A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome.

Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in the WFS1 (and WFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-old Wfs1∆exon8 mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.

A mildly inducible and selective cross-link methodology for RNA duplexes.

We here report on the furan oxidation methodology for interstrand cross-linking of RNA duplexes, which have a different structure and are more stiff, reactive and labile than their DNA counterparts. Through this mildly inducible approach, natural unmodified RNA can be selectively cross-linked in high yield. The method therefore has direct applications in the increasing number of RNA based technologies.

Emergency reversal of oral anticoagulation through PPSB-SD: the fastest procedure in Belgium.

OBJECTIVE: To corroborate results obtained in The Netherlands with PPSB-SD, showing a safe acute reversal of anticoagulation within 15 minutes of administration. MATERIAL AND METHODS: PPSB-SD is a concentrate prothrombin complex containing a relatively constant high level of vitamin K-dependant coagulation factors II, VII, IX and X. PPSB-SD was administered to 14 patients treated with oral anticoagulants, according the patient's weight, the initial and the target INR (< 2.0 for moderate haemorrhage and abdominal surgery, or < 1.5 for severe haemorrhage and cardio-vascular interventions). INR values were measured with the Coagucheck Pro (Roche Diagnostics) upon admission and at 15 minutes, 1, 3 and 5 hours after treatment, and confirmed by the hospitals' laboratory. RESULTS: Within 15 minutes 11 patients out of 12 reached their INR target (data were missing for 2 patients). INR decreased rapidly, then remained stable for the next 5 hours. All patients had a favourable outcome: bleeding was stopped and no haemorrhage occurred during surgery. Only one adverse event was reported, but it was not related to the PPSB-SD treatment. No sign of disseminated intravascular coagulation was observed during this study. The administration of PPSB-SD along with vitamin K and dosed according to body weight and initial and target INR allowed for optimal reversal of anticoagulation, as no second infusion was necessary. The recommended dosing worked also very well for patients with high initial INR (9.2 to 22.8) who were brought down to normal values (0.9 to 1.1) within 15 minutes. CONCLUSION: PPSB-SD can safely be used for the rapid reversal of anticoagulation as needed in emergency situations.

Contact dermatitis caused by airborne agents. A review and case reports.

A general review is given of airborne-induced contact dermatoses, particularly of the irritant and allergenic types. Because the reports in the literature often omit the term airborne, 12 volumes of Contact Dermatitis (January 1975-July 1985) were screened, and the cases cited were classified in function of the anamnesis, lesion locations, causative irritants and allergens, and other factors. The present article also discusses differential diagnoses, in particular with regard to contact dermatitis of the face, ears, and neck. Finally, seven case reports of occupational and nonoccupational contact dermatitis problems caused by airborne agents are presented. In some of the cases the allergens have not been mentioned in published literature previously.

Pustular reactions to hexafluorosilicate in foam rubber.

A case is reported of a foam rubber carrier with pustular lesions on the arms, wrists, thighs and trunk. Scratch and patch testing with the foam rubber components was negative. Animal testing revealed sodium hexafluorosilicate (Na2SiF6), one of the ingredients of the foam rubber, to be a pustulogen on previously damaged skin.