Miracle-dz/UniFAR-FTUs huggingface dataset:
Use of a Recombinant Cysteine Proteinase from Leishmania (Leishmania) infantum chagasi for the Immunotherapy of Canine Visceral Leishmaniasis

Background A recombinant cysteine proteinase from Leishmania (Leishmania) infantum chagasi (rLdccys1) was previously shown to induce protective immune responses against murine and canine visceral leishmaniasis. These findings encouraged us to use rLdccys1 in the immunotherapy of naturally infected dogs from Teresina, Piauí, a region of high incidence of visceral leishmaniasis in Brazil. Methodology/Principal Findings Thirty naturally infected mongrel dogs displaying clinical signs of visceral leishmaniasis were randomly divided in three groups: one group received three doses of rLdccys1 in combination with the adjuvant Propionibacterium acnes at one month interval between each dose; a second group received three doses of P. acnes alone; a third group received saline. The main findings were: 1) dogs that received rLdccys1 with P. acnes did not display increase of the following clinical signs: weight loss, alopecia, onychogryphosis, cachexia, anorexia, apathy, skin lesions, hyperkeratosis, ocular secretion, and enlarged lymph nodes; they also exhibited a significant reduction in the spleen parasite load in comparison to the control dogs; 2) rLdccys1-treated dogs exhibited a significant delayed type cutaneous hypersensitivity elicited by the recombinant antigen, as well as high IgG2 serum titers and low IgG1 serum titers; sera from rLdccys1-treated dogs also contained high IFN-γ and low IL-10 concentrations; 3) control dogs exhibited all of the clinical signs of visceral leishmaniasis and had low serum IgG2 and IFN-γ levels and high concentrations of IgG1 and IL-10; 4) all of the dogs treated with rLdccys1 were alive 12 months after treatment, whereas dogs which received either saline or P. acnes alone died within 3 to 7 months. Conclusions/Significance These findings illustrate the potential use of rLdccys1 as an additional tool for the immunotherapy of canine visceral leishmaniasis and support further studies designed to improve the efficacy of this recombinant antigen for the treatment of this neglected disease.
Mechanisms of Subcutaneous Absorption of Rituximab in Rats

Absorption of monoclonal antibodies (mAbs) after s.c. injection results from the interplay among several kinetic processes. The aims of this study were to investigate the absorption mechanisms of rituximab in rats by using slow s.c. infusion and coadministration with nonspecific IgG or hyaluronidase, and to evaluate the predictive performance of the pharmacokinetic model previously developed to describe the nonlinear absorption behavior of mAbs. Rituximab serum concentrations were measured after s.c. coadministration with nonspecific IgG and hyaluronidase to rats. Several dose levels and different injection sites were evaluated. For the back site, 6.5- and 2.6-fold decreases in the area under the concentration-time curve were obtained after coadministration with IgG for 1 and 10 mg/kg doses compared with administration of rituximab alone. For the abdomen, only a minor reduction in concentrations was observed. Hyaluronidase increased the rate of s.c. absorption and the bioavailability (1.9- and 1.6-fold for the back and the abdomen injection of 10 mg/kg). Our previously established pharmacokinetic model provided excellent predictions of the effect of nonspecific IgG on rituximab absorption. In conclusion, the magnitude of the effect of absorption modifiers is dependent on the site of injection and the dose level of rituximab. Pharmacokinetic profiles further support the hypothesis that neonatal Fc receptor–mediated transport is a major determinant of s.c. absorption of mAbs.
Chapter 28B - Prophylactic Antibiotics

receive prophylactic antibiotics, primarily for surgical procedures. Although early studies in the 1950s and 1960s concluded that prophylaxis was not helpful, many of these studies were poorly done, and the basic principles of appropriate prophylactic antibiotic use were not understood. In reality, patients often were given therapeutic antibiotics; that is, the infection had already occurred. Since these early studies, data have shown clearly that prophylactic antibiotics are useful in certain circumstances.
Short‐acting glucagon‐like peptide‐1 receptor agonists as add‐on to insulin therapy in type 1 diabetes: A review

A large proportion of patients with type 1 diabetes do not reach their glycaemic target of glycated hemoglobin (HbA1c) <7.0% (53 mmol/mol) and, furthermore, an increasing number of patients with type 1 diabetes are overweight and obese. Treatment of type 1 diabetes is based on insulin therapy, which is associated with well‐described and unfortunate adverse effects such as hypoglycaemia and increased body weight. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) are the focus of increasing interest as a possible adjunctive treatment to insulin in type 1 diabetes because of their glucagonostatic and extrapancreatic effects. So far, the focus has mainly been on the long‐acting GLP‐1RAs, but the risk–benefit ratio emerging from studies evaluating the effect of long‐acting GLP‐1RAs as adjunctive therapy to insulin therapy in patients with type 1 diabetes has been disappointing. This might be attributable to a lack of glucagonostatic effect of these long‐acting GLP‐1RAs in type 1 diabetes, alongside development of tachyphylaxis to GLP‐1‐induced retardation of gastric emptying. In contrast, the short‐acting GLP‐1RAs seem to have a preserved and sustained effect on glucagon secretion and gastric emptying in patients with type 1 diabetes, which could translate into effective lowering of postprandial glucose excursions; however, these observations regarding short‐acting GLP‐1RAs are all derived from small open‐label trials and should thus be interpreted with caution. In the present paper we review the potential role of GLP‐1RAs, in particular short‐acting GLP‐1RAs, as add‐on to insulin in the treatment of type 1 diabetes.
Radiation from a dipole embedded in a dielectric slab

A unified analytical treatment of the radiation from an electric dipole of arbitrary orientation embedded at an arbitrary location within a symmetrically clad dielectric slab is presented. Both the emission into three-dimensional (3-D) radiation modes, corresponding to emission within the critical angle escape cone within the dielectric slab, and into the two-dimensional (2-D) waveguide modes are evaluated from a single calculation. The model is valid for arbitrary dielectric contrast between the slab and the cladding. The mathematical approach uses well-known complex analysis techniques: the 3-D radiation is described by a steepest descents integration around branch cuts while the 2-D waveguide modes correspond to simple poles. The division of the radiated power between the 3-D and 2-D modes is evaluated across the entire range from small dielectric contrast appropriate to diode lasers (/spl lsim/1,1) to the very large dielectric contrast of free-standing semiconductor slabs (/spl sim/12-19). Both enhancement and suppression, depending on position, slab width, dielectric contrast, and wavelength, of the total radiated power in comparison with that in an unbounded dielectric-medium are found for slab widths on the order of a wavelength with a maximum enhancement of /spl sim/30% for these one-dimensional Fabry-Perot structures. For thicker slabs the total radiation is almost constant and equal to that in the unbounded medium for low dielectric contrast while still exhibiting some modulation as increasing thickness allows additional waveguide modes.
Chronic Infection Drives Expression of the Inhibitory Receptor CD200R, and Its Ligand CD200, by Mouse and Human CD4 T Cells

Certain parasites have evolved to evade the immune response and establish chronic infections that may persist for many years. T cell responses in these conditions become muted despite ongoing infection. Upregulation of surface receptors with inhibitory properties provides an immune cell-intrinsic mechanism that, under conditions of chronic infection, regulates immune responses and limits cellular activation and associated pathology. The negative regulator, CD200 receptor, and its ligand, CD200, have been shown to regulate macrophage activation and reduce pathology following infection. We show that CD4 T cells also increase expression of inhibitory CD200 receptors (CD200R) in response to chronic infection. CD200R was upregulated on murine effector T cells in response to infection with bacterial, Salmonella enterica, or helminth, Schistosoma mansoni, pathogens that respectively drive predominant Th1- or Th2-responses. In vitro chronic and prolonged stimuli were required for the sustained upregulation of CD200R, and its expression coincided with loss of multifunctional potential in T effector cells during infection. Importantly, we show an association between IL-4 production and CD200R expression on T effector cells from humans infected with Schistosoma haematobium that correlated effectively with egg burden and, thus infection intensity. Our results indicate a role of CD200R:CD200 in T cell responses to helminths which has diagnostic and prognostic relevance as a marker of infection for chronic schistosomiasis in mouse and man.
A 70-Kilodalton Recombinant Heat Shock Protein ofCandida albicans Is Highly Immunogenic and Enhances Systemic Murine Candidiasis

ABSTRACT The 70-kDa recombinant Candida albicans heat shock protein (CaHsp70) and its 21-kDa C-terminal and 28-kDa N-terminal fragments (CaHsp70-Cter and CaHsp70-Nter, respectively) were studied for their immunogenicity, including proinflammatory cytokine induction in vitro and in vivo, and protection in a murine model of hematogenous candidiasis. The whole protein and its two fragments were strong inducers of both antibody (Ab; immunoglobulin G1 [IgG1] and IgG2b were the prevalent isotypes) and cell-mediated immunity (CMI) responses in mice. CaHsp70 preparations were also recognized as CMI targets by peripheral blood mononuclear cells of healthy human subjects. Inoculation of CaHsp70 preparations into immunized mice induced rapid production of interleukin-6 (IL-6) and tumor necrosis factor alpha, peaking at 2 to 5 h and declining within 24 h. CaHsp70 and CaHsp70-Cter also induced gamma interferon (IFN-γ), IL-12, and IL-10 but not IL-4 production by CD4+ lymphocytes cocultured with splenic accessory cells from nonimmunized mice. In particular, the production of IFN-γ was equal if not superior to that induced in the same cells by whole, heat-inactivated fungal cells or the mitogenic lectin concanavalin A. In immunized mice, however, IL-4 but not IL-12 was produced in addition to IFN-γ upon in vitro stimulation of CD4+ cells with CaHsp70 and CaHsp70-Cter. These animals showed a decreased median survival time compared to nonimmunized mice, and their mortality was strictly associated with organ invasion by fungal hyphae. Their enhanced susceptibility was attributable to the immunization state, as it did not occur in congenitally athymic nude mice, which were unable to raise either Ab or CMI responses to CaHsp70 preparations. Together, our data demonstrate the elevated immunogenicity of CaHsp70, with which, however, no protection against but rather some enhancement of Candida infection seemed to occur in the mouse model used.
Pharmacogenetics of Antidepressant Drugs: An Update

SUMMARY Pharmacological treatment of depressive disorders is characterized by poor predictability of individual response. In recent years, the increasing evidence has demonstrated that genetic factors play a critical role in determining the differences in treatment outcome to antidepressant drugs. A number of pharmacogenetic studies on antidepressant drugs has been conducted, and genetic variations at level of drug metabolizing enzymes, drug transporters and drug targets, possibly influencing the clinical response, have been identified. Pharmacogenetics may hopefully provide the basis for individualized pharmacotherapy of depressive disorders in order to maximize the probability of a favorable response and minimize the risk of adverse drug reactions. In this article, the major findings related to the pharmacogenetics of genes involved in the pharmacokinetics and pharmacodynamics of antidepressant drugs are critically reviewed.
Topography of Lipid Droplet-Associated Proteins: Insights from Freeze-Fracture Replica Immunogold Labeling

Lipid droplets are not merely storage depots for superfluous intracellular lipids in times of hyperlipidemic stress, but metabolically active organelles involved in cellular homeostasis. Our concepts on the metabolic functions of lipid droplets have come from studies on lipid droplet-associated proteins. This realization has made the study of proteins, such as PAT family proteins, caveolins, and several others that are targeted to lipid droplets, an intriguing and rapidly developing area of intensive inquiry. Our existing understanding of the structure, protein organization, and biogenesis of the lipid droplet has relied heavily on microscopical techniques that lack resolution and the ability to preserve native cellular and protein composition. Freeze-fracture replica immunogold labeling overcomes these disadvantages and can be used to define at high resolution the precise location of lipid droplet-associated proteins. In this paper illustrative examples of how freeze-fracture immunocytochemistry has contributed to our understanding of the spatial organization in the membrane plane and function of PAT family proteins and caveolin-1 are presented. By revisiting the lipid droplet with freeze-fracture immunocytochemistry, new perspectives have emerged which challenge prevailing concepts of lipid droplet biology and may hopefully provide a timely impulse for many ongoing studies.
A Novel Geranylgeranyl Transferase Inhibitor in Combination with Lovastatin Inhibits Proliferation and Induces Autophagy in STS-26T MPNST Cells

Prenylation inhibitors have gained increasing attention as potential therapeutics for cancer. Initial work focused on inhibitors of farnesylation, but more recently geranylgeranyl transferase inhibitors (GGTIs) have begun to be evaluated for their potential antitumor activity in vitro and in vivo. In this study, we have developed a nonpeptidomimetic GGTI, termed GGTI-2Z [(5-nitrofuran-2-yl)methyl-(2Z,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl 4-chlorobutyl(methyl)phosphoramidate], which in combination with lovastatin inhibits geranylgeranyl transferase I (GGTase I) and GGTase II/RabGGTase, without affecting farnesylation. The combination treatment results in a G0/G1 arrest and synergistic inhibition of proliferation of cultured STS-26T malignant peripheral nerve sheath tumor cells. We also show that the antiproliferative activity of drugs in combination occurs in the context of autophagy. The combination treatment also induces autophagy in the MCF10.DCIS model of human breast ductal carcinoma in situ and in 1c1c7 murine hepatoma cells, where it also reduces proliferation. At the same time, there is no detectable toxicity in normal immortalized Schwann cells. These studies establish GGTI-2Z as a novel geranylgeranyl pyrophosphate derivative that may work through a new mechanism involving the induction of autophagy and, in combination with lovastatin, may serve as a valuable paradigm for developing more effective strategies in this class of antitumor therapeutics.
Transduction of Proteins into Leishmania Tarentolae by Formation of Non‐Covalent Complexes With Cell‐Penetrating Peptides

Cell‐penetrating peptides (CPPs) are used to transport peptides, proteins, different types of ribonucleic acids (or mimics of these molecules), and DNA into live cells, both plant and mammalian. Leishmania belongs to the class of protozoa having, in comparison to mammalian cells, a different lipid composition of the membrane, proteoglycans on the surface, and signal pathways. We investigated the uptake of two different and easily detectable proteins into the non‐pathogenic strain Leishmania tarentolae. From the large number of CPPs available, six and a histone were chosen specifically for their ability to form non‐covalent complexes. For Leishmania we used the enzyme β‐galactosidase and fluorescent labeled bovine serum albumin as cargoes. The results are compared to similar internalization studies using mammalian cells [Mussbach et al., ]. Leishmania cells can degrade CPPs by a secreted and membrane‐bound chymotrypsin‐like protease. Both cargo proteins were internalized with sufficient efficiency and achieved intramolecular concentrations similar to mammalian cells. The transport efficiencies of the CPPs differed from each other, and showed a different rank order for both cargoes. The intracellular distribution of fluorescent‐labeled bovine serum albumin showed highest concentrations in the nucleus and kinetoplast. Leishmania are susceptible to high concentrations of some CPPs, although comparably dissimilar to mammalian cells. MPG‐peptides are more cytotoxic in Leishmania than in mammalian cells, acting as antimicrobial peptides. Our results contribute to a better understanding of molecular interactions in Leishmania cells and possibly to new treatments of leishmaniasis. J. Cell. Biochem. 115: 243–252, 2014. © 2013 Wiley Periodicals, Inc.
REM sleep behavior disorder and vocal cord paralysis in Machado‐Joseph disease

We evaluated the occurrence of REM sleep behaviour disorder (RBD) and vocal cord abductor paralysis (VCAP) in a group of 9 Machado‐Joseph disease (MJD) patients. RBD was diagnosed by clinical history plus audiovisual polysomnography in 4 men and 1 woman (55%). While dreaming, 4 fell out of the bed and the other injured his arms. Laryngoscopy detected bilateral VCAP in 1 patient with stridor who required emergency tracheotomy, and partial vocal cord abductor restriction in 2. RBD and VCAP are two potentially injurious conditions that should be considered part of the clinical spectrum of MJD. © 2003 Movement Disorder Society
Left Ventricular Performance in Normal Subjects: A Comparison of the Responses to Exercise in the Upright and Supine Positions

Left ventricular (LV) performance at rest and during multilevel exercise in the supine and upright positions was studied in seven normal subjects with equilibrium radionuclide ventriculography. The mean left ventricular end-diastolic volume (LVEDV) during supine rest was 107 4 10 ml (± SEM) and 85 ± 6 ml (p < 0.02) in the upright position; the mean resting left ventricular end-systolic volumes (LVESV) were not diSferent in the upright and supine positions. The LV ejection fraction (LVEF) tended to be slightly higher in the supine (76 ± 2%) than in the upright position (72 4%). The resting hpart rate was 89 + 5 beats/min upright, compared with 71 ± 6 beats/min supine (p < 0.05). Multilevel exercise testing was carried out at a low work load of 300 kpm/min, an intermediate work load of 600–750 kpm/min and a peak work load of 1092 66 kpm/min supine and 946 ± 146 kpm/min upright (p < 0.05). With peak exercise, supine LVEDV increased significantly, to 135 ± 13 ml (27%), but LVESV did not change. LVEF increased from 76 ± 2% to 84 i 2% (p < 0.05). With upright exercise, LVEDV increased 39% above the resting level, to 116 ± 8 ml (p < 0.02), but remained lower than the supine LVEDVs at intermediate (p < 0.05) and peak work loads. LVESV decreased significantly by 41%, to 19 ± 3 ml, and was significantly smaller than the corresponding supine volume at intermediate and peak exercise (p < 0.05). LVEF increased from 72 ± 4% to 91 ± 2% (p <0.05), which was significantly higher than peak supine LVEF (p < 0.05). Heart rates at rest and during exercise were higher in the upright position (p < 0.05), but arterial pressures and double products did not differ significantly.Measurements of LV volumes at rest and during exercise in both the supine and upright positions by dynamic radionuclide scintigraphy suggest that stroke volume during exercise is maintained by a combination of the Frank-Starling mechanism and an enhanced contractile state.
Semantic analysis of normalisation by evaluation for typed lambda calculus

This paper studies normalisation by evaluation for typed lambda calculus from a categorical and algebraic viewpoint. The first part of the paper analyses the lambda definability result of Jung and Tiuryn via Kripke logical relations and shows how it can be adapted to unify definability and normalisation, yielding an extensional normalisation result. In the second part of the paper the analysis is refined further by considering intensional Kripke relations (in the form of glueing) and shown to provide a function for normalising terms, casting normalisation by evaluation in the context of categorical glueing. The technical development includes an algebraic treatment of the syntax and semantics of the typed lambda calculus that allows the definition of the normalisation function to be given within a simply typed meta-theory.
Textures of liquid crystals

Preface.Foreword. 1. Introduction.2. Surface Anchoring and Elasticity.3. Polarizing Microscopy.4. The Blue Phases.5. The Nematic and Cholesteric Phases.6. Twist Grain Boundary Phases.7. The Fluid Smectic Phases.8. The SmC Subphases.9. The Hexatic Phases.10. Soft Crystal Phases and Crystallization.11. Other Liquid Crystal Phases.Appendix A.Appendix B.Color Plates.Index.
Immunomodulating Therapy With Intravenous Immunoglobulin in Patients With Chronic Heart Failure

BackgroundCongestive heart failure (CHF) is characterized by enhanced immune activation, and immune-mediated mechanisms may play a pathogenic role in this disorder. Based on the immunomodulatory effects of intravenous immunoglobulin (IVIG), we hypothesized that IVIG could downregulate inflammatory responses in CHF patients and have potential beneficial effects on the left ventricular ejection fraction (LVEF). Methods and ResultsForty patients with chronic symptomatic CHF and LVEF of <40%, stratified according to cause (ie, ischemic and idiopathic dilated cardiomyopathy), were randomized in a double-blind fashion to receive therapy with IVIG or placebo for a total period of 26 weeks. Our main findings were that (1) IVIG, but not placebo, induced a marked rise in plasma levels of the anti-inflammatory mediators interleukin (IL)-10, IL-1 receptor antagonist, and soluble tumor necrosis factor receptors; (2) significantly correlated with these anti-inflammatory effects, IVIG, but not placebo, induced a significant increase in LVEF from 26±2% to 31±3% (P <0.01), and this was found independent of the cause of heart failure; and (3) N-terminal pro–atrial natriuretic peptide decreased significantly after induction therapy and continued to decrease toward the end of study during IVIG therapy (P <0.001) but remained unchanged during placebo. ConclusionsWe demonstrated an IVIG-induced change in the balance between inflammatory and anti-inflammatory cytokines that favored an anti-inflammatory net effect in CHF. This effect was significantly correlated with an improvement in LVEF, suggesting a potential for immunomodulating therapy in addition to optimal conventional cardiovascular treatment regimens in CHF patients.