Targeting VIP and PACAP receptor signalling: new therapeutic strategies in multiple sclerosis

MS (multiple sclerosis) is a chronic autoimmune and neurodegenerative pathology of the CNS (central nervous system) affecting approx. 2.5 million people worldwide. Current and emerging DMDs (disease-modifying drugs) predominantly target the immune system. These therapeutic agents slow progression and reduce severity at early stages of MS, but show little activity on the neurodegenerative component of the disease. As the latter determines permanent disability, there is a critical need to pursue alternative modalities. VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating peptide) have potent anti-inflammatory and neuroprotective actions, and have shown significant activity in animal inflammatory disease models including the EAE (experimental autoimmune encephalomyelitis) MS model. Thus, their receptors have become candidate targets for inflammatory diseases. Here, we will discuss the immunomodulatory and neuroprotective actions of VIP and PACAP and their signalling pathways, and then extensively review the structure–activity relationship data and biophysical interaction studies of these peptides with their cognate receptors

Kothe dual of Banach lattices generated by vector measures

We study the Kothe dual spaces of Banach function lattices generated by abstract methods having roots in the theory of interpolation spaces. We apply these results to Banach spaces of integrable functions with respect to Banach space valued countably additive vector measures. As an application we derive a description of the Banach dual of a large class of these spaces, including Orlicz spaces of integrable functions with respect to vector measuresThe first author was supported by the Foundation for Polish Science (FNP). The second author was supported by the Ministerio de Economia y Competitividad (Spain) under Grant #MTM2012-36740-C02-02.Mastylo, M.; Sánchez Pérez, EA. (2014). Kothe dual of Banach lattices generated by vector measures. Monatshefte fur Mathematik. 173(4):541-557. https://doi.org/10.1007/s00605-013-0560-8S5415571734Aronszajn, N., Gagliardo, E.: Interpolation spaces and interpolation methods. Ann. Mat. Pura. Appl. 68, 51–118 (1965)Bartle, R.G., Dunford, N., Schwartz, J.: Weak compactness and vector measures. Canad. J. Math. 7, 289–305 (1955)Brudnyi, Yu.A., Krugljak, N.Ya.: Interpolation functors and interpolation spaces $$I$$ I . North-Holland, Amsterdam (1991)Curbera, G.P.: Operators into $$L^1$$ L 1 of a vector measure and applications to Banach lattices. Math. Ann. 293, 317–330 (1992)Curbera, G.P., Ricker, W.J.: The Fatou property in $$p$$ p -convex Banach lattices. J. Math. Anal. Appl. 328, 287–294 (2007)Delgado, O.: Banach function subspaces of $$L^1$$ L 1 of a vector measure and related Orlicz spaces. Indag. Math. 15(4), 485–495 (2004)Diestel, J., Jr., Uhl, J.J.: Vector measures, Amer. Math. Soc. Surveys 15, Providence, R.I. (1977)Fernández, A., Mayoral, F., Naranjo, F., Sánchez-Pérez, E.A.: Spaces of $$p$$ p -integrable functions with respect to a vector measure. Positivity 10, 1–16 (2006)Ferrando, I., Rodríguez, J.: The weak topology on $$L_p$$ L p of a vector measure. Topol. Appl. 155, 1439–1444 (2008)Ferrando, I., Sánchez Pérez, E.A.: Tensor product representation of the (pre)dual of the $$L_p$$ L p -space of a vector measure. J. Aust. Math. Soc. 87, 211–225 (2009)Galaz-Fontes, F.: The dual space of $$L^p$$ L p of a vector measure. Positivity 14(4), 715–729 (2010)Kamińska, A.: Indices, convexity and concavity in Musielak-Orlicz spaces, dedicated to Julian Musielak. Funct. Approx. Comment. Math. 26, 67–84 (1998)Kantorovich, L.V., Akilov, G.P.: Functional analysis, 2nd edn. Pergamon Press, New York (1982)Krein, S.G., Petunin, Yu.I., Semenov, E.M.: Interpolation of linear operators. In: Translations of mathematical monographs, 54. American Mathematical Society, Providence, R.I., (1982)Lewis, D.R.: Integration with respect to vector measures. Pacific. J. Math. 33, 157–165 (1970)Lewis, D.R.: On integrability and summability in vector spaces. Ill. J. Math. 16, 583–599 (1973)Lindenstrauss, J., Tzafriri, L.: Classical Banach spaces II. Springer, Berlin (1979)Lozanovskii, G.Ya.: On some Banach lattices, (Russian). Sibirsk. Mat. Z. 10, 419–430 (1969)Musielak, J.: Orlicz spaces and modular spaces. In: Lecture Notes in Math. 1034, Springer-Verlag, Berlin (1983)Okada, S.: The dual space of $$L^1(\mu )$$ L 1 ( μ ) of a vector measure $$\mu$$ μ . J. Math. Anal. Appl. 177, 583–599 (1993)Okada, S., Ricker, W.J., Sánchez Pérez, E.A.: Optimal domain and integral extension of operators acting in function spaces, operator theory. Adv. Appl., vol. 180, Birkhäuser, Basel (2008)Rao, M.M., Zen, Z.D.: Applications of Orlicz spaces. Marcel Dekker, Inc., New York (2002)Rivera, M.J.: Orlicz spaces of integrable functions with respect to vector-valued measures. Rocky Mt. J. Math. 38(2), 619–637 (2008)Sánchez Pérez, E.A.: Compactness arguments for spaces of $$p$$ p -integrable functions with respect to a vector measure and factorization of operators through Lebesgue-Bochner spaces. Ill. J. Math. 45(3), 907–923 (2001)Sánchez Pérez, E.A.: Vector measure duality and tensor product representation of $$L_p$$ L p spaces of vector measures. Proc. Amer. Math. Soc. 132, 3319–3326 (2004)Zaanen, A.C.: Integration. North Holland, Amsterdam (1967

Role of computed tomography imaging for transcatheter valvular repair/insertion

During the last decade, the development of transcatheter based therapies has provided feasible therapeutic options for patients with symptomatic severe valvular heart disease who are deemed inoperable. The promising results of many nonrandomized series and recent landmark trials have increased the number of percutaneous transcatheter valve procedures in high operative risk patients. Pre-procedural imaging of the anatomy of the aortic or mitral valve and their spatial relationships is crucial to select the most appropriate device or prosthesis and to plan the percutaneous procedure. Multidetector row computed tomography provides 3-dimensional volumetric data sets allowing unlimited plane reconstructions and plays an important role in pre-procedural screening and procedural planning. This review will describe the evolving role of multidetector row computed tomography in patient selection and strategy planning of transcatheter aortic and mitral valve procedures

Maharam-type kernel representation for operators with a trigonometric domination

[EN] Consider a linear and continuous operator T between Banach function spaces. We prove that under certain requirements an integral inequality for T is equivalent to a factorization of T through a specific kernel operator: in other words, the operator T has what we call a Maharam-type kernel representation. In the case that the inequality provides a domination involving trigonometric functions, a special factorization through the Fourier operator is given. We apply this result to study the problem that motivates the paper: the approximation of functions in L2[0, 1] by means of trigonometric series whose Fourier coefficients are given by weighted trigonometric integrals.This research has been supported by MTM2016-77054-C2-1-P (Ministerio de Economia, Industria y Competitividad, Spain).Sánchez Pérez, EA. (2017). Maharam-type kernel representation for operators with a trigonometric domination. Aequationes Mathematicae. 91(6):1073-1091. https://doi.org/10.1007/s00010-017-0507-6S10731091916Calabuig, J.M., Delgado, O., Sánchez Pérez, E.A.: Generalized perfect spaces. Indag. Math. 19(3), 359–378 (2008)Calabuig, J.M., Delgado, O., Sánchez Pérez, E.A.: Factorizing operators on Banach function spaces through spaces of multiplication operators. J. Math. Anal. Appl. 364, 88–103 (2010)Delgado, O., Sánchez Pérez, E.A.: Strong factorizations between couples of operators on Banach function spaces. J. Convex Anal. 20(3), 599–616 (2013)Dodds, P.G., Huijsmans, C.B., de Pagter, B.: Characterizations of conditional expectation type operators. Pacific J. Math. 141(1), 55–77 (1990)Flores, J., Hernández, F.L., Tradacete, P.: Domination problems for strictly singular operators and other related classes. Positivity 15(4), 595–616 (2011). 2011Fremlin, D.H.: Tensor products of Banach lattices. Math. Ann. 211, 87–106 (1974)Hu, G.: Weighted norm inequalities for bilinear Fourier multiplier operators. Math. Ineq. Appl. 18(4), 1409–1425 (2015)Halmos, P., Sunder, V.: Bounded Integral Operators on $$L^2$$ L 2 Spaces. Springer, Berlin (1978)Kantorovitch, L., Vulich, B.: Sur la représentation des opérations linéaires. Compositio Math. 5, 119–165 (1938)Kolwicz, P., Leśnik, K., Maligranda, L.: Pointwise multipliers of Calderón- Lozanovskii spaces. Math. Nachr. 286, 876–907 (2013)Kolwicz, P., Leśnik, K., Maligranda, L.: Pointwise products of some Banach function spaces and factorization. J. Funct. Anal. 266(2), 616–659 (2014)Kuo, W.-C., Labuschagne, C.C.A., Watson, B.A.: Conditional expectations on Riesz spaces. J. Math. Anal. Appl. 303, 509–521 (2005)Lindenstrauss, J., Tzafriri, L.: Classical Banach Spaces II. Springer, Berlin (1979)Maharam, D.: The representation of abstract integrals. Trans. Am. Math. Soc. 75, 154–184 (1953)Maharam, D.: On kernel representation of linear operators. Trans. Am. Math. Soc. 79, 229–255 (1955)Maligranda, L., Persson, L.E.: Generalized duality of some Banach function spaces. Indag. Math. 51, 323–338 (1989)Neugebauer, C.J.: Weighted norm inequalities for averaging operators of monotone functions. Publ. Mat. 35, 429–447 (1991)Okada, S., Ricker, W.J., Sánchez Pérez, E.A.: Optimal Domain and Integral Extension of Operators Acting in Function Spaces. Operator Theory: Adv. Appl., vol. 180. Birkhäuser, Basel (2008)Rota, G.C.: On the representation of averaging operators. Rend. Sem. Mat. Univ. Padova. 30, 52–64 (1960)Sánchez Pérez, E.A.: Factorization theorems for multiplication operators on Banach function spaces. Integr. Equ. Oper. Theory 80(1), 117–135 (2014)Schep, A.R.: Factorization of positive multilinear maps. Ill. J. Math. 28(4), 579–591 (1984)Schep, A.R.: Products and factors of Banach function spaces. Positivity 14(2), 301–319 (2010

Strong coupling, discrete symmetry and flavour

We show how two principles - strong coupling and discrete symmetry - can work together to generate the flavour structure of the Standard Model. We propose that in the UV the full theory has a discrete flavour symmetry, typically only associated with tribimaximal mixing in the neutrino sector. Hierarchies in the particle masses and mixing matrices then emerge from multiple strongly coupled sectors that break this symmetry. This allows for a realistic flavour structure, even in models built around an underlying grand unified theory. We use two different techniques to understand the strongly coupled physics: confinement in N=1 supersymmetry and the AdS/CFT correspondence. Both approaches yield equivalent results and can be represented in a clear, graphical way where the flavour symmetry is realised geometrically.Comment: 31 pages, 5 figures, updated references and figure

A Randomised Controlled Trial to Assess the Efficacy of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Falciparum Malaria in Peru

Background. Multi-drug resistant falciparum malaria is an important health problem in the Peruvian Amazon region. We carried out a randomised open label clinical trial comparing mefloquine-artesunate, the current first line treatment in this region, with dihydroartemisinin-piperaquine. Methods and Findings. Between July 2003 and July 2005, 522 patients with P. falciparum uncomplicated malaria were recruited, randomized (260 with mefloquine-artesunate and 262 with dihydroartemisinin-piperaquine), treated and followed up for 63 days. PCR-adjusted adequate clinical and parasitological response, estimated by Kaplan Meier survival and Per Protocol analysis, was extremely high for both drugs (99.6% for mefloquine-artesunate and 98.4% and for dihydroartemisinin-piperaquine) (RR: 0.99, 95%CI [0.97-1.01], Fisher Exact p=0.21). All recrudescences were late parasitological failures. Overall, gametocytes were cleared faster in the mefloquine-artesunate group (28 vs 35 days) and new gametocytes tended to appear more frequently in patients treated with dihydroartemisinin-piperaquine (day 7: 8 ( 3.6%) vs 2 (0.9%), RR: 3.84, 95%CI [0.82-17.87]). Adverse events such as anxiety and insomnia were significantly more frequent in the mefloquine-artesunate group, both in adults and children. Conclusion. Dihydroartemisinin-piperaquine is as effective as mefloquine-artesunate in treating uncomplicated P. falciparum malaria but it is better tolerated and more affordable than mefloquine-artesunate (US$1.0 versus US$18.65 on the local market). Therefore, it should be considered as a potential candidate for the first line treatment of P. falciparum malaria in Peru. Trial Registration. ClinicalTrials.gov NCT00373607 [http://www.clinicaltrials.gov/ct/show/NCT00373607]

Bat lung epithelial cells show greater host species-specific innate resistance than MDCK cells to human and avian influenza viruses

Background With the recent discovery of novel H17N10 and H18N11 influenza viral RNA in bats and report on high frequency of avian H9 seroconversion in a species of free ranging bats, an important issue to address is the extent bats are susceptible to conventional avian and human influenza A viruses. Method To this end, three bat species (Eidolon helvum, Carollia perspicillata and Tadarida brasiliensis) of lung epithelial cells were separately infected with two avian and two human influenza viruses to determine their relative host innate immune resistance to infection. Results All three species of bat cells were more resistant than positive control Madin-Darby canine kidney (MDCK) cells to all four influenza viruses. TB1-Lu cells lacked sialic acid α2,6-Gal receptors and were most resistant among the three bat species. Interestingly, avian viruses were relatively more replication permissive in all three bat species of cells than with the use of human viruses which suggest that bats could potentially play a role in the ecology of avian influenza viruses. Chemical inhibition of the JAK-STAT pathway in bat cells had no effect on virus production suggesting that type I interferon signalling is not a major factor in resisting influenza virus infection. Conclusion Although all three species of bat cells are relatively more resistant to influenza virus infection than control MDCK cells, they are more permissive to avian than human viruses which suggest that bats could have a contributory role in the ecology of avian influenza viruses

Maurey-Rosenthal domination for abstract Banach lattices

We extend the Maurey-Rosenthal theorem on integral domination and factorization of p-concave operators from a p-convex Banach function space through Lp-spaces for the case of operators on abstract p-convex Banach lattices satisfying some essential lattice requirements - mainly order density of its order continuous part - that are shown to be necessary. We prove that these geometric properties can be characterized by means of an integral inequality giving a domination of the pointwise evaluation of the operator for a suitable weight also in the case of abstract Banach lattices. We obtain in this way what in a sense can be considered the most general factorization theorem of operators through Lp-spaces. In order to do this, we prove a new representation theorem for abstract p-convex Banach lattices with the Fatou property as spaces of p-integrable functions with respect to a vector measure.The authors are supported by grants MTM2011-23164 and MTM2012-36740-C02-02 of the Ministerio de Economia y Competitividad (Spain).Juan Blanco, MA.; Sánchez Pérez, EA. (2013). Maurey-Rosenthal domination for abstract Banach lattices. Journal of Inequalities and Applications. (213). https://doi.org/10.1186/1029-242X-2013-213S213Defant A: Variants of the Maurey-Rosenthal theorem for quasi Köthe function spaces. Positivity 2001, 5: 153–175. 10.1023/A:1011466509838Defant A, Sánchez Pérez EA: Maurey-Rosenthal factorization of positive operators and convexity. J. Math. Anal. Appl. 2004, 297: 771–790. 10.1016/j.jmaa.2004.04.047Defant A, Sánchez Pérez EA: Domination of operators on function spaces. Math. Proc. Camb. Philos. Soc. 2009, 146: 57–66. 10.1017/S0305004108001734Fernández A, Mayoral F, Naranjo F, Sáez C, Sánchez-Pérez EA: Vector measure Maurey-Rosenthal type factorizations and l -sums of L 1 -spaces. J. Funct. Anal. 2005, 220: 460–485. 10.1016/j.jfa.2004.06.010Palazuelos C, Sánchez Pérez EA, Tradacete P: Maurey-Rosenthal factorization for p -summing operators and Dodds-Fremlin domination. J. Oper. Theory 2012, 68(1):205–222.Luxemburg WAJ, Zaanen AC: Riesz Spaces I. North-Holland, Amsterdam; 1971.Zaanen AC: Riesz Spaces II. North-Holland, Amsterdam; 1983.Lindenstrauss J, Tzafriri L: Classical Banach Spaces II. Springer, Berlin; 1979.Aliprantis CD, Burkinshaw O: Positive Operators. Academic Press, New York; 1985.Curbera GP, Ricker WJ: Vector measures, integration and applications. Trends Math. In Positivity. Birkhäuser, Basel; 2007:127–160.Okada S, Ricker WJ, Sánchez Pérez EA: Optimal domains and integral extensions of operators acting in function spaces. 180. In Operator Theory Advances and Applications. Birkhäuser, Basel; 2008.Delgado O: L 1 -spaces of vector measures defined on δ -rings. Arch. Math. 2005, 84: 432–443. 10.1007/s00013-005-1128-1Calabuig, JM, Delgado, O, Juan, MA, Sánchez Pérez, EA: On the Banach lattice structure of L w 1 of a vector measure on a δ-ring. Collect. Math. doi:10.1007/s13348–013–0081–8Calabuig JM, Delgado O, Sánchez Pérez EA: Factorizing operators on Banach function spaces through spaces of multiplication operators. J. Math. Anal. Appl. 2010, 364: 88–103. 10.1016/j.jmaa.2009.10.034Delgado O:Optimal domains for kernel operators on [ 0 , ∞ ) × [ 0 , ∞ ) .Stud. Math. 2006, 174: 131–145. 10.4064/sm174-2-2Delgado O, Soria J: Optimal domain for the Hardy operator. J. Funct. Anal. 2007, 244: 119–133. 10.1016/j.jfa.2006.12.011Jiménez Fernández E, Juan MA, Sánchez Pérez EA: A Komlós theorem for abstract Banach lattices of measurable functions. J. Math. Anal. Appl. 2011, 383: 130–136. 10.1016/j.jmaa.2011.05.010Curbera, GP: El espacio de funciones integrables respecto de una medida vectorial. PhD thesis, Univ. of Sevilla (1992)Sánchez Pérez EA: Compactness arguments for spaces of p -integrable functions with respect to a vector measure and factorization of operators through Lebesgue-Bochner spaces. Ill. J. Math. 2001, 45(3):907–923.Fernández A, Mayoral F, Naranjo F, Sáez C, Sánchez-Pérez EA: Spaces of p -integrable functions with respect to a vector measure. Positivity 2006, 10: 1–16. 10.1007/s11117-005-0016-zCalabuig JM, Juan MA, Sánchez Pérez EA: Spaces of p -integrable functions with respect to a vector measure defined on a δ -ring. Oper. Matrices 2012, 6: 241–262.Lewis DR: On integrability and summability in vector spaces. Ill. J. Math. 1972, 16: 294–307.Masani PR, Niemi H: The integration theory of Banach space valued measures and the Tonelli-Fubini theorems. I. Scalar-valued measures on δ -rings. Adv. 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Income level and regional policies, underlying factors associated with unwarranted variations in conservative breast cancer surgery in Spain

<p>Abstract</p> <p>Background</p> <p>Geographical variations in medical practice are expected to be small when the evidence about the effectiveness and safety of a particular technology is abundant. This would be the case of the prescription of conservative surgery in breast cancer patients. In these cases, when variation is larger than expected by need, socioeconomic factors have been argued as an explanation. Objectives: Using an ecologic design, our study aims at describing the variability in the use of surgical conservative versus non-conservative treatment. Additionally, it seeks to establish whether the socioeconomic status of the healthcare area influences the use of one or the other technique.</p> <p>Methods</p> <p>81,868 mastectomies performed between 2002 and 2006 in 180 healthcare areas were studied. Standardized utilization rates of breast cancer conservative (CS) and non-conservative (NCS) procedures were estimated as well as the variation among areas, using small area statistics. Concentration curves and dominance tests were estimated to determine the impact of income and instruction levels in the healthcare area on surgery rates. Multilevel analyses were performed to determine the influence of regional policies.</p> <p>Results</p> <p>Variation in the use of CS was massive (4-fold factor between the highest and the lowest rate) and larger than in the case of NCS (2-fold), whichever the age group. Healthcare areas with higher economic and instruction levels showed highest rates of CS, regardless of the age group, while areas with lower economic and educational levels yielded higher rates of NCS interventions. Living in a particular Autonomous Community (AC), explained a substantial part of the CS residual variance (up to a 60.5% in women 50 to 70).</p> <p>Conclusion</p> <p>The place where a woman lives -income level and regional policies- explain the unexpectedly high variation found in utilization rates of conservative breast cancer surgery.</p

Circulating tumor cells criteria (CyCAR) versus standard RECIST criteria for treatment response assessment in metastatic colorectal cancer patients

The use of circulating tumor cells (CTCs) as indicators of treatment response in metastatic colorectal cancer (mCRC) needs to be clarified. The objective of this study is to compare the Response Evaluation Criteria in Solid Tumors (RECIST) with the Cytologic Criteria Assessing Response (CyCAR), based on the presence and phenotypic characterization of CTCs, as indicators of FOLFOX–bevacizumab treatment response. We observed a decrease of CTCs (42.8 vs. 18.2%) and VEGFR positivity (69.7% vs. 41.7%) after treatment. According to RECIST, 6.45% of the patients did not show any clinical benefit, whereas 93.55% patients showed a favorable response at 12 weeks. According to CyCAR, 29% had a non-favorable response and 71% patients did not. No significant differences were found between the response assessment by RECIST and CyCAR at 12 or 24 weeks. However, in the multivariate analysis, RECIST at 12 weeks and CyCAR at 24 weeks were independent prognostic factors for OS (HR: 0.1, 95% CI 0.02–0.58 and HR: 0.35, 95% CI 0.12–0.99 respectively). CyCAR results were comparable to RECIST in evaluating the response in mCRC and can be used as an alternative when the limitation of RECIST requires additional response analysis techniques.This work was supported by Roche Spain and a Ph.D. grant from the University of Granada