Intravenous immunoglobulin in the treatment of primary trigeminal neuralgia refractory to carbamazepine: a study protocol[ISRCTN33042138]

BACKGROUND: We have recently reported successful treatment of patients with chronic pain syndromes using human pooled intravenous immunoglobulin (IVIG) in a prospective, open-label cohort study. A randomised, placebo controlled, double blinded study is needed to confirm these results. We chose to study patients with carbamazepine resistant primary Trigeminal Neuralgia (rpTN), as these had responded particularly well to IVIG. A protocol involving the use of IVIG in rpTN is complex for three reasons: 1. The effect of IVIG does not follow simple dose-response rules; 2. The response pattern of patients to IVIG was variable and ranged between no effect at all and pain free remission between two weeks and >1 year; 3. TN is characterized by extremely severe pain, for which operative intervention is (if temporarily) helpful in most patients. DESIGN: A placebo controlled, parallel, add-on model was developed and the primary outcome variable defined as the length of time during which patients remain in the study. Study groups are compared using Kaplan-Maier survival analysis. Patients record their response to treatment ("severe, moderate, slight, no pain"). The study coordinator monitors pain diaries. Severe or moderate pain of three days duration will result in termination of the study for that patient. CONCLUSIONS: This study design utilizes a method of survival analysis and is novel in chronic pain research. It allows for both early departure from the study and voluntary crossover upon non-response. It may be applicable to the analysis of IVIG efficacy in other chronic pain syndromes

Toxoplasma effectors targeting host signaling and transcription

Early electron microscopy studies revealed the elaborate cellular features that define the unique adaptations of apicomplexan parasites. Among these were bulbous rhoptry (ROP) organelles and small, dense granules (GRAs), both of which are secreted during invasion of host cells. These early morphological studies were followed by the exploration of the cellular contents of these secretory organelles, revealing them to be comprised of highly divergent protein families with few conserved domains or predicted functions. In parallel, studies on host-pathogen interactions identified many host signaling pathways that were mysteriously altered by infection. It was only with the advent of forward and reverse genetic strategies that the connections between individual parasite effectors and the specific host pathways that they targeted finally became clear. The current repertoire of parasite effectors includes ROP kinases and pseudokinases that are secreted during invasion and that block host immune pathways. Similarly, many secretory GRA proteins alter host gene expression by activating host transcription factors, through modification of chromatin, or by inducing small noncoding RNAs. These effectors highlight novel mechanisms by whichhas learned to harness host signaling to favor intracellular survival and will guide future studies designed to uncover the additional complexity of this intricate host-pathogen interaction

Geometric properties and continuity of the pre-duality mapping in Banach space

We use the preduality mapping in proving characterizations of some geometric properties of Banach spaces. In particular, those include nearly strongly convexity, nearly uniform convexity-a property introduced by K. Goebel and T. Sekowski-, and nearly very convexity.We thank a referee for the careful reading of the manuscript. His/her observations substantially improved the overall aspect of the present work, detected several misprints and made some convenient changes. This work was supported by: (1) The National Natural Science Foundation of China (Grant no. 11271248). (2) Specific Academic Discipline Project of Shanghai Municipal Education Commission (Grant no. B-8932-13-0136). (3) Project MTM2011-22417, Ministerio de Ciencia e Innovacion, Spain (V. Montesinos).Zhang, ZH.; Montesinos Santalucia, V.; Liu, CY.; Gong, WZ. (2015). Geometric properties and continuity of the pre-duality mapping in Banach space. Revista de la Real Academia de Ciencias Exactas, Fisicas y Naturales. Serie A. Matematicas. 109(2):407-416. https://doi.org/10.1007/s13398-014-0190-6S4074161092Bandyopadhyay, P., Huang, D., Lin, B.L., Troyanski, S.L.: Some generalizations of local uniform rotundity. J. Math. Anal. Appl. 252, 906–916 (2000)Bandyopadhyay, P., Li, Y., Lin, B., Narayana, D.: Proximinality in Banach spaces. J. Math. Anal. Appl. 341, 309–317 (2008)Diestel, J.: Geometry of Banach Spaces. Selected Topics, LNM, vol. 485. Springer, Berlin (1975)Fabian, M., Habala, P., Hájek, P., Montesinos, V., Zizler, V.: Banach Space Theory. The Basis for Linear and Nonlinear Analysis, CMS Books in Mathematics. Springer, Berlin (2011)Giles, J.R., Gregory, D.A., Sims, B.: Geometrical implications of upper semi-continuity of the duality mapping on a Banach space. Pacific J. Math. 79(1), 99–109 (1978)Goebel, K., Sekowski, T.: The modulus of non-compact convexity. Ann. Univ. M. Curie-Sklodowska, Sect. A 38, 41–48 (1984)Guirao, A.J., Montesinos, V.: A note in approximative compactness and continuity of metric projections in Banach spaces. J. Convex Anal. 18, 397–401 (2011)Huff, R.: Banach spaces which are nearly uniformly convex. Rocky Mountain J. Math. 10(4), 743–749 (1980)Kutzarova, D., Rolewicz, S.: On nearly uniformly convex sets. Arch. Math. 57, 385–394 (1991)Kutzarova, D., Lin, B.L., Zhang, W.: Some geometrical properties of Banach spaces related to nearly uniform convexity. Contemp. Math. 144, 165–171 (1993)Kutzarova, D., Prus, S.: Operators which factor through nearly uniformly convex spaces. Boll. Un. Mat. Ital. B (7) 9, 2, 479–494 (1995)Montesinos, V.: Drop property equals reflexivity. Studia Math. 87, 93–100 (1987)Phelps, R.R.: Convex Functions, Monotone Operators and Differentiability, LNM, vol. 1364, 2nd edn. Springer, Berlin (1993)Rolewicz, S.: On drop property. Studia Math. 85, 27–37 (1986)Rolewicz, S.: On $$\Delta$$ Δ -uniform convexity and drop property. Studia Math. 87, 181–191 (1987)Wu, C.X., Li, Y.J.: Strong convexity in Banach spaces. J. Math. Wuhan Univ. 13(1), 105–108 (1993)Wang, J.H., Nan, C.X.: The continuity of subdifferential mapping. J. Math. Anal. Appl. 210, 206–214 (1997)Wang, J.H., Zhang, Z.H.: Characterization of the property (C-K). Acta Math. Sci. Ser. A Chin. Ed. 17(A)(3), 280–284 (1997)Zhang, Z.H., Liu, C.Y.: Some generalization of locally and weakly locally uniformly convex space. Nonlinear Anal. 74(12), 3896–3902 (2011)Zhang, Z.H., Liu, C.Y.: Convexity and proximinality in Banach spaces. J. Funct. Spaces Appl. 2012, 11 (2012). doi: 10.1155/2012/724120 . Article ID 724120Zhang, Z.H., Liu, C.Y.: Convexity and existence of the farthest point. Abstract Appl. Anal. 2011, 9 (2011). doi: 10.1155/2011/139597 . Article ID 139597Zhang, Z.H., Shi, Z.R.: Convexities and approximative compactness and continuity of the metric projection in Banach spaces. J. Approx. Theory 161(2), 802–812 (2009)Zhang, Z.H., Zhang, C.J.: On very rotund Banach spaces. Appl. Math. Mech. (English Ed.) 21(8), 965–970 (2000

Cortical depth dependent functional responses in humans at 7T: improved specificity with 3D GRASE

Ultra high fields (7T and above) allow functional imaging with high contrast-to-noise ratios and improved spatial resolution. This, along with improved hardware and imaging techniques, allow investigating columnar and laminar functional responses. Using gradient-echo (GE) (T2* weighted) based sequences, layer specific responses have been recorded from human (and animal) primary visual areas. However, their increased sensitivity to large surface veins potentially clouds detecting and interpreting layer specific responses. Conversely, spin-echo (SE) (T2 weighted) sequences are less sensitive to large veins and have been used to map cortical columns in humans. T2 weighted 3D GRASE with inner volume selection provides high isotropic resolution over extended volumes, overcoming some of the many technical limitations of conventional 2D SE-EPI, whereby making layer specific investigations feasible. Further, the demonstration of columnar level specificity with 3D GRASE, despite contributions from both stimulated echoes and conventional T2 contrast, has made it an attractive alternative over 2D SE-EPI. Here, we assess the spatial specificity of cortical depth dependent 3D GRASE functional responses in human V1 and hMT by comparing it to GE responses. In doing so we demonstrate that 3D GRASE is less sensitive to contributions from large veins in superficial layers, while showing increased specificity (functional tuning) throughout the cortex compared to GE

Testing Evolutionary and Dispersion Scenarios for the Settlement of the New World

Background: Discussion surrounding the settlement of the New World has recently gained momentum with advances in molecular biology, archaeology and bioanthropology. Recent evidence from these diverse fields is found to support different colonization scenarios. The currently available genetic evidence suggests a ""single migration'' model, in which both early and later Native American groups derive from one expansion event into the continent. In contrast, the pronounced anatomical differences between early and late Native American populations have led others to propose more complex scenarios, involving separate colonization events of the New World and a distinct origin for these groups. Methodology/Principal Findings: Using large samples of Early American crania, we: 1) calculated the rate of morphological differentiation between Early and Late American samples under three different time divergence assumptions, and compared our findings to the predicted morphological differentiation under neutral conditions in each case; and 2) further tested three dispersal scenarios for the colonization of the New World by comparing the morphological distances among early and late Amerindians, East Asians, Australo-Melanesians and early modern humans from Asia to geographical distances associated with each dispersion model. Results indicate that the assumption of a last shared common ancestor outside the continent better explains the observed morphological differences between early and late American groups. This result is corroborated by our finding that a model comprising two Asian waves of migration coming through Bering into the Americas fits the cranial anatomical evidence best, especially when the effects of diversifying selection to climate are taken into account. Conclusions: We conclude that the morphological diversity documented through time in the New World is best accounted for by a model postulating two waves of human expansion into the continent originating in East Asia and entering through Beringia.Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT)[11070091]Fundacao de Amparo a Ciencia do Estado de Sao Paulo (FAPESP)[04/01253-0]Conselho Nacional de Pesquisa (CNPq)[301126-04.6]Max Planck GesellschaftEVAN Marie Curie Research Training Network[MRTN-CT-019564

The role of non-medical therapeutic approaches in the rehabilitation of Complex Regional Pain Syndrome

Purpose of the review: Non-medical therapeutic approaches are fundamental to the management of Complex Regional Pain Syndrome (CRPS) in order to promote the best outcome for patients. This review focuses on three key approaches underpinning CRPS rehabilitation, namely: physiotherapy and occupational therapy, psychological approaches and education and self-management. Recent Findings: Recently published European standards outline the quality of therapeutic care that people with CRPS must receive. Early initiated therapy is essential to optimise outcomes, underpinned by patient education. Therapists should promote early movement of the affected limb and encourage re-engagement with usual activities as immobilisation is known to have negative outcomes. There is evidence to support the possible long-term benefit of graded motor imagery and mirror therapy. Psychological assessment should include identification of depression and post-traumatic stress disorder, as treatment of these conditions may improve the trajectory of CRPS. Novel therapies include neurocognitive approaches and those addressing spatial bias, both of which should provide a focus for future research.Summary: There exists a broad range of non-medical therapeutic approaches to rehabilitation for CPRS that are thought to be important. However, the evidence for their efficacy is limited. Further research using standardised outcomes would be helpful in developing targeted therapies for the future

Angular and Current-Target Correlations in Deep Inelastic Scattering at HERA

Correlations between charged particles in deep inelastic ep scattering have been studied in the Breit frame with the ZEUS detector at HERA using an integrated luminosity of 6.4 pb-1. Short-range correlations are analysed in terms of the angular separation between current-region particles within a cone centred around the virtual photon axis. Long-range correlations between the current and target regions have also been measured. The data support predictions for the scaling behaviour of the angular correlations at high Q2 and for anti-correlations between the current and target regions over a large range in Q2 and in the Bjorken scaling variable x. Analytic QCD calculations and Monte Carlo models correctly describe the trends of the data at high Q2, but show quantitative discrepancies. The data show differences between the correlations in deep inelastic scattering and e+e- annihilation.Comment: 26 pages including 10 figures (submitted to Eur. J. Phys. C

Visually Driven Activation in Macaque Areas V2 and V3 without Input from the Primary Visual Cortex

Creating focal lesions in primary visual cortex (V1) provides an opportunity to study the role of extra-geniculo-striate pathways for activating extrastriate visual cortex. Previous studies have shown that more than 95% of neurons in macaque area V2 and V3 stop firing after reversibly cooling V1 [1], [2], [3]. However, no studies on long term recovery in areas V2, V3 following permanent V1 lesions have been reported in the macaque. Here we use macaque fMRI to study area V2, V3 activity patterns from 1 to 22 months after lesioning area V1. We find that visually driven BOLD responses persist inside the V1-lesion projection zones (LPZ) of areas V2 and V3, but are reduced in strength by ∼70%, on average, compared to pre-lesion levels. Monitoring the LPZ activity over time starting one month following the V1 lesion did not reveal systematic changes in BOLD signal amplitude. Surprisingly, the retinotopic organization inside the LPZ of areas V2, V3 remained similar to that of the non-lesioned hemisphere, suggesting that LPZ activation in V2, V3 is not the result of input arising from nearby (non-lesioned) V1 cortex. Electrophysiology recordings of multi-unit activity corroborated the BOLD observations: visually driven multi-unit responses could be elicited inside the V2 LPZ, even when the visual stimulus was entirely contained within the scotoma induced by the V1 lesion. Restricting the stimulus to the intact visual hemi-field produced no significant BOLD modulation inside the V2, V3 LPZs. We conclude that the observed activity patterns are largely mediated by parallel, V1-bypassing, subcortical pathways that can activate areas V2 and V3 in the absence of V1 input. Such pathways may contribute to the behavioral phenomenon of blindsight

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration