Lars Alexander Schneider

Molecular mechanism of mast cell–mediated innate defense against endothelin and snake venom sarafotoxin

Mast cells are protective against snake venom sarafotoxins that belong to the endothelin (ET) peptide family. The molecular mechanism underlying this recently recognized innate defense pathway is unknown, but secretory granule proteases have been invoked. To specifically disrupt a single protease function without affecting expression of other proteases, we have generated a mouse mutant selectively lacking mast cell carboxypeptidase A (Mc-cpa) activity. Using this mutant, we have now identified Mc-cpa as the essential protective mast cell enzyme. Mass spectrometry of peptide substrates after cleavage by normal or mutant mast cells showed that removal of a single amino acid, the C-terminal tryptophan, from ET and sarafotoxin by Mc-cpa is the principle molecular mechanism underlying this very rapid mast cell response. Mast cell proteases can also cleave ET and sarafotoxin internally, but such “nicking” is not protective because intramolecular disulfide bridges maintain peptide function. We conclude that mast cells attack ET and sarafotoxin exactly at the structure required for toxicity, and hence sarafotoxins could not “evade” Mc-cpas substrate specificity without loss of toxicity.

Unexpected delayed-type hypersensitivity skin reactions to the ultra-low-molecular-weight heparin fondaparinux

(a) lactose is obtained from whey by ultrafiltration; (b) lactose is hydrolyzed to galactose and glucose by immobilized lactase; (c) glucose is separated from the galactose by chromatographic separation; (d) the galactose stream is isomerized to tagatose by adding calcium hydroxide in a process that increases the pH to pH 12 for a prolonged period; (e) the tagatose stream is demineralized using ion exchangers; (f) the tagatose stream is purified by chromatographic separation; (g) the tagatose solution is decolorized using an active carbon filter; (h) tagatose is crystallized; (i) the tagatose is dried by fluid-bed drying.

Protective and determining factors for the overall lipid peroxidation in ultraviolet A1-irradiated fibroblasts: in vitro and in vivo investigations.

Summary  Background Lipid peroxidation (LPO) is one major effector mechanism by which ultraviolet (UV) A contributes to photoageing and the promotion of skin cancer. It is a fingerprint of photo‐oxidative stress within the skin, and is initiated by several pathways, with different reactive oxygen species (ROS) and iron ions being involved.

Adaptive cellular protection against UVA-1-induced lipid peroxidation in human dermal fibroblasts shows donor-to-donor variability and is glutathione dependent.

Photo-oxidative stress and subsequent lipid peroxidation (LPO) is one of the major mechanisms of UVA-related skin pathology. The skin’s protection system against photo-oxidative stress involves low molecular scavengers as well as highly specialised antioxidant enzymes like glutathione peroxidase (GPX). Against repetitive UVA-1 exposures in vitro it is partly adaptive, as recent studies have shown exemplarily for antioxidant enzymes. We now investigated in vitro by repetitively irradiating human dermal fibroblasts with UVA-1 whether this adaptive response might reflect itself in reduced cellular membrane damage, that is, LPO. Our experiments show that the degree of cellular protection against LPO and the adaptive potential of the cells against a repetitive UVA-1 exposure varies from donor-to-donor and depends highly on glutathione.

Cutaneous leukaemic infiltrations in a patient with previously undiagnosed myelodysplastic syndrome.

We report the rare case of a patient with leukaemia cutis first presenting only on the hand and fingers and then subsequently spreading over the trunk and face. The lesions heralded the transformation of a previously undiagnosed myelodysplastic syndrome type RAEB (refractory anaemia with blast excess) into frank myeloid leukaemia. The haematological disease was first detected by the dermatohistopathologist. This case underlines the need to look meticulously for skin changes and perform early skin biopsies in haematological patients, as the skin can reveal the first clinical signs of an otherwise not evident bone marrow disorder. Leukaemia cutis as the initial clinical presentation of a transforming myelodysplastic syndrome type RAEB into acute myeloid leukaemia has been reported only very rarely.

Surgical treatment of melanoma in pregnancy: a practical guideline.

A tumor primarily requiring surgical treatment, newly diagnosed or preexisting melanoma during pregnancy is a clinical rarity. In such cases, the surgeon faces the challenge of having to decide on the appropriate therapeutic course of action. Based on our clinical experience and a review of the literature, we herein provide a guideline on how to practically deal with this rare clinical conundrum. In our experience, pregnant melanoma patients require thorough counseling with respect to their therapeutic options. They naturally tend to put their unborn child first, and are hesitant to consent to necessary surgery despite a potentially life‐threatening diagnosis. It is therefore crucial to clearly inform these patients that – based on existing medical experience – pregnancy by itself is no reason to hold off on any type of necessary melanoma surgery. However, various parameters such as preoperative imaging procedures, positioning on the operating table, monitoring, anesthesia, and perioperative medication require certain adjustments in order to comply with this special situation.

C1-INH and C3/C4 levels do not correlate with long-term danazole dosage and HAE-1 attack-free interval.

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Intermittent vemurafenib therapy in malignant melanoma: Correspondence

Herein, we report on three female patients with inoperable stage IIIC and IV, BRAF V600E-mutant melanoma treated with intermittent dosing of the BRAF inhibitor vemurafenib. Common to all three patients, enrollment in a study was neither feasible nor requested, and – due to drug toxicity – continuous treatment (even following dose reduction in order to manage side effects) was not tolerated, either. On intermittent therapy, consisting of four weeks of the maximum tolerable vemurafenib dose followed by a two-week treatment-free interval, all three patients showed stable disease for at least 24 months.

When professional forceps are not available: Efficient tick removal using a no. 15 scalpel as a spade

Ticks are nasty parasites which often move to the armpits, groins and the neck. The bite is painless. Therefore many patients will not notice the bite immediately and present themselves to an emergency department at night. Ticks transmit a variety of serious bacterial infections. The most common ones are Lyme borreliosis, tularaemia, Rocky Mountain spotted fever and Q-fever [1]. Apart from bacteria, they transmit several virus-associated fever and encephalitis syndromes [2-4]. Around 15-30% of the [...]

Self-detection frequency and recognition patterns in medium to high-risk cutaneous melanoma patients

The question of how frequently patients with medium to high‐risk melanomas become aware of their tumors and which self‐detection patterns exist remains unanswered.