Acute aortic dissection is a rare but life-threatening condition with a lethality rate of 1 to 2% per hour after onset of symptoms in untreated patients. Therefore, its prompt and proper diagnosis is vital to increase a patient's chance of survival and to prevent grievous complications. Typical symptoms of acute aortic dissection include severe chest pain, hypotension or syncope and, hence, mimic acute myocardial infarction or pulmonary embolism. Advanced age, male gender, long-term history of arterial hypertension and the presence of aortic aneurysm confer the greatest population attributable risk. However, patients with genetic connective tissue disorders such as Marfan, Loeys Dietz or Ehlers Danlos syndrome, and patients with bicuspid aortic valves are at the increased risk of aortic dissection at a much younger age. Imaging provides a robust foundation for diagnosing acute aortic dissection, as well as for monitoring of patients at increased risk of aortic disease. As yet, easily accessible blood tests play only a small role but have the potential to make diagnosis and monitoring of patients simpler and more cost-effective.
To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt–Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study (‘cerebrospinal fluid markers’) we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-β1–42) and evaluated the specificity of 14-3-3 in Creutzfeldt–Jakob disease diagnosis for the years 1998–2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt–Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt–Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt–Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95–97%) and non-neurological conditions (91–97%). We observed lower specificity in the differential diagnoses of acute neurological diseases (82–87%). A marked and constant increase in cerebrospinal fluid test referrals per year in all centres did not influence 14-3-3 test specificity and no change in spectrum of differential diagnosis was observed. Cerebrospinal fluid protein 14-3-3 detection remains an important test in the diagnosis of Creutzfeldt–Jakob disease. Due to a loss in specificity in acute neurological events, the interpretation of positive 14-3-3 results needs to be performed in the clinical context. The spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions such as inflammatory diseases and non-neurological origin.
BackgroundFabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene causing deficiency of α-galactosidase A which results in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3), in body liquids and lysosomes. In a large cohort of FD patients, we aimed to establish genotype/phenotype relations as indicated by serum LysoGb3 (deacylated Gb3). MethodsIn 69 consecutive adult FD patients (males: n=28 (41%)) with a GLA-mutation confirmed diagnosis, we conducted a multidisciplinary clinical characterization during their routine annual examinations, and measured serum LysoGb3 levels by highsensitive electrospray ionization liquid chromatography tandem mass spectrometry. ResultsSerum levels of LysoGb3 were significantly higher in Classic compared with LaterOnset phenotype and higher in the latter compared with controls, both in males (52
The 14-3-3 protein test has been shown to support the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) when associated with an adequate clinical context, and a high differential potential for the diagnosis of sporadic CJD has been attributed to other cerebrospinal fluid (CSF) proteins such as tau protein, S100b and neuron specific enolase (NSE). So far there has been only limited information available about biochemical markers in genetic transmissible spongiform encephalopathies (gTSE), although they represent 10–15% of human TSEs. In this study, we analyzed CSF of 174 patients with gTSEs for 14-3-3 (n = 166), tau protein (n = 78), S100b (n = 46) and NSE (n = 50). Levels of brain-derived proteins in CSF varied in different forms of gTSE. Biomarkers were found positive in the majority of gCJD (81%) and insert gTSE (69%), while they were negative in most cases of fatal familial insomnia (13%) and Gerstmann-Sträussler-Scheinker syndrome (10%). Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD.
Transmissible spongiform encephalopathies such as scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and bovine sporadic encephalopathy in cattle are characterized by the accumulation of a misfolded protein: the pathological prion protein. Ever since bovine sporadic encephalopathy was discovered as the likely cause of the new variant of CJD in humans , parallels between human and animal transmissible spongiform encephalopathies must be viewed under the aspect of a disease risk for humans. In our study we have compared prion characteristics of different forms of sheep scrapie with those of different phenotypes of sporadic CJD. The disease characteristics of sporadic CJD depend considerably on the prion type 1 or 2. Our results show that there are obvious parallels between sporadic CJD type 1 and the so-called atypical/Nor98 scrapie. These parelleles apply to the deposition form of pathological prion protein in the brain, detected by the paraffin-embedded-tissue blot and the prion aggregate stability with regard to denaturation by the chaotropic salt guanidine hydrochloride. The same applies to sporadic CJD type 2 and classical scrapie. The observed parallels between types of sporadic CJD and types of sheep scrapie demonstrate that distinct groups of prion disease exist in different species. This should be taken into consideration when discussing interspecies transmission.
Background: The 8-hydroxy-2 deoxyguanosine (8-OHdG) is a product of nucleoside oxidation of DNA and a reliable marker of oxidative stress markers. Increased levels of oxidative stress have been reported in the cerebrospinal fluid (CSF) of patients with various neurodegenerative disorders. Objective: In search of a biochemical indicator of Parkinson’s disease (PD), we analyzed the levels 8-OHdG in the CSF of 99 patients, using ELISA to assess the differences between various neurodegenerative disorders. Results: Statistically significant higher CSF levels (p = 0.022) of 8-OHdG in non-demented PD patients as compared to the control group were observed. No differences between CSF 8-OHdG levels and age at the time of lumbar puncture, presence or severity of dementia, or gender were found. Conclusions: 8-OHdG levels could be potentially useful in the neurochemically supported diagnosis of PD.
Background: Cardiac troponin T (cTnT) and cTnI are considered cardiac-specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a non-cardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMD). Methods: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in four hospitals in two countries. After cardiac work-up, patients were adjudicated into three predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed using high-sensitivity cTnT (hs-cTnT-Elecsys) and three hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista), and compared to controls without SMD presenting with adjudicated non-cardiac chest pain to the emergency department (n=3508, mean age 55y, 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared to biopsies obtained in controls without SMD. Results: Among 211 patients (mean age 57y, 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) mild and 59 (28%) severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no versus mild versus severe cardiac disease for all assays (all p<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus controls (median 16ng/L (IQR 7-32.5) versus 5ng/L (IQR 3-9), p<0.001) while hs-cTnI concentrations were mostly similar (hs-cTnI-Architect 2.5ng/L (IQR 1.2-6.2) versus 2.9ng/L (IQR 1.8-5.0), hs-cTnI-Access 3.3ng/L (IQR 2.4-6.1) versus 2.7ng/L (IQR 1.6-5.0) and hs-cTnI-Vista 7.4ng/L (IQR 5.2-13.4) versus 7.5ng/L (IQR 6-10)). hs-cTnT-Elecsys concentrations were above the upper-limit of normal (ULN) in 55% of patients with SMD vs 13% of controls (p<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from non-inflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI); versus controls (n=16, pWald <0.001), the expression correlated with pathological disease activity (R=0.59, pt-statistic <0.001) and circulating hs-cTnT concentrations (R=0.26, pt-statistic =0.031). Conclusions: In patients with active chronic SMD, elevations in cTnT concentrations are common and not due to cardiac disease in the majority. This was not observed for cTnI, and may in part be explained by re-expression of cTnT in skeletal muscle.
These findings may help to elucidate the disease mechanisms and confirm the hypothesis of disturbed cholesterol and phospholipid metabolism in schizophrenia, and thus reveal the final role players. Moreover, a grouped protein expression analysis of apolipoprotein E, apolipoprotein A-I, and prostaglandin-H2 D-isomerase in cerebrospinal fluid from patients might be a potential diagnostic tool for schizophrenia.
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