Toscana virus encephalitis in Southwest Germany: a retrospective study.

BACKGROUND: Toscana virus (TOSV) is an arthropod-borne virus transmitted by phlebotomine sandflies (Phlebotomus sp.) widespread throughout the Mediterranean having the potential to cause meningoencephalitis in humans. In Germany, the vectors of TOSV are introduced recently and become endemic especially in Southwestern Germany. As TOSV is not investigated regularly in patients with meningoencephalitis, cases of TOSV-neuroinvasive disease may remain mostly undetected. METHODS: We conducted a retrospective cohort study on patients with meningoencephalitis without identification of a causal pathogen from 2006 to 2016. Serologic assessment for anti-TOSV-IgG and IgM was performed on serum and CSF. Demographic, clinical and CSF data from TOSV-positive patients were compared to a cohort of patients with meningoencephalitis due to enterovirus. Informed consent was obtained from all included patients. RESULTS: We found 138 patients with meningoencephalitis without identified causal pathogen. From 98 of these patients CSF and serum was available for further testing. Additionally, we included 27 patients with meningoencephalitis due to enterovirus. We identified two patients with serological confirmed TOSV-neuroinvasive disease (TOSV-IgM and IgG positive, 2%) and two patients with possible TOSV-neuroinvasive disease (isolated TOSV-IgM positive, 2%). Overall, TOSV-neuroinvasive was detected in 4% of our cases with suspected viral meningoencephalitis. None of them had a history of recent travel to an endemic area. CONCLUSIONS: We found cases of TOSV-neuroinvasive disease in our German cohort of patients with meningoencephalitis. As no recent history of travel to an endemic area was reported, it remains probable that these cases resemble autochthonous infections, albeit we cannot draw conclusions regarding the origin of the respective vectors. TOSV could be considered in patients with meningoencephalitis in Germany.

The type 2 cannabinoid receptor regulates susceptibility to osteoarthritis in mice.

OBJECTIVE: Cannabinoid receptors and their ligands have been implicated in the regulation of various physiological processes but their role in osteoarthritis has not been investigated. The aim of this study was to evaluate the role of the type 2 cannabinoid receptor (Cnr2) in regulating susceptibility to osteoarthritis in mice. METHODS: We analysed the severity of knee osteoarthritis as assessed by the Osteoarthritis Research Society International (OARSI) scoring system in mice with targeted deletion of Cnr2 (Cnr2(-/-)) and wild type (WT) littermates. Studies were conducted in mice subjected to surgical destabilisation of the medial meniscus (DMM) and in those with spontaneous age-related osteoarthritis (OA). RESULTS: Osteoarthritis was more severe following DMM in the medial compartment of the knee in Cnr2(-/-) compared with WT mice (mean ± sem score = 4.9 ± 0.5 vs 3.6 ± 0.3; P = 0.017). Treatment of WT mice with the CB2-selective agonist HU308 following DMM reduced the severity of OA in the whole joint (HU308 = 8.4 ± 0.2 vs vehicle = 10.4 ± 0.6; P = 0.007). Spontaneous age related osteoarthritis was also more severe in the medial compartment of the knee in 12-month old Cnr2(-/-) mice compared with WT (5.6 ± 0.5 vs 3.5 ± 0.3, P = 0.008). Cultured articular chondrocytes from Cnr2(-/-) mice produced less proteoglycans in vitro than wild type chondrocytes. CONCLUSION: These studies demonstrate that the Cnr2 pathway plays a role in the pathophysiology of osteoarthritis in mice and shows that pharmacological activation of CB2 has a protective effect. Further studies of the role of cannabinoid receptors in the pathogenesis of osteoarthritis in man are warranted.

Circulating endogenous digitalis-like factor(s) (EDLF) in man is derived from the adrenals and its secretion is ACTH-dependent.

Adrenal origin and ACTH-dependent secretion of endogenous digitalis-like factor(s) (EDLF) was investigated. Twelve normal weight normotensive subjects (normal group) and 10 patients with Addison's disease (Addison group) were subjected to prolonged ACTH stimulation with 1 mg tetracosactin-depot im. Blood sampling was at 0 and 240 min. Digitalis-like reactivity was monitored in plasma extracts (combined organic solvent solid phase method) by digoxin and ouabain radioimmunoassay (RIAD and RIAO, respectively). 3H-ouabain concentration on erythrocytes (OBS) was also determined. Na+, K+-ATPase inhibition by normal plasma extract was tested by measuring Vmax and Km of 86Rb+-transport into human erythrocytes. In the normal group basal median plasma concentrations RIAD (0.07 nmol/l) and RIAO (0.89 nmol/l) increased significantly after ACTH administration (median 0.31 and 1.83, respectively; Wilcoxon, p<0.01). In contrast, in the Addison group no plasma RIAD and RIAO reactivity was detected before or after ACTH administration with minor exceptions. The OBS remained unchanged in the Addison group at 0 and 240 min; in the normal group there was a significant decline at 240 min (Wilcoxon, p<0.05) implying increase in circulating EDLF after ACTH stimulation. In the 86Rb+-transport experiments, 2 nmol/l ouabain or 2 nmol/l plasma-extracted ouabain reactivity both significantly impaired substrate affinity equally increasing Km without affecting Vmax. In men, the adrenals may produce and secrete EDLF, whose secretion appears to be ACTH-dependent.