RepoMed (Medizinische Hochschule Hannover)
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HLA-F Allele-Specific Peptide Restriction Represents an Exceptional Proteomic Footprint.
No full textPeptide-dependent engagement between human leucocyte antigens class I (HLA-I) molecules and their cognate receptors has been extensively analyzed. HLA-F belongs to the non-classical HLA-Ib molecules with marginal polymorphic nature and tissue restricted distribution. The three common allelic variants HLA-F*01:01/01:03/01:04 are distinguished by polymorphism outside the peptide binding pockets (residue 50, α1 or residue 251, α3) and are therefore not considered relevant for attention. However, peptide selection and presentation undergoes a most elaborated extraction from the whole available proteome. It is known that HLA-F confers a beneficial effect on disease outcome during HIV-1 infections. The interaction with the NK cell receptor initiates an antiviral downstream immune response and lead to delayed disease progression. During the time of HIV infection, HLA-F expression is upregulated, while its interaction with KIR3DS1 is diminished. The non-polymorphic nature of HLA-F facilitates the conclusion that understanding HLA-F peptide selection and presentation is essential to a comprehensive understanding of this dynamic immune response. Utilizing soluble HLA technology we recovered stable pHLA-F*01:01, 01:03 and 01:04 complexes from K562 cells and analyzed the peptides presented. Utilizing a sophisticated LC-MS-method, we analyzed the complete K562 proteome and matched the peptides presented by the respective HLA-F subtypes with detected proteins. All peptides featured a length of 8 to 24 amino acids and are not N-terminally anchored; the C-terminus is preferably anchored by Lys. To comprehend the alteration of the pHLA-F surface we structurally compared HLA-F variants bound to selected peptides. The peptides were selected from the same cellular content; however, no overlap between the proteomic source of F*01:01, 01:03 or 01:04 selected peptides could be observed. Recognizing the balance between HLA-F expression, HLA-F polymorphism and peptide selection will support to understand the role of HLA-F in viral pathogenesis
Das Lidocainderivat QX-314 permeiert die humane Isoform von TRPV1 und vermittelt eine Inhibition spannungsabhängiger Natriumkanäle
Get PDFAltered Neurometabolic Profile in Early Parkinson's Disease: A Study With Short Echo-Time Whole Brain MR Spectroscopic Imaging.
No full textObjective: To estimate alterations in neurometabolic profile of patients with early stage Parkinson's disease (PD) by using a short echo-time whole brain magnetic resonance spectroscopic imaging (wbMRSI) as possible biomarker for early diagnosis and monitoring of PD. Methods: 20 PD patients in early stage (H&Y ≤ 2) without evidence of severe other diseases and 20 age and sex matched healthy controls underwent wbMRSI. In each subject brain regional concentrations of metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), glutamine (Gln), glutamate (Glu), and myo-inositol (mIns) were obtained in atlas-defined lobar structures including subcortical basal ganglia structures (the left and right frontal lobes, temporal lobes, parietal lobes, occipital lobes, and the cerebellum) and compared between patients and matched healthy controls. Clinical characteristics of the PD patients were correlated with spectroscopic findings. Results: In comparison to controls the PD patients revealed altered lobar metabolite levels in all brain lobes contralateral to dominantly affected body side, i.e., decreases of temporal NAA, Cho, and tCr, parietal NAA and tCr, and frontal as well as occipital NAA. The frontal NAA correlated negatively with the MDS-UPDRS II (R = 22120.585, p = 0.008), MDS-UPDRS IV (R = -0.458, p = 0.048) and total MDS-UPDRS scores (R = -0.679, p = 0.001). Conclusion: In early PD stages metabolic alterations are evident in all contralateral brain lobes demonstrating that the neurodegenerative process affects not only local areas by dopaminergic denervation, but also the functional network within different brain regions. The wbMRSI-detectable brain metabolic alterations reveal the potential to serve as biomarkers for early PD
Common pre-diagnostic features in individuals with different rare diseases represent a key for diagnostic support with computerized pattern recognition?
Get PDFBACKGROUND:Rare diseases (RD) result in a wide variety of clinical presentations, and this creates a significant diagnostic challenge for health care professionals. We hypothesized that there exist a set of consistent and shared phenomena among all individuals affected by (different) RD during the time before diagnosis is established. OBJECTIVE:We aimed to identify commonalities between different RD and developed a machine learning diagnostic support tool for RD. METHODS:20 interviews with affected individuals with different RD, focusing on the time period before their diagnosis, were performed and qualitatively analyzed. Out of these pre-diagnostic experiences, we distilled key phenomena and created a questionnaire which was then distributed among individuals with the established diagnosis of i.) RD, ii.) other common non-rare diseases (NRO) iii.) common chronic diseases (CD), iv.), or psychosomatic/somatoform disorders (PSY). Finally, four combined single machine learning methods and a fusion algorithm were used to distinguish the different answer patterns of the questionnaires. RESULTS:The questionnaire contained 53 questions. A total sum of 1763 questionnaires (758 RD, 149 CD, 48 PSY, 200 NRO, 34 healthy individuals and 574 not evaluable questionnaires) were collected. Based on 3 independent data sets the 10-fold stratified cross-validation method for the answer-pattern recognition resulted in sensitivity values of 88.9% to detect the answer pattern of a RD, 86.6% for NRO, 87.7% for CD and 84.2% for PSY. CONCLUSION:Despite the great diversity in presentation and pathogenesis of each RD, patients with RD share surprisingly similar pre-diagnosis experiences. Our questionnaire and data-mining based approach successfully detected unique patterns in groups of individuals affected by a broad range of different rare diseases. Therefore, these results indicate distinct patterns that may be used for diagnostic support in RD
Mikroleakage an implantatgetragenen Brücken: eine In-vitro-Untersuchung an CAD/CAM-gefertigten mehrspannigen Brücken auf Implantat- und Abutment-Level
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Transmurale linksventrikuläre Unterschiede des Remodelings in einem Tiermodell der Herzinsuffizienz mit erhaltener Ejektionsfraktion
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Public preferences for primary care provision in Germany - a discrete choice experiment.
No full textBACKGROUND:Primary care is a central element of healthcare and addresses the main health problems of the population. While primary care gains in importance due to an aging population, there is an ongoing debate on physician shortages in German rural regions. The study aims on analyzing the population's preferences on primary healthcare and, therefore, on helping policy makers to make care delivery more responsive to patients' needs when planning political reforms of primary care. METHODS:A paper-based discrete choice experiment (DCE) was used to assess preferences of the population of eight rural regions in Germany. Based on literature search and qualitative research, six attributes were selected and included in the choice experiment. The survey presented participants with eight choice sets in which they had to choose between two possible scenarios of care. A conditional logistic regression as well as a latent class model (LCM) were used to analyze preferences for primary healthcare. RESULTS:Nine hundred four participants completed the survey (response rate 46.1%). The conditional logistic regression showed significant impact of the attributes "home visits", "distance to practice", "number of healthcare providers", "opening hours of the practice", and "diagnostic facilities" on the respondents' choices of primary healthcare alternatives. Moreover, the LCM identified four classes that can be characterized by preference homogeneity within and heterogeneity between the classes. CONCLUSION:Although the study revealed heterogeneous preferences among the latent classes, several similarities in preferences for primary care could be detected. The knowledge on these public preferences may help policy makers when implementing new models of primary care and, thus, raise the populations' acceptance of future primary care provision and innovative care models
Cerebral metabolite alterations in patients with posttransplant encephalopathy after liver transplantation.
Get PDFBACKGROUND:In the first weeks after liver transplantation about 30% of the patients develop a posttransplant encephalopathy. A posttransplant encephalopathy comprises metabolic-toxic caused symptoms such as disorientation, confusion, hallucinations, cognitive dysfunction and seizures. We hypothesize that alterations of cerebral metabolites before liver transplantation predispose posttransplant encephalopathy development after liver transplantation. METHODS:31 patients with chronic liver disease underwent magnetic resonance spectroscopy (MRS) before liver transplantation to assess glutamine/glutamate (Glx), myo-Inositol (mI), choline (Cho), creatine/phosphocreatine- and N-acetyl-aspartate/N-acetyl-aspartate-glutamate concentrations in the thalamus, lentiform nucleus and white matter. Of these, 14 patients underwent MRS additionally after liver transplantation. Furthermore, 15 patients received MRS only after liver transplantation. Patients' data were compared to 20 healthy age adjusted controls. RESULTS:Patients showed significantly increased Glx and decreased mI and Cho concentrations compared to controls before liver transplantation (p≤0.01). The MRS values before liver transplantation of patients with posttransplant encephalopathy showed no significant difference compared to patients without posttransplant encephalopathy. Patients after liver transplantation showed increased Glx concentrations (p≤0.01) compared to controls, however, patients with and without posttransplant encephalopathy did not differ. Patients with posttransplant encephalopathy who underwent MRS before and after liver transplantation showed a significant mI increase in all three brain regions (p<0.04) and Glx decrease in the lentiform nucleus after liver transplantation (p = 0.04) while patients without posttransplant encephalopathy only showed a mI increase in the thalamus (p = 0.04). CONCLUSION:Patients with and without posttransplant encephalopathy showed no significant difference in cerebral metabolites before liver transplantation. However, the paired sub-analysis indicates that the extent of cerebral metabolite alterations in patients with liver cirrhosis might be critical for the development of posttransplant encephalopathy after liver transplantation