Pretreatment With Fragments of Substance-P or With Cholecystokinin Differentially Affects Recovery From Sub-Total Nigrostriatal 6-Hydroxydopamine Lesion

The neuropeptide substance P is known to have mnemogenic and reinforcing actions and can exert neurotrophic and regenerative effects in vitro as well as in vivo. Furthermore, our previous work in the rat showed that either pre- or post-lesion treatment with substance P can promote functional recovery in cases of partial nigrostriatal dopamine lesions. Other work has provided evidence that the effects of substance P might be differentially encoded by its C- and N-terminal fragments. The C-terminal fragment was found to be reinforcing, whereas the mnemogenic as well as neurotrophic properties have been ascribed to the N-terminal sequences. Given these relations, we asked here whether pre-lesion treatment with either a C- or an N-terminal fragment of substance P might differentially affect the behavioral and neurochemical outcome of nigrostriatal dopamine lesions. Therefore, either substance P1−7 or substance P5−11 (37 nmol/kg each) was administered intraperitoneally daily for eight consecutive days before unilateral 6-hydroxy-dopamine lesions of the substantia nigra. Control rats received prelesion treatment with vehicle. Furthermore, we investigated the effects of pre-treatment with Boc-cholecystokinin-4 (0.91 nmol/kg), as we had found an increase in dopamine metabolism in animals that were pre-treated with cholecystokinin-8 in a former study. In accordance with our previous work, drug treatment effects were observed when excluding animals with most severe dopamine lesions: In animals with partial lesions (residual neostriatal dopamine levels of more than 10%), lesion-dependent asymmetries in turning behavior were observed in animals that were pre-treated with vehicle-, substance P1−7 , or Boc-cholecysto-kinin–4,. whereas turning after pre-treatment with substance P5−11 was not significantly asymmetrical. Furthermore, the ipsi- and contra-lateral neostriatal dopamine levels did not differ significantly in this group. Moreover, pre treatment with substance P5−11 affected dopamine metabolism in the neostriatum and in the venral striatum, as indicated by increased ratios of dihydroxyphenyllic acid to dopamine. The data provide the first evidence that the promotive effects of substance-P treatment in the unilateral dopamine lesion model might be mediated by its C-terminal and might depend on actions on residual dopamine mechanisms

{beta}3GnT2 Maintains Adenylyl Cyclase-3 Signaling and Axon Guidance Molecule Expression in the Olfactory Epithelium

In the olfactory epithelium (OE), odorant receptor stimulation generates cAMP signals that function in both odor detection and the regulation of axon guidance molecule expression. The enzyme that synthesizes cAMP, adenylyl cyclase 3 (AC3), is coexpressed in olfactory sensory neurons (OSNs) with poly-N-acetyllactosamine (PLN) oligosaccharides determined by the glycosyltransferase beta3GnT2. The loss of either enzyme results in similar defects in olfactory bulb (OB) innervation and OSN survival, suggesting that glycosylation may be important for AC3 function. We show here that AC3 is extensively modified with N-linked PLN, which is essential for AC3 activity and localization. On Western blots, AC3 from the wild-type OE migrates diffusely as a heavily glycosylated 200 kDa band that interacts with the PLN-binding lectin LEA. AC3 from the beta3GnT2(-/-) OE loses these PLN modifications, migrating instead as a 140 kDa glycoprotein. Furthermore, basal and forskolin-stimulated cAMP production is reduced 80-90% in the beta3GnT2(-/-) OE. Although AC3 traffics normally to null OSN cilia, it is absent from axon projections that aberrantly target the OB. The cAMP-dependent guidance receptor neuropilin-1 is also lost from beta3GnT2(-/-) OSNs and axons, while semaphorin-3A ligand expression is upregulated. In addition, kirrel2, a mosaically expressed adhesion molecule that functions in axon sorting, is absent from beta3GnT2(-/-) OB projections. These results demonstrate that PLN glycans are essential in OSNs for proper AC3 localization and function. We propose that the loss of cAMP-dependent guidance cues is also a critical factor in the severe axon guidance defects observed in beta3GnT2(-/-) mice

Case report of a cervical myelomalacia caused by a thoracolumbar intradural disc herniation leading to intracranial hypotension

A 50-year-old patient was admitted with symptoms of intracranial hypotension. MRI revealed a cervical myelomalacia caused by engorged epidural veins leading to a stenosis of the spinal canal. This condition is rarely described in patients with hydrocephalus and ventricular shunts suffering from chronic overdrainage. However, the reason in this patient was a CSF leak caused by an intradural disc herniation at T12/L1. After surgery, symptoms resolved and the cervical myelomalacia and the swollen epidural veins disappeared on postoperative MRI. In patients with engorged cervical epidural veins without a ventricular shunt, a CSF leak has to be considered

THU0366 SYSTEMATIC CORONARY RISK EVALUATION (SCORE) MISCLASSIFIES CARDIOVASCULAR RISK IN ANTISYNTHETASE SYNDROME: RESULTS OF THE PILOT MULTICENTRIC STUDY RI.CAR.D.A.

Background:Antisynthetase Syndrom (ASyS) is an autoimmune overlap disease characterized by antiaminoacyl-tRNA-synthetase (anti-ARS) antibodies and the classic triad of arthritis, myositis and interstitial lung disease (ILD) (1). Markers of cardiovascular (CV) or cerebrovascular (CVB) risk have never been examined in ASyS.Objectives:Aim of this study (RIsk of CARdiovascular Disease in ASyS: RI.CAR.D.A.) was to test the ability of an established traditional CV risk prediction score (Systematic Coronary Risk Evaluation-SCORE) and its EULAR modified version (mSCORE) to identify ASyS patients at high CV risk. Moreover, we sought to examine for the first time associations of CV surrogate markers with clinical and immunological ASyS parameters.Methods:SCORE/mSCORE and the gold standard marker of aortic stiffness (carotid-femoral pulse wave velocity-cfPWV) were examined in patients with ASyS and healthy controls in a multicenter setting (6 Rheumatology Centers). Moreover, sonography of the common- (CCA), internal- (ICA) and external- (ECA) carotid arteries was performed in subsets of both groups, evaluating carotid intima-media-thickness (cIMT), plaques and duplex-sonographic indices of CBV risk such as the resistance- (RI) and pulsatility-index (PI).Figure 1.Carotid Doppler surrogate markers of cardiovascular and cerebrovascular risk in controls and ASyS (case).cIMTCarotid intima media thickness;CAA(common-),ICA(internal),ECA(external) carotid artery;RIresistance index;PIpulsatility index. (all;p0.9 mm) (SCA) in85.7%of the patients respectively. ROC analyses showed similarly poor diagnostic performances of SCORE/mSCORE in comparison to cfPWV(>10 m/s) and SAC by areas under the curve (AUC) of0.56 (95%CI=0.39-0.73) and0.63 (95%CI=0.3-0.96),respectively. cfPWV and SCA were higher in ASyS patients compared to controls (padj=0.021andp=0.003, respectively). cfPWV and cIMT correlated in the patient group significantly with age (r=0.679; p<0.001 and r=0.664; p<0.001,respectively).Moreover, cfPWV correlated with BMI (padj=0.001) and diabetes(padj=0.043). ACC-RI and ACC-PI showed significant associations with a marker of myositis activity [creatine phosphokinase (CPK):r=0.629;p=0.012andr=0.574;p=0.032, respectively]. Finally, ACI-RI and ACI-PI values were higher in patients with ILD (both;p=0.039).Conclusion:This is the first report of higher aortic stiffness and SCA in ASyS patients compared to controls. Active myositis and presence of ILD were associated with higher CVB risk parameters. Furthermore, SCORE/mSCORE performed poorly in identifying patients at high CV risk and carotid arteriosclerosis compared to cfPWV and CS respectively. Thus, cfPWV and CS could improve CV and CBV screening in ASyS patients.References:[1]Cavagna L, et al. Clinical Spectrum Time Course in Anti Jo-1 Positive Antisynthetase Syndrome.Medicine2015;94:1144.Disclosure of Interests:None declare

Olfactory discrimination largely persists in mice with defects in odorant receptor expression and axon guidance

<p>Abstract</p> <p>Background</p> <p>The defining feature of the main olfactory system in mice is that each olfactory sensory neuron expresses only one of more than a thousand different odorant receptor genes. Axons expressing the same odorant receptor converge onto a small number of targets in the olfactory bulb such that each glomerulus is made up of axon terminals expressing just one odorant receptor. It is thought that this precision in axon targeting is required to maintain highly refined odor discrimination. We previously showed that β3GnT2^−/− mice have severe developmental and axon guidance defects. The phenotype of these mice is similar to adenylyl cyclase 3 (AC3) knockout mice largely due to the significant down-regulation of AC3 activity in β3GnT2^−/− neurons.</p> <p>Results</p> <p>Microarray analysis reveals that nearly one quarter of all odorant receptor genes are down regulated in β3GnT2^−/− mice compared to controls. Analysis of OR expression by quantitative PCR and <it>in situ</it> hybridization demonstrates that the number of neurons expressing some odorant receptors, such as mOR256-17, is increased by nearly 60% whereas for others such as mOR28 the number of neurons is decreased by more than 75% in β3GnT2^−/− olfactory epithelia. Analysis of axon trajectories confirms that many axons track to inappropriate targets in β3GnT2^−/− mice, and some glomeruli are populated by axons expressing more than one odorant receptor. Results show that mutant mice perform nearly as well as control mice in an odor discrimination task. In addition, <it>in situ</it> hybridization studies indicate that the expression of several activity dependent genes is unaffected in β3GnT2^−/− olfactory neurons.</p> <p>Conclusions</p> <p>Results presented here show that many odorant receptors are under-expressed in β3GnT2^−/− mice and further demonstrate that additional axon subsets grow into inappropriate targets or minimally innervate glomeruli in the olfactory bulb. Odor evoked gene expression is unchanged and β3GnT2^−/− mice exhibit a relatively small deficit in their ability to discriminate divergent odors. Results suggest that despite the fact that β3GnT2^−/− mice have decreased AC3 activity, decreased expression of many ORs, and display many axon growth and guidance errors, odor-evoked activity in cilia of mutant olfactory neurons remains largely intact.</p

Yardstick Competition in German Municipalities

Does increasing transparency improve fiscal policy behavior of local governments? One way this could take place is via Yardstick Competition between incumbents of neighboring municipalities. This paper contributes to the literature by introducing a simple model which employs probabilistic voting to show the effect of Yardstick Competition on the amount of political rents diverted from the tax revenue. Since additional rents lower the probability of being reelected, the incumbent will reduce equilibrium rents if voters use information on fiscal performance in similar municipalities to evaluate the incumbent's quality. I test this hypothesis on a panel dataset of municipal budget and electoral data in the german state of Northrine-Westphalia. I show evidence for Yardstick Competition in the local business and property tax rates.Kann zunehmende Transparenz im kommunalen Budgetprozess die fiskalpolitische Disziplin der politischen Entscheidungsträger verbessern? In dieser Arbeit wird ein positiver Modellrahmen entwickelt, anhand dessen die Wirkungsweise von steigen - der Transparenz auf das Entscheidungsverhalten von Kommunalpolitikern durch den Yardstick Competition Effekt dargestellt werden kann. Politiker reduzieren die Veruntreuung finanzieller Mittel, wenn ihr Verhalten von den Wählern relativ zur Leistung von Politikern in benachbarten Kommunen bewertet wird. Unter Anwendung von Methoden der räumlichen Ökonometrie auf kommunale Haushalts- und Wahldaten der Jahre 1989 bis 2004 wird gezeigt, dass die räumliche Korrelation in den Gewerbe- und Grundsteuerhebesätzen in Nordrhein-Westfalen auf die Existenz von Yardstick Competition zurückzuführen ist

Estimates for vector valued Dirichlet polynomials

[EN] We estimate the -norm of finite Dirichlet polynomials with coefficients in a Banach space. Our estimates quantify several recent results on Bohr's strips of uniform but non absolute convergence of Dirichlet series in Banach spaces.A. Defant and P. Sevilla-Peris were supported by MICINN Project MTM2011-22417.Defant, A.; Schwarting, U.; Sevilla Peris, P. (2014). Estimates for vector valued Dirichlet polynomials. Monatshefte f�r Mathematik. 175(1):89-116. https://doi.org/10.1007/s00605-013-0600-4S891161751Balasubramanian, R., Calado, B., Queffélec, H.: The Bohr inequality for ordinary Dirichlet series. Studia Math. 175(3), 285–304 (2006)Bayart, F.: Hardy spaces of Dirichlet series and their composition operators. Monatsh. Math. 136(3), 203–236 (2002)Bennett, G.: Inclusion mappings between $$l^{p}$$ l p spaces. J. Funct. Anal. 13, 20–27 (1973)Bohnenblust, H.F., Hille, E.: On the absolute convergence of Dirichlet series. Ann. Math. (2) 32(3), 600–622 (1931)Bohr, H.: Über die Bedeutung der Potenzreihen unendlich vieler Variablen in der Theorie der Dirichlet–schen Reihen $$\sum \frac{a_n}{n^s}$$ ∑ a n n s . Nachr. Ges. Wiss. Göttingen Math. Phys. Kl., Heft 4, 441–488 (1913)Bohr, H.: Über die gleichmäßige Konvergenz Dirichletscher Reihen. J. Reine Angew. Math. 143, 203–211 (1913)Carl, B.: Absolut- $$(p,\,1)$$ ( p , 1 ) -summierende identische Operatoren von $$l_{u}$$ l u in $$l_{v}$$ l v . Math. Nachr. 63, 353–360 (1974)Carlson, F.: Contributions à la théorie des séries de Dirichlet. Note i. Ark. fö”r Mat., Astron. och Fys. 16(18), 1–19 (1922)de la Bretèche, R.: Sur l’ordre de grandeur des polynômes de Dirichlet. Acta Arith. 134(2), 141–148 (2008)Defant, A., Frerick, L., Ortega-Cerdà, J., Ounaïes, M., Seip, K.: The Bohnenblust–Hille inequality for homogeneous polynomials is hypercontractive. Ann. Math. (2) 174(1), 485–497 (2011)Defant, A., García, D., Maestre, M., Pérez-García, D.: Bohr’s strip for vector valued Dirichlet series. Math. Ann. 342(3), 533–555 (2008)Defant, A., García, D., Maestre, M., Sevilla-Peris, P.: Bohr’s strips for Dirichlet series in Banach spaces. Funct. Approx. Comment. Math. 44(part 2), 165–189 (2011)Defant, A., Maestre, M., Schwarting, U.: Bohr radii of vector valued holomorphic functions. Adv. Math. 231(5), 2837–2857 (2012)Defant, A., Popa, D., Schwarting, U.: Coordinatewise multiple summing operators in Banach spaces. J. Funct. Anal. 259(1), 220–242 (2010)Defant, A., Sevilla-Peris, P.: Convergence of Dirichlet polynomials in Banach spaces. Trans. Am. Math. Soc. 363(2), 681–697 (2011)Diestel, J., Jarchow, H., Tonge, A.: Absolutely Summing Operators. Cambridge Studies in Advanced Mathematics, vol. 43. Cambridge University Press, Cambridge (1995)Harris, L.A.: Bounds on the derivatives of holomorphic functions of vectors. In: Analyse fonctionnelle et applications (Comptes Rendus Colloq. Analyse, Inst. Mat., Univ. Federal Rio de Janeiro, Rio de Janeiro, 1972), pp. 145–163. Actualités Aci. Indust., No. 1367. Hermann, Paris (1975)Hedenmalm, H., Lindqvist, P., Seip, K.: A Hilbert space of Dirichlet series and systems of dilated functions in $$L^2(0,1)$$ L 2 ( 0 , 1 ) . Duke Math. J. 86(1), 1–37 (1997)Kahane, J.-P.: Some Random Series of Functions. Cambridge Studies in Advanced Mathematics, vol. 5, 2nd edn. Cambridge University Press, Cambridge (1985)Konyagin, S.V., Queffélec, H.: The translation $$\frac{1}{2}$$ 1 2 in the theory of Dirichlet series. Real Anal. Exch. 27(1):155–175 (2001/2002)Kwapień, S.: Some remarks on $$(p,\, q)$$ ( p , q ) -absolutely summing operators in $$l_{p}$$ l p -spaces. Studia Math. 29, 327–337 (1968)Ledoux, M., Talagrand, M.: Probability in Banach Spaces: Isoperimetry and Processes, reprint of the 1991 edn. Classics in Mathematics. Springer, Berlin (2011)Lindenstrauss, J., Tzafriri, L.: Classical Banach Spaces. I. Sequence Spaces, Ergebnisse der Mathematik und ihrer Grenzgebiete, vol. 92. Springer, Berlin (1977)Lindenstrauss, J., Tzafriri, L.: Classical Banach Spaces. II, Function Spaces. Ergebnisse der Mathematik und ihrer Grenzgebiete [Results in Mathematics and Related Areas], vol. 97. Springer, Berlin (1979)Maurizi, B., Queffélec, H.: Some remarks on the algebra of bounded Dirichlet series. J. Fourier Anal. Appl. 16, 676–692 (2010)Prachar, K.: Primzahlverteilung. Springer, Berlin (1957)Queffélec, H.: H. Bohr’s vision of ordinary Dirichlet series; old and new results. J. Anal. 3, 43–60 (1995)Tomczak-Jaegermann, N.: Banach–Mazur Distances and Finite-Dimensional Operator Ideals. Pitman Monographs and Surveys in Pure and Applied Mathematics, vol. 38. Longman Scientific & Technical, Harlow (1989

Bidirectional regulation of bone formation by exogenous and osteosarcoma-derived Sema3A

Semaphorin 3A (Sema3A), a secreted member of the Semaphorin family, increases osteoblast differentiation, stimulates bone formation and enhances fracture healing. Here, we report a previously unknown role of Sema3A in the regulation of ectopic bone formation and osteolysis related to osteosarcoma. Human recombinant (exogenous) Sema3A promoted the expression of osteoblastic phenotype in a panel of human osteosarcoma cell lines and inhibited the ability of these cells to migrate and enhance osteoclastogenesis in vitro. In vivo, administration of exogenous Sema3A in mice after paratibial inoculation of KHOS cells increased bone volume in non-inoculated and tumour-bearing legs. In contrast, Sema3A overexpression reduced the ability of KHOS cells to cause ectopic bone formation in mice and to increase bone nodule formation by engaging DKK1/β-catenin signalling. Thus, Sema3A is of potential therapeutic efficacy in osteosarcoma. However, inhibition of bone formation associated with continuous exposure to Sema3A may limit its long-term usefulness as therapeutic agent

Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID)

ObjectiveThe objective of this article is to evaluate the safety and clinical outcome of rituximab treatment in systemic lupus erythematosus (SLE) patients refractory to standard of care therapy in a real-life setting in Germany. MethodsThe GRAID registry included patients with different autoimmune diseases who were given off-label treatment with rituximab. Data on safety and clinical response were collected retrospectively. In SLE patients, clinical parameters included tender and swollen joint counts, fatigue, myalgia, general wellbeing, Raynaud's and the SLEDAI index. Laboratory tests included dsDNA antibody titres, complement factors, hematologic parameters and proteinuria. Finally, the investigators rated their patients as non-, partial or complete responders based on clinical grounds. ResultsData from 85 SLE patients were collected, 69 female and 16 male, with a mean disease duration of 9.8 years. The mean follow-up period was 9.67.4 months, resulting in 66.8 patient years of observation. A complete response was reported in 37 patients (46.8%), partial response in 27 (34.2%), no response in 15 (19.0%). On average, major clinical as well as laboratory efficacy parameters improved substantially, with the SLEDAI decreasing significantly from 12.2 to 3.3 points. Concerning safety, one infusion reaction leading to discontinuation of treatment occurred. Infections were reported with a rate of 19.5 (including six severe infections) per 100 patient years. ConclusionWith the restrictions of a retrospective data collection, the results of this study confirm data of other registries, which suggest a favourable benefit-risk ratio of rituximab in patients with treatment-refractory SLE