TY  - JOUR
A1  - Panayotova-Dimitrova, Diana
A1  - Feoktistova, Maria
A1  - Ploesser, Michaela
A1  - Kellert, Beate
A1  - Hupe, Mike
A1  - Horn, Sebastian
A1  - Makarov, Roman
A1  - Jensen, Federico
A1  - Porubsky, Stefan
A1  - Schmieder, Astrid
A1  - Zenclussen, Ana Claudia
A1  - Marx, Alexander
A1  - Kerstan, Andreas
A1  - Geserick, Peter
A1  - He, You-Wen
A1  - Leverkus, Martin
T1  - cFLIP Regulates Skin Homeostasis and Protects against TNF-Induced Keratinocyte Apoptosis
JF  - Cell Reports
N2  - FADD, caspase-8, and cFLIP regulate the outcome of cell death signaling. Mice that constitutively lack these molecules die at an early embryonic age, whereas tissue-specific constitutive deletion of FADD or caspase-8 results in inflammatory skin disease caused by increased necroptosis. The function of cFLIP in the skin in vivo is unknown. In contrast to tissue-specific caspase-8 knockout, we show that mice constitutively lacking cFLIP in the epidermis die around embryonic days 10 and 11. When cFLIP expression was abrogated in adult skin of cFLIP(fl/fl)-K14CreER(tam) mice, severe inflammation of the skin with concomitant caspase activation and apoptotic, but not necroptotic, cell death developed. Apoptosis was dependent of autocrine tumor necrosis factor production triggered by loss of cFLIP. In addition, epidermal cFLIP protein was lost in patients with severe drug reactions associated with epidermal apoptosis. Our data demonstrate the importance of cFLIP for the integrity of the epidermis and for silencing of spontaneous skin inflammation.
KW  - eczematous dermatitis
KW  - programmed necrosis
KW  - gene induction
KW  - in-vivo
KW  - activation
KW  - mediated apoptosis
KW  - c-flip
KW  - cell-death
KW  - Stevens-Johnson syndrome
KW  - toxic epidermal necrolysis
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122155
VL  - 5
ER  - 
TY  - JOUR
A1  - Klingler, Werner
A1  - Heiderich, Sebastian
A1  - Girard, Thierry
A1  - Gravino, Elvira
A1  - Heffron, James J. A.
A1  - Johannsen, Stephan
A1  - Jurkat-Rott, Karin
A1  - Rüffert, Henrik
A1  - Schuster, Frank
A1  - Snoeck, Marc
A1  - Sorrentino, Vincenzo
A1  - Tegazzin, Vincenzo
A1  - Lehmann-Horn, Frank
T1  - Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study
JF  - Orphanet Journal of Rare Diseases
N2  - Background: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. 
Methods: In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro. 
Results: A total of 200 patients met the inclusion criteria. Two MH crises (1%) were triggered by SCh (1 MHS, 1 MHE), 18% by volatile anesthetics and 81% by a combination of both. Patients were 70% male and 50% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles. 
Conclusions: An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.
KW  - susceptibility
KW  - central core disease
KW  - skeletal muscle
KW  - North American
KW  - malignant hyperthermia
KW  - succinylcholine
KW  - suxamethonium
KW  - volatile anesthetics
KW  - RyR1 mutations
KW  - New Zealand
KW  - inhalation anesthetics
KW  - sarcoplasmic reticulum
KW  - ryanodine receptor gene
KW  - vitro contracture test
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117630
SN  - 1750-1172
VL  - 9
IS  - 8
ER  -