The Cutaneous Lesions of Dioxin Exposure: Lessons from the Poisoning of Victor Yushchenko

Several million people are exposed to dioxin and dioxin-like compounds, primarily through food consumption. Skin lesions historically called "chloracne” are the most specific sign of abnormal dioxin exposure and classically used as a key marker in humans. We followed for 5 years a man who had been exposed to the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), at a single oral dose of 5 million-fold more than the accepted daily exposure in the general population. We adopted a molecular medicine approach, aimed at identifying appropriate therapy. Skin lesions, which progressively covered up to 40% of the body surface, were found to be hamartomas, which developed parallel to a complete and sustained involution of sebaceous glands, with concurrent transcriptomic alterations pointing to the inhibition of lipid metabolism and the involvement of bone morphogenetic proteins signaling. Hamartomas created a new compartment that concentrated TCDD up to 10-fold compared with serum and strongly expressed the TCDD-metabolizing enzyme cytochrome P450 1A1, thus representing a potentially significant source of enzymatic activity, which may add to the xenobiotic metabolism potential of the classical organs such as the liver. This historical case provides a unique set of data on the human tissue response to dioxin for the identification of new markers of exposure in human populations. The herein discovered adaptive cutaneous response to TCDD also points to the potential role of the skin in the metabolism of food xenobiotic

Gegenüberstellung der operativen Thrombembolektomie zur endovaskulären Therapie bei der akuten Beinischämie

Fragestellung: Endovaskuläre (ER) und offen-chirurgische (OR) Therapien sind derzeitige Optionen in der Behandlung der akuten Beinischämie (ALI). Trotz diverser randomisierter kontrollierter Studien, die diese zwei Optionen miteinander verglichen, gibt es gegenwärtig keinen Therapieansatz, der für die Primärtherapie universal empfohlen wird. Das Ziel dieser Studie ist der Vergleich gegenwärtiger endovaskulärer und offen-chirurgischer Behandlungsoptionen, um die Therapie der ALI optimieren zu können. Methodik: In die Studie eingeschlossen wurden Patienten, die im Zeitraum von 2012 bis 2013 wegen einer ALI endovaskulär oder offen-chirurgisch im Universitätsklinikum Gießen und Marburg GmbH am Standort Marburg behandelt wurden. Dabei stellte der 1-Jahres-Beinerhalt den primären Endpunkt dar. Die sekundären Endpunkte der Studie waren die Mortalitäts-, Komplikations-, Gesamtamputations-, Reinterventionsraten und Zeit bis zur Reintervention. Statistisch wurden uni- und multivariate Analysen inklusive einer Cox-Regressionsanalyse für die popliteale und femorale Verschlusshöhe durchgeführt. Ergebnisse: Insgesamt wurden 124 Patienten in die retrospektive Studie eingeschlossen. Davon wurden 56 endovaskulär und 68 offen-chirurgisch behandelt. Die offen-chirurgisch behandelten Patienten waren signifikant älter (ER 67,9 vs. 75,2 Jahre, p < 0,01). Der 1-Jahres-Beinerhalt unterschied sich zwischen der ER-Gruppe mit 58,9% vs. 45,6% in der OR nicht signifikant (p = 0,139). Die 30-Tages-Mortalitätssrate betrug 27,9% (OR) vs. 10,7% (ER) (p = 0,0173), die 1-Jahres-Mortalitätsrate lag bei 51,5% (OR) vs. 16,1% (ER) (p < 0,001) und die Gesamtmortalität war 52,9% (OR) vs. 19,6% (ER) (p < 0,001). Die Gesamtamputationsrate (Major- und Minoramputationen) betrug 14,7% (OR) vs. 41,1%(ER) (p=0,01). In der Cox-Regressionsanalyse zeigten sich für popliteale und femorale Verschlüsse keine Unterschiede im 1-Jahres-Beinerhalt (45,7% OR vs. 56,7% ER, p=0,412). Durchschnittlich wurden bei offen-chirurgisch behandelten Patienten 4,00 (±3,44 SD) vs. 4,67 ER (±3,02 SD) (p = 0,458) Reinterventionen durchgeführt. Die Zeit bis zur Reintervention lag in der OR Gruppe bei 226,91 ± 306,35d vs. 114,29 ± 242,66d (p = 0,028) in der ER-Gruppe. Folgerung: Es besteht kein signifikanter Unterschied im 1-Jahres-Beinerhalt zwischen endovaskulären und offen-chirurgischen Therapiemaßnahmen. Die Mortalitätsraten sind in der OR-Gruppe signifikant höher. Mehr als 50% der OR therapierten Patienten sind nach einem Jahr verstorben. Demgegenüber stehen signifikant höhere Gesamtamputationsraten (Minor- und Majoramputationen) in der ER-Gruppe. Zudem zeigt die Regressionsanalyse, dass endovaskulär therapierte Patienten in einem signifikant kürzeren Zeitabstand eine Reintervention benötigen. Die endovaskulären und offen-chirurgischen Verfahren sind effektive Methoden, um die Extremität zu erhalten. Dennoch gibt es eine hohe Gesamtmortalitätsrate, die durch die Altersstruktur und die Multimorbidität erklärt werden kann. Somit sind für die zukünftige ALI Therapie präventive Maßnahmen und eine standardisierte längerfristige Nachbeobachtung beispielsweise durch eine zentrale Patientendatenbank zu fordern

Infliximab then efalizumab, the 'hit and run' approach does not work

BACKGROUND: In a previous paper we described 2 patients treated with a sequential biologic therapy for chronic plaque psoriasis. We used infliximab as an induction treatment followed by efalizumab. We extended this approach to 3 other patients. OBJECTIVE: The purpose was to show the feasibility of a sequential approach with biologicals. METHODS: Five patients received three infusions of infliximab followed by weekly injections of efalizumab from week 10 on. RESULTS: The most important findings, summarized in a table, show that none of the patients continued the treatment for more than a year either because of non-responsiveness or because of spontaneous stopping. Moreover, 4 out of 5 patients did not respond or had serious adverse events on reintroduction of infliximab. CONCLUSION: Overall, we cannot recommend sequential therapy using infliximab and efalizumab

Three campaigns of MATISS: multi-months experiments of surface contamination in the Columbus Module (ISS)

International audienceFuture long-duration human spaceflights require developments to limit biocontamination of surface habitats. The three MATISS (Microbial Aerosol Tethering on Innovative Surfaces in the International Space Station) campaigns exposed surface treatments over several months in the ISS. To this end, eight sample holders designed were mounted with lamella-bearing FDTS ((1 H , 1 H , 2 H , 2 H )-perfluorodecyltrichlorosilane), SiOCH, and parylene hydrophobic coatings, at two different locations, for several months, during three distinct periods from 2016 to 2020. Tile scanning optical microscopy (×3 and ×30 magnifications) detected several thousand particles, indicating a relatively clean environment (a few particles per mm 2 ). In previous studies, exposure rates were analyzed for all the coarse and fine particles detected on the largest total area of the integrated FDTS area exposed in the ISS (several cm 2 ). Here, the contamination rates observed for a smaller constant area unit (the 0.66-cm 2 window area of the holder) were statistically analyzed. Therefore, a statistical difference in rate distributions between RGSH (Return Grid Sensor House) and EDR (European Drawer Rack) and between FDTS and either SiOCH or parylene was shown for the coarse particles but not for the fine particles. The contamination rates were found to be low, confirming the efficiency of the long-term air purification system. The rates tend to vary with the astronaut occupancy rates. Surfaces of spacecraft for long-duration exploration left unmanned during dormancy periods can be considered safe from biocontamination

The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko

Several million people are exposed to dioxin and dioxin-like compounds, primarily through food consumption. Skin lesions historically called "chloracne" are the most specific sign of abnormal dioxin exposure and classically used as a key marker in humans. We followed for 5 years a man who had been exposed to the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), at a single oral dose of 5 million-fold more than the accepted daily exposure in the general population. We adopted a molecular medicine approach, aimed at identifying appropriate therapy. Skin lesions, which progressively covered up to 40% of the body surface, were found to be hamartomas, which developed parallel to a complete and sustained involution of sebaceous glands, with concurrent transcriptomic alterations pointing to the inhibition of lipid metabolism and the involvement of bone morphogenetic proteins signaling. Hamartomas created a new compartment that concentrated TCDD up to 10-fold compared with serum and strongly expressed the TCDD-metabolizing enzyme cytochrome P450 1A1, thus representing a potentially significant source of enzymatic activity, which may add to the xenobiotic metabolism potential of the classical organs such as the liver. This historical case provides a unique set of data on the human tissue response to dioxin for the identification of new markers of exposure in human populations. The herein discovered adaptive cutaneous response to TCDD also points to the potential role of the skin in the metabolism of food xenobiotics

Heterozygous NTF4 Mutations Impairing Neurotrophin-4 Signaling in Patients with Primary Open-Angle Glaucoma

Glaucoma, a main cause of blindness in the developed world, is characterized by progressive degeneration of retinal ganglion cells (RGCs), resulting in irreversible loss of vision. Although members of the neurotrophin gene family in various species are known to support the survival of numerous neuronal populations, including RGCs, it is less clear whether they are also required for survival and maintenance of adult neurons in humans. Here, we report seven different heterozygous mutations in the Neurotrophin-4 (NTF4) gene accounting for about 1.7% of primary open-angle glaucoma patients of European origin. Molecular modeling predicted a decreased affinity of neurotrophin 4 protein (NT-4) mutants with its specific tyrosine kinase receptor B (TrkB). Expression of recombinant NT-4 carrying the most frequent mutation was demonstrated to lead to decreased activation of TrkB. These findings suggest a pathway in the pathophysiology of glaucoma through loss of neurotrophic function and may eventually open the possibility of using ligands activating TrkB to prevent the progression of the disease

Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer

A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored1–5. We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns