Decreased vitamin B12 availability induces ER stress through impaired SIRT1-deacetylation of HSF1.

Vitamin B12 (cobalamin) is a key determinant of S-adenosyl methionine (SAM)-dependent epigenomic cellular regulations related to methylation/acetylation and its deficiency produces neurodegenerative disorders by elusive mechanisms. Sirtuin 1 deacetylase (SIRT1) triggers cell response to nutritional stress through endoplasmic reticulum (ER) stress. Recently, we have established a N1E115 dopaminergic cell model by stable expression of a transcobalamin-oleosin chimera (TO), which impairs cellular availability of vitamin B12, decreases methionine synthase activity and SAM level, and reduces cell proliferation. In contrast, oleosin-transcobalamin chimera (OT) does not modify the phenotype of transfected cells. Presently, the impaired cellular availability of vitamin B12 in TO cells activated irreversible ER stress pathways, with increased P-eIF-2α, P-PERK, P-IRE1α, ATF6, ATF4, decreased chaperon proteins and increased pro-apoptotic markers, CHOP and cleaved caspase 3, through reduced SIRT1 expression and consequently greater acetylation of heat-shock factor protein 1 (HSF1). Adding either B12, SIRT1, or HSF1 activators as well as overexpressing SIRT1 or HSF1 dramatically reduced the activation of ER stress pathways in TO cells. Conversely, impairing SIRT1 and HSF1 by siRNA, expressing a dominant negative form of HSF1, or adding a SIRT1 inhibitor led to B12-dependent ER stress in OT cells. Addition of B12 abolished the activation of stress transducers and apoptosis, and increased the expression of protein chaperons in OT cells subjected to thapsigargin, a strong ER stress stimulator. AdoX, an inhibitor of methyltransferase activities, produced similar effects than decreased B12 availability on SIRT1 and ER stress by a mechanism related to increased expression of hypermethylated in cancer 1 (HIC1). Taken together, these data show that cellular vitamin B12 has a strong modulating influence on ER stress in N1E115 dopaminergic cells. The impaired cellular availability in vitamin B12 induces irreversible ER stress by greater acetylation of HSF1 through decreased SIRT1 expression, whereas adding vitamin B12 produces protective effects in cells subjected to ER stress stimulation.

Sandflies and leishmaniasis in Germany.

This study has provided evidence for the natural occurrence of sandflies in Germany. Two species belonging to the genus Phlebotomus were detected. Phlebotomus (Larroussius) perniciosus, a proven vector of leishmaniasis, was found in association with an autochthonous case of canine leishmaniasis near Kaiserslautern. Two hundred thirty-seven specimens of Phlebotomus (Transphlebotomus) mascittii were caught in 17 different locations in Baden-Wuerttemberg and Rhineland-Palatinate. The northernmost finding in Germany (and Europe) was near Cochem (Moselle). P. mascittii has not yet been confirmed as a vector of leishmaniasis, but its competence is strongly suspected. In addition to the detection of the vector, since 1991, there have been 11 cases of leishmaniasis in Germany in which an autochthonous origin was confirmed or which were highly likely to have been of indigenous origin. Data from the German meteorological service indicate that Germany currently has a Mediterranean climate, with an annual average temperature of 10 degrees C being reached or exceeded in several regions. This type of climate is also appropriate for the living conditions of sandflies. Therefore, it is assumed that sandflies have a greater geographical distribution in Germany than the first studies suggested, being mainly restricted to the southern region of Baden-Wuerttemberg. The risk of an autochthonous canine infection occurring in Germany is very low. The rapidly increasing number of imported cases of leishmaniasis in dogs means that special attention must be focused on veterinary advice to dog owners about prophylaxis. The results indicate that the use of repellents and preventive behavioural measures is vital.

Winter activity of Phlebotomus (Transphlebotomus) mascittii, Grassi 1908 (Diptera: Psychodidae) on the island of Corsica.

In the first week of February 2008 on the island of Corsica, 55 Phlebotomus (Transphlebotomus) mascittii, 39 males and 16 females, were caught in a railway tunnel. This is the first proof of the winter activity of the adult P. mascittii in Europe.

Cytolocalization of glycogen, starch, and other insoluble polysaccharides during ontogeny of Paxillus involutus-Betula pendula ectomycorrhizas.

The Paxillus involutus (Fries) Karsten-Betula pendula Roth association was studied during the early stages of formation. Cytological studies revealed fungal colonization behind the root cap and gradually around the entire root apex. Ultrastructural investigations were carried out and insoluble polysaccharide distribution was followed. The density of starch grains increased in plant cells especially after 4 d of contact between the two partners, but later on decreased strongly in the root cap. Large amounts of glycogen were revealed in the hyphae in certain mycorrhizal regions after 6 d of contact: in the Hartig net, in the inner sheath but only near the net, and all along the outer sheath surrounding the mycorrhiza. Thickenings of the epidermal cell walls were detected as early as 2 d after contact and then varied according to the distance from the root tip. Such polysaccharide distributions are assumed to show a transfer of carbohydrates from the root to the fungus and are discussed in terms of carbon requirements for both partners.

Effect of influenza vaccine in patients receiving long-term warfarin therapy.

The effect of influenza vaccine on anticoagulant response in 12 patients receiving long-term warfarin therapy was studied. Study criteria required that all patients have stable prothrombin times and be on stable warfarin dosages before immunization. Patients were immunized with 1982-83 trivalent influenza vaccine (subvirion), types A and B 0.5 mL i.m. on day 0 of the study. Prothrombin times were determined on days--7, 0, 2, 5, 7, 14, and 21, and results were reported as ratios with control values. Influenza immunization produced a small but significant increase in the prothrombin-time ratio. Before immunization the mean ratio was 1.68, and the mean ratio increased to 1.81 after immunization. The maximal increase occurred on day 14 and represented a 7.6% increase over the baseline (day 0) value. The prothrombin-time ratio was not influenced by warfarin sodium dosage (less than or equal to 5 mg/day versus greater than 5 mg/day) or by the sex of the patient. During the 1984-85 influenza season, an additional 26 patients were immunized with the 1984-85 trivalent influenza vaccine (subvirion), types A and B. The prothrombin-time ratio on days 0 and 14 were not significantly different in these patients. Although the administration of influenza vaccine to patients receiving long-term treatment with warfarin appears to be safe, patients should be monitored after immunization for possible increases in anticoagulant response.