RepoMed (Medizinische Hochschule Hannover)
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The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity.
No full textDrug hypersensitivity reactions that resemble acute immune reactions are linked to certain human leucocyte antigen (HLA) alleles. Severe and life-threatening Stevens Johnson Syndrome and Toxic Epidermal Necrolysis following treatment with the antiepileptic and psychotropic drug Carbamazepine are associated with HLA-B*15:02; whereas carriers of HLA-A*31:01 develop milder symptoms. It is not understood how these immunogenic differences emerge genotype-specific. For HLA-B*15:02 an altered peptide presentation has been described following exposure to the main metabolite of carbamazepine that is binding to certain amino acids in the F pocket of the HLA molecule. The difference in the molecular mechanism of these diseases has not been comprehensively analyzed, yet; and is addressed in this study. Soluble HLA-technology was utilized to examine peptide presentation of HLA-A*31:01 in presence and absence of carbamazepine and its main metabolite and to examine the mode of peptide loading. Proteome analysis of drug-treated and untreated cells was performed. Alterations in sA*31:01-presented peptides after treatment with carbamazepine revealed different half-life times of peptide-HLA- or peptide-drug-HLA complexes. Together with observed changes in the proteome elicited through carbamazepine or its metabolite these results illustrate the mechanistic differences in carbamazepine hypersensitivity for HLA-A*31:01 or B*15:02 patients and constitute the bridge between pharmacology and pharmacogenetics for personalized therapeutics
Klinische und radiologische Ergebnisse von individuell angefertigtem Beckenteilersatz bei ausgedehnten azetabulären Defekten
Get PDFFormation of three-dimensional tubular endothelial cell networks under defined serum-free cell culture conditions in human collagen hydrogels
Get PDFImplementation of tubular endothelial cell networks is a prerequisite for 3D
tissue engineering of constructs with clinically relevant size as nourishment of
cells is challenged by the diffusion limit. In vitro generation of 3D networks is
often achieved under conditions using serum containing cell culture medium and/or
animal derived matrices. Here, 3D endothelial cell networks were generated by
using human umbilical vein endothelial cells (HUVECs) in combination with human
adipose tissue derived stromal cells (hASCs) employing human collagen I as
hydrogel and decellularized porcine small intestinal submucosa as starter matrix.
Matrigel/rat tail collagen I hydrogel was used as control. Resulting constructs
were cultivated either in serum-free medium or in endothelial growth medium-2
serving as control. Endothelial cell networks were quantified, tested for lumen
formation, and interaction of HUVECs and hASCs. Tube diameter was slightly larger
in constructs containing human collagen I compared to Matrigel/rat tail collagen
I constructs under serum-free conditions. All other network parameters were
mostly similar. Thereby, the feasibility of generating 3D endothelial cell
networks under serum-free culture conditions in human collagen I as hydrogel was
demonstrated. In summary, the presented achievements pave the way for the
generation of clinical applicable construct
A sensitive scoring system for the longitudinal clinical evaluation and prediction of lethal disease outcomes in newborn mice
No full textNeonatal animal models are increasingly employed in order to unravel age-specific disease mechanisms. Appropriate tools objectifying the clinical condition of murine neonates are lacking. In this study, we tested a scoring system specifically designed for newborn mice that relies on clinical observation and examination. Both, in a neonatal sepsis model and an endotoxic shock model, the scoring results strongly correlated with disease-induced death rates. Full as well as observation-restricted scoring, reliably predicted fatality and the remaining time until death. Clinical scores even proved as more sensitive biomarker than 6 traditionally used plasma cytokine levels in detecting sepsis at an early disease stage. In conclusion, we propose a simple scoring system that detects health impairments of newborn mice in a non-invasive longitudinal and highly sensitive manner. Its usage will help to meet animal welfare requirements and might improve the understanding of neonatal disease mechanism
Hypersexual behavior in a large online sample: Individual characteristics and signs of coercive sexual behavior
No full textBACKGROUND AND AIMS: Despite the high prevalence of perceived problems relating
to symptoms of hypersexual disorder (HD), important aspects remain
underinvestigated. This study examines symptoms of depression, symptoms of
problematic cybersex, and coercive sexual behavior in a large online sample from
a German-speaking population. METHODS: In an online survey, N = 1,194 (n = 564
women) participated in this study and completed measures including self-report
questionnaires to assess depressive symptoms (PHQ-9), HD (HBI-19), symptoms of
problematic cybersex (s-IATsex), as well as questions characterizing participants
sexually, including fantasies and actual sexual coercive behaviors. RESULTS: Men
reported increased levels of HD symptom severity, pornography consumption,
masturbation, and partnered sexual activity. Moreover, 59% of men and 18% of
women reported fantasies of sexual coercion, whereas 21% of men and 4% of women
reported acts of sexual coercion. Moderated regression analyses showed that
symptoms of depression as well as sexual coercive fantasies and behaviors were
associated with levels of HD symptom severity. Problematic cybersex, total sexual
outlet (TSO), pornography consumption, and number of sexual partners were also
associated with HD symptom severity. Interaction effects indicated that, in
women, the connection of TSO as well as pornography was more strongly associated
with levels of HD symptom severity than in men. CONCLUSIONS: This survey
indicated that levels of HD symptom severity are often associated with severe
intra- and interpersonal difficulties. Furthermore, the amount of sexual activity
seems to be more strongly connected to levels of HD symptom severity in women
than in me
Hepatobiliary Events in Migraine Therapy with Herbs—The Case of Petadolex, A Petasites Hybridus Extract
No full textPetadolex((R)), a defined butterbur extract has clinically proven efficacy against migraine attacks. However, spontaneous reports indicate cases of herbal induced liver injury (HILI). While most HILI patients presented mild serum biochemistry changes (45 and 90-fold MCD bile duct hyperplasia was observed but could not be confirmed in an explorative minipig study at 218-fold MCD. Human hepatocyte studies at 49-fold Cmax serum petasins (=active ingredient) and therapeutic Ibuprofen, Paracetamol and Naratriptan concentrations evidenced liver transaminase and CYP-monooxygenase changes. Collectively, Petadolex((R)) HILI cases are rare, idiosyncratic and frequently confounded by co-medications. A physician-supervised self-medication plan with herbs and pain relief medication is needed to minimize risk for HIL
Routine Cerebrospinal Fluid Cytology Reveals Unique Inclusions in Macrophages During Treatment With Nusinersen
No full textBackground: Spinal muscular atrophy (SMA) is an autosomal recessive
neurodegenerative disorder characterized by degeneration of spinal motor neurons
leading to muscular weakness. The antisense oligonucleotide nusinersen was
approved for the treatment of patients with 5q-associated SMA. Treatment must be
repeatedly administered intrathecally by lumbar puncture. So far, data regarding
cerebrospinal fluid (CSF) parameters are sparse and examinations of CSF cytology
during nusinersen treatment are completely missing. Methods: 87 CSF samples from
19 adult SMA patients who underwent repeated lumbar punctures for intrathecal
injections of nusinersen were investigated. CSF specimens were quantitatively
assessed regarding leukocyte subpopulations by routine cytology after Pappenheim
staining. A control group with 38 CSF samples from 10 patients with repeated
lumbar punctures due to other diseases was used. Results: Treatment with
nusinersen did not result in persistent inflammatory cellular changes or a
relevant shift of leukocyte subpopulations in the CSF. During nusinersen therapy
unique macrophages with numerous sharply defined purple and granular inclusions
were detected in all patients. These macrophages were not found in CSF of
patients with other diseases who underwent repeated lumbar punctures. Discussion:
Routine CSF cytology performed by experienced personnel represents an important
and feasible tool for safety monitoring during treatment with intrathecally
administered therapeutics. Analysis of leukocyte subpopulations did not raise
safety concerns during nusinersen therapy. The potential significance of the
unique phagocytic cells for disease course and treatment response needs to be
further elucidated in the futur
Sturzrisiko-Assessment neurologischer Rehabilitanden: Überprüfung der Hessisch Oldendorfer Sturzrisiko-Skala (HOSS) : eine Beobachtungsstudie
No full textCADDIE2 - evaluation of a clinical decision-support system for early detection of systemic inflammatory response syndrome in paediatric intensive care: study protocol for a diagnostic study
No full textINTRODUCTION: Systemic inflammatory response syndrome (SIRS) is one of the most critical indicators determining the clinical outcome of paediatric intensive care patients. Clinical decision support systems (CDSS) can be designed to support clinicians in detection and treatment. However, the use of such systems is highly discussed as they are often associated with accuracy problems and 'alert fatigue'. We designed a CDSS for detection of paediatric SIRS and hypothesise that a high diagnostic accuracy together with an adequate alerting will accelerate the use. Our study will (1) determine the diagnostic accuracy of the CDSS compared with gold standard decisions created by two blinded, experienced paediatricians, and (2) compare the system's diagnostic accuracy with that of routine clinical care decisions compared with the same gold standard. METHODS AND ANALYSIS: CADDIE2 is a prospective diagnostic accuracy study taking place at the Department of Pediatric Cardiology and Intensive Care Medicine at the Hannover Medical School; it represents the second step towards our vision of cross-institutional and data-driven decision-support for intensive care environments (CADDIE). The study comprises (1) recruitment of up to 300 patients (start date 1 August 2018), (2) creation of gold standard decisions (start date 1 May 2019), (3) routine SIRS assessments by physicians (starts with recruitment), (4) SIRS assessments by a CDSS (start date 1 May 2019), and (5) statistical analysis with a modified approach for determining sensitivity and specificity and comparing the accuracy results of the different diagnostic approaches (planned start date 1 July 2019). ETHICS AND DISSEMINATION: Ethics approval was obtained at the study centre (Ethics Committee of Hannover Medical School). Results of the main study will be communicated via publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03661450; Pre-result