrophil responses than the non-fimbriated vector controls. The results demonstrated that transformation with the pap or fim DNA sequences is sufficient to convert an E. coli K-12 strain to a host response inducer, and that fimbriation enhances neutrophil recruitment in vitro and in vivo. Epithelial chemokine production provides a molecular link between the fimbriated bacteria that adhere to epithelial cells and tissue inflammation.
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| 19. |
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| 20. |
- Håkansson, Anders P, et al.
(författare)
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A folding variant of alpha-lactalbumin with bactericidal activity against Streptococcus pneumoniae
- 2000
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Ingår i: Molecular Microbiology. - : Wiley. - 0950-382X .- 1365-2958. ; 35:3, s. 589-600
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Tidskriftsartikel (refereegranskat)abstract
- This study describes an alpha-lactalbumin folding variant from human milk with bactericidal activity against antibiotic-resistant and -susceptible strains of Streptococcus pneumoniae. The active complex precipitated with the casein fraction at pH 4.6 and was purified from casein by a combination of anion exchange and gel chromatography. Unlike other casein components, the active complex was retained on the ion-exchange matrix and eluted only with high salt. The eluted fraction showed N-terminal and mass spectrometric identity with human milk alpha-lactalbumin, but native alpha-lactalbumin had no bactericidal effect. Spectroscopic analysis demonstrated that the active form of the molecule was in a different folding state, with secondary structure identical to alpha-lactalbumin from human milk whey, but fluctuating tertiary structure. Native alpha-lactalbumin could be converted to the active bactericidal form by ion-exchange chromatography in the presence of a cofactor from human milk casein, characterized as a C18:1 fatty acid. Analysis of the antibacterial spectrum showed selectivity for streptococci; Gram-negative and other Gram-positive bacteria were resistant. The folding variant of alpha-lactalbumin is a new example of naturally occurring molecules with antimicrobial activity.
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| 21. |
- Håkansson, Anders P, et al.
(författare)
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Apoptosis induced by a human milk protein
- 1995
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 92:17, s. 8064-8068
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Tidskriftsartikel (refereegranskat)abstract
- To the breast-fed infant, human milk is more than a source of nutrients; it furnishes a wide array of molecules that restrict microbes, such as antibodies, bactericidins, and inhibitors of bacterial adherence. However, it has rarely been considered that human milk may also contain substances bioactive toward host cells. While investigating the effect of human milk on bacterial adherence to a human lung cancer cell line, we were surprised to discover that the milk killed the cells. Analysis of this effect revealed that a component of milk in a particular physical state--multimeric alpha-lact-albumin--is a potent Ca(2+)-elevating and apoptosis-inducing agent with broad, yet selective, cytotoxic activity. Multimeric alpha-lactalbumin killed all transformed, embryonic, and lymphoid cells tested but spared mature epithelial elements. These findings raise the possibility that milk contributes to mucosal immunity not only by furnishing antimicrobial molecules but also by policing the function of lymphocytes and epithelium. Finally, analysis of the mechanism by which multimeric alpha-lactalbumin induces apoptosis in transformed epithelial cells could lead to the design of antitumor agents.
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| 22. |
- Håkansson, Anders P, et al.
(författare)
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Apoptosis-Like Death in Bacteria Induced by HAMLET, a Human Milk Lipid-Protein Complex
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. Methodology/Principal Findings: We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity) to execute cell death. Conclusions/Significance: Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells.
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| 23. |
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| 24. |
- Köhler, Camilla, et al.
(författare)
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A folding variant of human alpha-lactalbumin induces mitochondrial permeability transition in isolated mitochondria
- 2001
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956. ; 268:1, s. 186-191
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Tidskriftsartikel (refereegranskat)abstract
- A human milk fraction containing multimeric alpha-lactalbumin (MAL) is able to kill cells via apoptosis. MAL is a protein complex of a folding variant of alpha-lactalbumin and lipids. Previous results have shown that upon treatment of transformed cells, MAL localizes to the mitochondria and cytochrome c is released into the cytosol. This is followed by activation of the caspase cascade. In this study, we further investigated the involvement of mitochondria in apoptosis induced by the folding variant of alpha-lactalbumin. Addition of MAL to isolated rat liver mitochondria induced a loss of the mitochondrial membrane potential (Delta Psi(m)), mitochondrial swelling and the release of cytochrome c. These changes were Ca(2+)-dependent and were prevented by cyclosporin A, an inhibitor of mitochondrial permeability transition. MAL also increased the rate of state 4 respiration in isolated mitochondria by exerting an uncoupling effect. This effect was due to the presence of fatty acids in the MAL complex because it was abolished completely by BSA. BSA delayed, but failed to prevent, mitochondrial swelling as well as dissipation of Delta Psi(m), indicating that the fatty acid content of MAL facilitated, rather than caused, these effects. Similar results were obtained with HAMLET (human alpha-lactalbumin made lethal to tumour cells), which is native alpha-lactalbumin converted in vitro to the apoptosis-inducing folding variant of the protein in complex with oleic acid. Our findings demonstrate that a folding variant of alpha-lactalbumin induces mitochondrial permeability transition with subsequent cytochrome c release, which in transformed cells may lead to activation of the caspase cascade and apoptotic death.
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| 25. |
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| 26. |
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| 27. |
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| 28. |
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| 29. |
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| 30. |
- Ruck, Christian, et al.
(författare)
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Capsulotomy for Obsessive-Compulsive Disorder : long term follow up of 25 patients
- 2008
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Ingår i: Archives of General Psychiatry. - : American Medical Association (AMA). - 0003-990X .- 1538-3636. ; 65:8, s. 914-922
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Context: Capsulotomy is sometimes used as a treatment of last resort in severe and treatment refractory cases of Obsessive-Compulsive Disorder (OCD). Objective: To evaluate the long-term efficacy and safety of capsulotomy in OCD. Design: Non-controlled long-term follow-up trial (mean 10.9 years after surgery). Setting: University hospital referral center. Patients: 25 consecutive OCD patients having undergone capsulotomy between the years 1988 and 2000. Intervention: Unilateral or bilateral capsulotomy. Lesions were created either by conventional heating or by gamma-radiation (radiosurgery). Main Outcome Measure: Yale-Brown Obsessive-Compulsive Rating Scale (Y-BOCS). Results: Mean Y-BOCS was 34 preoperatively and dropped to 18 at long-term follow-up (p<0.0001). Response (defined as ≥ 35 % reduction at long-term compared to baseline) was seen in 12 patients at long-term. Eight patients were in remission (Y-BOCS < 16) at long-term follow-up. Response rates did not differ between surgical method. A mean weight gain of 6 kg was reported in the first postoperative year. Ten patients were considered to sufferer from significant problems in the area of executive functioning, apathy or disinhibition. Six of these ten patients had either had high doses of radiation or multiple surgical procedures. Our MRI analysis of 11 patients suggests that the OCD symptom reduction may be increased by reducing the lateral extension of the lesions, and a reduction in the medial and posterior extension may limit the risk of side effects, that is, smaller lesions may produce better results. Conclusions: Capsulotomy is effective in reducing OCD symptoms. There is a substantial risk of side effects and the risk may vary between surgical methods. Our findings suggest that smaller lesions are safer and that high radiation doses and multiple procedures should be avoided.
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| 31. |
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| 32. |
- Ruck, C, et al.
(författare)
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Lesion topography in capsulotomy for refractory anxiety--is the right side the right side?
- 2005
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Ingår i: Stereotactic and functional neurosurgery. - : S. Karger AG. - 1011-6125 .- 1423-0372. ; 83:4, s. 172-179
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Tidskriftsartikel (refereegranskat)abstract
- <i>Objective:</i> A previous report on bilateral capsulotomy in obsessive-compulsive disorder showed common topographic features of lesions in the right-sided internal capsule in all patients responding to the treatment. The aims of the present study were to test if the same region was involved in anxiety patients responding to surgery and to examine whether lesion area and site correlated with adverse events and effect on target symptoms. <i>Method:</i> Eleven anxiety patients who had undergone bilateral thermocapsulotomy were examined after 8–23 years. A quantitative MRI evaluation of the lesions within the internal capsule was conducted in three axial planes. <i>Results:</i> None of the eight responders had lesions that corresponded to the earlier reported right-sided anatomical denominator. Four patients out of 11 were rated as having significant clinical symptoms indicating frontal lobe dysfunction. The total sum of the lesion area determined in each of the three anatomical levels did not correlate with the degree of anxiety reduction. However, the lesion area appeared to be related to a rating of executive dysfunctioning, apathy and disinhibtion.
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| 33. |
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| 34. |
- Svanborg, Catharina, et al.
(författare)
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The 'innate' host response protects and damages the infected urinary tract
- 2001
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Ingår i: Annals of Medicine. - 1365-2060. ; 33:9, s. 563-570
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Tidskriftsartikel (refereegranskat)abstract
- Symptoms of infection and tissue pathology are caused by the host response; not by the microbe per se. The same response is also critical for the defence and is needed to clear infection. It is therefore essential to understand how the host response is activated and to identify the critical effector mechanisms of the defence. We have studied these issues in the urinary tract infection (UTI) model. The symptoms of UTI and the host defence both rely on the so-called 'innate' immune system, making this one of the best characterized human disease models of 'innate immunity. We discuss the critical molecular events that determine whether the host response will be activated by P-fimbriated uropathogenic Escherichia coli as well as factors determining whether the patient develops acute pyelonephritis or asymptomatic bacteriuria. We will describe the glycoconjugate receptors used by the P-fimbriated bacteria adhering to host tissues, the recruitment of TLR4 co-receptors and the signalling pathways that allow progression to symptomatic disease, and discuss how these mechanisms are altered in asymptomatic carriers, presenting the possible genetic basis for unresponsiveness. We have shown that neutrophils are the critical effectors of the host defence and that neutrophil dysfunctions lead to acute pyelonephritis and renal scarring. Here we discuss the mechanisms of neutrophil-mediated, chemokine receptor (CXCR1)-dependent clearance, and the defect in interleukin-8 receptor homolog knock-out (IL-8Rh KO) mice and describe the data linking low CXCR1 expression to recurrent pyelonephritis in man, as well as the information on the genetic basis for low CXCR1 expression in affected patients. Finally, the mechanisms of renal scarring in IL8Rh KO mice will be discussed in relation to human disease. Our studies hold the promise to provide a molecular and genetic explanation for disease susceptibility in some patients with UTI and to offer more precise tools for the diagnosis and therapy of these infections.
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| 35. |
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| 36. |
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| 37. |
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Svanborg, P, et al.
(författare)
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Associations between plasma glucose and DSM-III-R cluster B personality traits in psychiatric outpatients
- 2000
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Ingår i: Neuropsychobiology. - : S. Karger AG. - 0302-282X .- 1423-0224. ; 41:2, s. 79-87
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Tidskriftsartikel (refereegranskat)abstract
- Associations between personality traits, measured with the Karolinska Scales of Personality, the Impulsiveness subscale from the Impulsiveness, Venturesomeness and Empathy (IVE) Inventory, and with self-assessed personality traits and disorders (SCID-II Screen Questionnaire), and plasma insulin, glucagon and glucose, respectively, were explored in a sample of 101 psychiatric outpatients of both sexes. No relationships between the peptide hormones and personality measures were found. However, fasting glucose values, which were all essentially within the normal biological variation, were significantly related to several personality measures. For males, a low blood glucose was associated with low stable general level of functioning, with high IVE Impulsiveness, and with self-assessed histrionic and narcissistic traits. High number of self-assessed personality traits for all cluster B personality disorders was strongly associated with high IVE Impulsiveness. The results of the present study support the generalizability of earlier findings from alcoholic impulsive offenders: in males, low blood glucose is associated with an extrovert and impulsive, acting-out behavior that includes the breaking of societal norms and rules. In contrast, for females a positive relationship between fasting glucose and self-assessed histrionic personality traits was found. Because no association between global level of functioning and glucose was found in women, these personality traits may not necessarily be maladaptive, as was the case for males.
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| 42. |
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| 44. |
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| 45. |
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| 46. |
- Svensson, Majlis, et al.
(författare)
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Neutrophil activation and renal scarring - Reply
- 2005
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Ingår i: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 67:6, s. 2504-2505
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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