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  • 1
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    Multiple spin‐echo spectroscopic imaging for rapid quantitative assessment of N‐acetylaspartate and lactate in acute stroke
    Wiley ; 2004
    In:  Magnetic Resonance in Medicine Vol. 52, No. 2 ( 2004-08), p. 228-238
    Details
    In: Magnetic Resonance in Medicine, Wiley, Vol. 52, No. 2 ( 2004-08), p. 228-238
    Abstract: Monitoring the signal levels of lactate (Lac) and N‐acetylaspartate (NAA) by chemical shift imaging can provide additional knowledge about tissue damage in acute stroke. Despite the need for this metabolic information, spectroscopic imaging (SI) has not been used routinely for acute stroke patients, mainly due to the long acquisition time required. The presented data demonstrate that the application of a fast multiple spin‐echo (MSE) SI sequence can reduce the measurement time to 6 min (four spin echoes per echo train, 32 × 32 matrix). Quantification of Lac and NAA in terms of absolute concentrations (i.e., mmol/l) can be achieved by means of the phantom replacement approach, with correction terms for the longitudinal and transversal relaxation adapted to the multiple spin‐echo sequence. In this pilot study of 10 stroke patients (symptom onset 〈 24 hr), metabolite concentrations obtained from MSE‐SI add important information regarding tissue viability that is not provided by other sequences (e.g., diffusion‐weighted imaging (DWI) and perfusion‐weighted imaging (PWI)). Metabolic changes extended beyond the borders of the apparent diffusion coefficient (ADC) lesion in nine of the 10 patients, showing a rise in Lac concentrations up to 18 mmol/l, while NAA levels sometimes dropped below the detection level. Considerable differences among the patients in terms of the Lac concentrations and the size of the SI‐ADC mismatch were observed. Magn Reson Med 52:228–238, 2004. © 2004 Wiley‐Liss, Inc.
    Type of Medium: Online Resource
    ISSN: 0740-3194 , 1522-2594
    URL: Issue
    URL: Article
    DOI: 10.1002/mrm.v52:2
    DOI: 10.1002/mrm.20171
    Language: English
    Publisher: Wiley
    Publication Date: 2004
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  • 2
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    A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 3 ( 2023-03-01), p. 977-990
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 3 ( 2023-03-01), p. 977-990
    Abstract: Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P & lt; 5 × 10−8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10−16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187–0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci ( & gt;90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10−4, OR = 2.5, 95%CI = 1.499–4.157) and DRB1*04:01 allele (P = 8.3 × 10−5, OR = 2.4, 95%CI = 1.548–3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac119
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 3
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    Characterization of Adenosine-A1 Receptor–Mediated Antilipolysis in Rats by Tissue Microdialysis, 1H-Spectroscopy, and Glucose Clamp Studies
    American Diabetes Association ; 2004
    In:  Diabetes Vol. 53, No. 7 ( 2004-07-01), p. 1920-1926
    Details
    In: Diabetes, American Diabetes Association, Vol. 53, No. 7 ( 2004-07-01), p. 1920-1926
    Abstract: Increased supply of fatty acids to muscle and liver is causally involved in the insulin resistance syndrome. Using a tissue microdialysis technique in Wistar and Zucker fatty (ZF) rats, we determined tissue glycerol levels as a marker of lipolysis in gastrocnemius muscle (gMT), subcutaneous adipose (SAT), and visceral adipose tissue (VAT) as well as the reduction of plasma free fatty acids, glycerol, and triglycerides caused by the antilipolysis-specific adenosine-A1 receptor agonist (ARA). In Wistar and ZF rats, ARA significantly lowered dialysate glycerol levels in SAT, VAT, and gMT. Whereas in SAT and VAT the decrease in dialysate glycerol indicated adipocytic antilipolysis, this decrease in gMT was not caused by a direct effect of ARA on intramyocellular lipolysis, as demonstrated by the lack of inhibition of the protein kinase A activity ratio in gMT. In addition, no differences of the fed-starved-refed dynamics of intramyocellular triglyceride levels compared with untreated controls were measured by in vivo 1H-spectroscopy, excluding any adenylate cyclase–independent antilipolysis in muscle. Treatment with ARA resulted in pronounced reductions of plasma free fatty acids, glycerol, and triglycerides. Furthermore, in ZF rats, ARA treatment caused an immediate improvement of peripheral insulin sensitivity measured by the euglycemic-hyperinsulinemic glucose clamp technique.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.53.7.1920
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2004
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  • 4
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    Specific creatine rise in learned helplessness induced by electroconvulsive shock treatment
    Ovid Technologies (Wolters Kluwer Health) ; 2003
    In:  NeuroReport Vol. 14, No. 17 ( 2003-12), p. 2199-2201
    Details
    In: NeuroReport, Ovid Technologies (Wolters Kluwer Health), Vol. 14, No. 17 ( 2003-12), p. 2199-2201
    Type of Medium: Online Resource
    ISSN: 0959-4965
    URL: Article
    DOI: 10.1097/00001756-200312020-00013
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2003
    detail.hit.zdb_id: 1049746-8
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  • 5
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    Intramyocellular Lipid and Insulin Resistance
    American Diabetes Association ; 2003
    In:  Diabetes Vol. 52, No. 1 ( 2003-01-01), p. 138-144
    Details
    In: Diabetes, American Diabetes Association, Vol. 52, No. 1 ( 2003-01-01), p. 138-144
    Abstract: Insulin resistance plays an important role in the pathogenesis of human type 2 diabetes. In humans, a negative correlation between insulin sensitivity and intramyocellular lipid (IMCL) content has been shown; thus, IMCL becomes a marker for insulin resistance. Recently, magnetic resonance spectroscopy (MRS) has been established as a dependable method for selective detection and quantification of IMCL in humans. To validate the interrelation between insulin sensitivity and IMCL in an animal model of type 2 diabetes, we established volume selective 1H-MRS at 7 Tesla to noninvasively assess IMCL in the rat. In male obese Zucker Diabetic Fatty rats and their lean littermates, IMCL levels were determined repeatedly over 4 months, and insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp method at 6–7 and at 22–24 weeks of age. A distinct relation between IMCL and insulin sensitivity was demonstrated as well as age dependence for both parameters. Rosiglitazone treatment caused a clear reduction of IMCL and hepatic fat despite increased body weight, and a marked improvement of insulin sensitivity. Thus, the insulin sensitizing properties of rosiglitazone were consistent with a redistribution of lipids from nonadipocytic (skeletal muscle, liver) back into fat tissue.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.52.1.138
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2003
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  • 6
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    Determinants of intramyocellular lipid concentrations in rat hindleg muscle
    Wiley ; 2003
    In:  Magnetic Resonance in Medicine Vol. 50, No. 2 ( 2003-08), p. 242-248
    Details
    In: Magnetic Resonance in Medicine, Wiley, Vol. 50, No. 2 ( 2003-08), p. 242-248
    Abstract: The investigation of intramyocellular lipids (IMCLs) with proton MR spectroscopy ( 1 H‐MRS) in humans has recently received increasing attention. IMCL levels correlate with insulin resistance and are affected by diet and exercise, making IMCL an interesting marker for metabolic investigations. In the present in vivo study, the feasibility of using 1 H MRS for the detection of IMCL in rats is demonstrated, and the influence of various factors, such as age, gender, muscle type, and rat strain, on IMCL levels is systematically analyzed. In healthy Wistar and Sprague Dawley (SD) rats, the highest ratios of IMCL/tCr were found in young rats, and IMCL/tCr decreased with increasing age. In addition, IMCL concentration was clearly influenced by gender and muscle type. Insulin‐resistant, male, obese, Zucker diabetic fatty (ZDF) rats showed significantly higher IMCL levels than Wistar or SD rats. In conclusion, although IMCL levels are clearly influenced by insulin resistance, several other factors influence IMCL levels, such as age, gender, muscle type, and rat strain. Therefore, when using IMCL as a surrogate marker for insulin resistance, it is necessary to carefully compare results with age‐ and gender‐matched controls, and to use identical conditions. Magn Reson Med 50:242–248, 2003. © 2003 Wiley‐Liss, Inc.
    Type of Medium: Online Resource
    ISSN: 0740-3194 , 1522-2594
    URL: Issue
    URL: Article
    DOI: 10.1002/mrm.v50:2
    DOI: 10.1002/mrm.10518
    Language: English
    Publisher: Wiley
    Publication Date: 2003
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  • 7
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    In vivo neuroprotective effects of ACEA 1021 confirmed by magnetic resonance imaging in ischemic stroke
    Elsevier BV ; 2003
    In:  European Journal of Pharmacology Vol. 474, No. 1 ( 2003-8), p. 53-62
    Details
    In: European Journal of Pharmacology, Elsevier BV, Vol. 474, No. 1 ( 2003-8), p. 53-62
    Type of Medium: Online Resource
    ISSN: 0014-2999
    URL: Article
    DOI: 10.1016/S0014-2999(03)02002-8
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2003
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    SSG: 15,3
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  • 8
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    Quantitative Signal Intensity in Fluid-Attenuated Inversion Recovery and Treatment Effect in the WAKE-UP Trial
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Stroke Vol. 51, No. 1 ( 2020-01), p. 209-215
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 1 ( 2020-01), p. 209-215
    Abstract: Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (fluid-attenuated inversion recovery relative signal intensity [FLAIR-rSI]) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke Trial), intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of diffusion weighted imaging fluid-attenuated inversion recovery mismatch, that is, in those with no marked fluid-attenuated inversion recovery hyperintensity in the region of the acute diffusion weighted imaging lesion. In this post hoc analysis, we investigated whether quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods— FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analyzed by binary logistic regression using different end points, that is, favorable outcome defined as mRS score of 0 to 1, independent outcome defined as mRS score of 0 to 2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for National Institutes of Health Stroke Scale at symptom onset and stroke lesion volume. Results— FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD, 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS score of 0 to 1 ( P =0.169) and shift analysis ( P =0.086) but reached significance for mRS score of 0 to 2 ( P =0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical end points with increasing FLAIR-rSI. Conclusions— In patients in whom no marked parenchymal fluid-attenuated inversion recovery hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of diffusion weighted imaging lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.119.027390
    RVK:
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    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 9
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    Abstract 8779: Effect of Cathepsin a Inhibition on Cardiac Function and Remodeling in Rats with Heart Failure Induced by Ischemia and Long-Term Reperfusion
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation Vol. 124, No. suppl_21 ( 2011-11-22)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 124, No. suppl_21 ( 2011-11-22)
    Abstract: Introduction: Cathepsin A (CathA) is a lysosomal carboxypeptidase involved in the cardiac metabolism of various peptide hormones. Its expression is significantly upregulated in the border zone after myocardial infarction (MI) in rats. Affymetrix profiling in MI patients revealed a similar regulation. Method: Male Wistar rats were randomized in: (1) Sham-OP, (2) I/R-Placebo (I/R=30min ischemia/reperfusion of the left coronary artery), (3) I/R-ramipril (RA 1 mg/kg/d p.o.), (4) I/R - CathA Inhibitor SAR1 (SAR1 30 mg/kg/d p.o.). After 9 weeks of treatment a magnetic resonance imaging (MRI)-investigation was done. Thereafter, left ventricles (LV) were fixed for histological evaluation and gene expression analysis by Taqman PCR. Brain natriuretic peptide (BNP) was measured in serum by ELISA. Results: Inhibition of CathA with SAR1 attenuated left ventricular (LV) remodeling observed after I/R without altering blood pressure. MRI analysis revealed preserved ventricular wall geometry in infarcted and non-infarcted regions. Global parameters such as ejection fraction, cardiac output, stroke volume, end-diastolic volume, end-systolic volume and left ventricle peak filling rate were significantly improved during dobutamin stress when compared to placebo treated I/R-rats. Especially the regional parameters such as wall motion and systolic wall thickness were improved in the infarcted area and even normalized in the non-infarcted area in SAR-treated I/R-rats. In contrast, RA treatment did not prevent the adverse remodeling. In all parameters SAR1 was clearly superior to RA. Histological investigations confirmed the beneficial effects of SAR1 treatment and serum levels of BNP were significantly reduced in SAR1 treated animals. LV gene expression of TGFβ, ANP, collagen type III and CD14 was decreased by ramipril and SAR1 treatment. Conclusion: We identified hitherto unknown functions of CathA in cardiac disease. Especially the dramatic improvement in LV wall geometry after inhibition of CathA with SAR1 makes this enzyme a highly promising target for the treatment of post-MI heart failure patients. SAR1 has the potential to introduce a new treatment option for patients with acute MI to further preserve myocardial function on top of standard treatment.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.124.suppl_21.A8779
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
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  • 10
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    Muscle type-specific fatty acid metabolism in insulin resistance: an integrated in vivo study in Zucker diabetic fatty rats
    American Physiological Society ; 2006
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 290, No. 5 ( 2006-05), p. E989-E997
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 290, No. 5 ( 2006-05), p. E989-E997
    Abstract: Intramyocellular lipid content (IMCL) serves as a good biomarker of skeletal muscle insulin resistance (IR). However, intracellular fatty acid metabolites [malonyl-CoA, long-chain acyl-CoA (LCACoA)] rather than IMCL are considered to be responsible for IR. This study aimed to investigate dynamics of IMCL and fatty acid metabolites during fed-to-starved-to-refed transition in lean and obese (IR) Zucker diabetic fatty rats in the following different muscle types: soleus (oxidative), extensor digitorum longus (EDL, intermediary), and white tibialis anterior (wTA, glycolytic). In the fed state, IMCL was significantly elevated in obese compared with lean rats in all three muscle types (soleus: 304%, EDL: 333%, wTA: 394%) in the presence of elevated serum triglycerides but similar levels of free fatty acids (FFA), malonyl-CoA, and total LCACoAs. During starvation, IMCL in soleus remained relatively constant, whereas in both rat groups IMCL increased significantly in wTA and EDL after comparable dynamics of starvation-induced FFA availability. The decreases of malonyl-CoA in wTA and EDL during starvation were more pronounced in lean than in obese rats, although there were no changes in soleus muscles for both groups. The concomitant increase in IMCL with the fall of malonyl-CoA support the concept that, as a reaction to starvation-induced FFA availability, muscle will activate lipid oxidation more the lower its oxidative capacity and then store the rest as IMCL.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00459.2005
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2006
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    detail.hit.zdb_id: 603841-4
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