Polarization transfer observables for quasielastic proton-nucleus scattering in terms of a complete Lorentz invariant representation of the NN scattering matrix

For the calculation of polarization transfer observables for quasielastic scattering of protons on nuclei, a formalism in the context of the Relativistic Plane Wave Impulse Approximation is developed, in which the interaction matrix is expanded in terms of a complete set of 44 independent invariant amplitudes. A boson-exchange model is used to predict the 39 amplitudes which were omitted in the formerly used five-term parameterization(the SPVAT form) of the nucleon-nucleon scattering matrix. Use of the complete set of amplitudes eliminates the arbitrariness of the five-term representation.Comment: 29 pages, 2 figure

Time-dependent Density Functional calculation of e-H scattering

Phase shifts for single-channel elastic electron-atom scattering are derived from time-dependent density functional theory. The H$^-$ ion is placed in a spherical box, its discrete spectrum found, and phase shifts deduced. Exact-exchange yields an excellent approximation to the ground-state Kohn-Sham potential, while the adiabatic local density approximation yields good singlet and triplet phase shifts.Comment: 5 pages, 4 figures, 1 tabl

Feynman-Schwinger representation approach to nonperturbative physics

The Feynman-Schwinger representation provides a convenient framework for the cal culation of nonperturbative propagators. In this paper we first investigate an analytically solvable case, namely the scalar QED in 0+1 dimension. With this toy model we illustrate how the formalism works. The analytic result for the self energy is compared with the perturbative result. Next, using a $\chi^2\phi$ interaction, we discuss the regularization of various divergences encountered in this formalism. The ultraviolet divergence, which is common in standard perturbative field theory applications, is removed by using a Pauli-Villars regularization. We show that the divergence associated with large values of Feynman-Schwinger parameter $s$ is spurious and it can be avoided by using an imaginary Feynman parameter $is$.Comment: 26 pages, 9 figures, minor correctio

Two-pion exchange potential and the πN\pi N amplitude

We discuss the two-pion exchange potential which emerges from a box diagram with one nucleon (the spectator) restricted to its mass shell, and the other nucleon line replaced by a subtracted, covariant $\pi N$ scattering amplitude which includes $\Delta$, Roper, and $D_{13}$ isobars, as well as contact terms and off-shell (non-pole) dressed nucleon terms. The $\pi N$ amplitude satisfies chiral symmetry constraints and fits $\pi N$ data below $\sim$ 700 MeV pion energy. We find that this TPE potential can be well approximated by the exchange of an effective sigma and delta meson, with parameters close to the ones used in one-boson-exchange models that fit $NN$ data below the pion production threshold.Comment: 9 pages (RevTex) and 7 postscript figures, in one uuencoded gzipped tar fil

Effect of Vasopressin on the Hypothalamic-Pituitary-Adrenal Axis in ADPKD Patients during V2 Receptor Antagonism

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) are treated with a vasopressin V2 receptor antagonist (V2RA) to slow disease progression. This drug increases vasopressin considerably in these patients with already elevated baseline levels. Vasopressin is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis through V1 and V3 receptor activation. It is unknown whether this increase in vasopressin during V2RA treatment affects glucocorticoid production. Methods: Twenty-seven ADPKD patients were studied on and off treatment with a V2RA and compared to age- and sex-matched healthy controls and IgA nephropathy patients, the latter also matched for kidney function. Vasopressin was measured by its surrogate copeptin. Twenty-four-hour urinary excretions of cortisol, cortisone, tetrahydrocortisone, tetrahydrocortisol, allotetrahydrocortisol, and the total glucocorticoid pool were measured. Results: At baseline, ADPKD patients demonstrated a higher copeptin concentration in comparison with healthy controls, while urinary excretion of cortisol and cortisone was lower (medians of 0.23 vs. 0.34 mu mol/24 h, p = 0.007, and 0.29 vs. 0.53 mu mol/24 h, p <0.001, respectively). There were no differences in cortisol and cortisone excretion compared to IgA nephropathy patients. Cortisol, cortisone, and total glucocorticoid excretions correlated with kidney function (R = 0.37, 0.58, and 0.19, respectively; all p <0.05). Despite that V2RA treatment resulted in a 3-fold increase in copeptin, only cortisone excretion increased (median of 0.44 vs. baseline 0.29 mu mol/24 h, p <0.001), whereas no changes in cortisol or total glucocorticoid excretion were observed. Conclusions: Increased concentration of vasopressin in ADPKD patients at baseline and during V2RA treatment does not result in activation of the HPA axis. The impaired glucocorticoid production in these patients is related to their degree of kidney function impairment

Asymptotic Behavior of Inflated Lattice Polygons

We study the inflated phase of two dimensional lattice polygons with fixed perimeter $N$ and variable area, associating a weight $\exp[pA - Jb ]$ to a polygon with area $A$ and $b$ bends. For convex and column-convex polygons, we show that $/A_{max} = 1 - K(J)/\tilde{p}^2 + \mathcal{O}(\rho^{-\tilde{p}})$, where $\tilde{p}=pN \gg 1$, and $\rho<1$. The constant $K(J)$ is found to be the same for both types of polygons. We argue that self-avoiding polygons should exhibit the same asymptotic behavior. For self-avoiding polygons, our predictions are in good agreement with exact enumeration data for J=0 and Monte Carlo simulations for $J \neq 0$. We also study polygons where self-intersections are allowed, verifying numerically that the asymptotic behavior described above continues to hold.Comment: 7 page

The Effect of Tryptophan 2,3-Dioxygenase Inhibition on Kynurenine Metabolism and Cognitive Function in the APP23 Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD) is associated with progressive endogenous neurotoxicity and hampered inflammatory regulation. The kynurenine (Kyn) pathway, which is controlled by tryptophan 2,3-dioxygenase (TDO), produces neuroactive and anti-inflammatory metabolites. Age-related Kyn pathway activation might contribute to AD pathology in humans, and inhibition of TDO was found to reduce AD-related cellular toxicity and behavioral deficits in animal models. To further explore the effect of aging on the Kyn pathway in the context of AD, we analyzed Kyn metabolite profiles in serum and brain tissue of the APP23 amyloidosis mouse model. We found that aging had genotype-independent effects on Kyn metabolite profiles in serum, cortex, hippocampus and cerebellum, whereas serum concentrations of many Kyn metabolites were reduced in APP23 mice. Next, to further establish the role of TDO in AD-related behavioral deficits, we investigated the effect of long-term pharmacological TDO inhibition on cognitive performance in APP23 mice. Our results indicated that TDO inhibition reversed recognition memory deficits without producing measurable changes in cerebral Kyn metabolites. TDO inhibition did not affect spatial learning and memory or anxiety-related behavior. These data indicate that age-related Kyn pathway activation is not specific for humans and could represent a cross-species phenotype of aging. These data warrant further investigation on the role of peripheral Kyn pathway disturbances and cerebral TDO activity in AD pathophysiology

Age- and Disease-Specific Changes of the Kynurenine Pathway in Parkinson's and Alzheimer's Disease

The Kynurenine (Kyn) pathway, which regulates neuroinflammation and n-methyl-d-aspartate (NMDA) receptor activation, is implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). Age-related changes in Kyn metabolism and altered cerebral Kyn uptake along large-neutral amino acid (LNAA) transporters, could contribute to these diseases. To gain further insight into the role and prognostic potential of the Kyn pathway in PD and AD, we investigated systemic and cerebral Kyn metabolite production and estimations of their transporter-mediated uptake in the brain. Kyn metabolites and LNAAs were retrospectively measured in serum and cerebrospinal fluid (CSF) of clinically well-characterized PD patients (n=33), AD patients (n=33) and age-matched controls (n=39) using solid-phase extraction-liquid chromatographic-tandem mass spectrometry. Aging was disease-independently associated with increased Kyn, kynurenic acid and quinolinic acid in serum and CSF. Concentrations of kynurenic acid were reduced in CSF of PD and AD patients (p=.001; p=.002) but estimations of Kyn brain uptake did not differ between diseased and controls. Furthermore, serum Kyn and quinolinic acid levels strongly correlated with their respective content in CSF and Kyn in serum negatively correlated with AD disease severity (p=.002). Kyn metabolites accumulated with aging in serum and CSF similarly in PD patients, AD patients and control subjects. In contrast, kynurenic acid was strongly reduced in CSF of PD and AD patients. Differential transporter-mediated Kyn uptake is unlikely to majorly contribute to these cerebral Kyn pathway disturbances. We hypothesize that the combination of age- and disease-specific changes in cerebral Kyn pathway activity could contribute to reduced neurogenesis and increased excitotoxicity in neurodegenerative disease. This article is protected by copyright. All rights reserved

Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients

Introduction: In dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations. Methods: Concentrations of metabolites of dopaminergic, serotonergic and noradrenergic pathways were measured in platelet-rich plasma in 41 myoclonus-dystonia (M-D), 25 dopa-responsive dystonia (DRD), 50 cervical dystonia (CD) patients and 55 healthy individuals. (Non-)motor symptoms were assessed using validated instruments, and correlated with concentrations of metabolites. Results: A significantly higher concentration of 3-methoxytyramine (0.03 vs. 0.02 nmol/L, p < 0.01), a metabolite of dopamine, and a reduced concentration of tryptophan (50 vs. 53 μmol/L, p = 0.03), the precursor of serotonin was found in dystonia patients compared to controls. The dopamine/levodopa ratio was higher in CD patients compared to other dystonia groups (p < 0.01). Surprisingly, relatively high concentrations of levodopa were found in the untreated DRD patients. Low concentrations of levodopa were associated with severity of dystonia (rs = −0.3, p < 0.01), depression (rs = −0.3, p < 0.01) and fatigue (rs = −0.2, p = 0.04). Conclusion: This study shows alterations in the dopaminergic and serotonergic metabolism of patients with dystonia, with dystonia subtype specific changes. Low concentrations of levodopa, but not of serotonergic metabolites, were associated with both motor and non-motor symptoms. Further insight into the dopaminergic and serotonergic systems in dystonia with a special attention to the kinetics of enzymes involved in these pathways, might lead to better treatment options

Neuroendocrine tumours and their microenvironment

Tumours can escape the immune system by expressing programmed death-ligand-1 (PD-L1), which allows them to bind to PD-1 on T-cells and avoid recognition by the immune system. Regulatory T-cells (Tregs), indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) also play a role in immune suppression. Knowledge about the interaction of neuroendocrine tumours (NETs) with their immune microenvironment and the role of immunotherapy in patients with NET is scarce. Here, we investigated the immune microenvironment of serotonin-producing (SP) and non-serotonin-producing NETs (NSP-NETs). Tumours of 33 patients with SP-NET and 18 patients with NSP-NET were studied. Immunohistochemical analyses were performed for PD-L1, T-cells, IDO, TDO, mismatch repair proteins (MMRp) and activated fibroblasts. PD-L1 expression was seen in <1% of tumour and T-cells. T-cells were present in 33% of NETs, varying between 1 and 10% T-cells per high power field. IDO was expressed in tumour cells in 55% of SP-NETs and 22% of NSP-NETs (p = 0.039). TDO was expressed in stromal cells in 64% of SP-NETs and 13% of NSP-NETs (p = 0.001). No tumours had loss of MMRp. TDO-expressing stromal cells also strongly expressed alpha-SMA and were identified as cancer-associated fibroblasts (CAFs). Factors that are associated with a response to checkpoint inhibitor treatment were absent or only present to a limited extent in the tumour microenvironment of NETs. The expression of IDO and TDO in a substantial part of NETs and the presence of CAFs suggest two mechanisms that could be responsible for the cold immune microenvironment, which should be explored to enhance anti-tumour immunity and clinical responses