Positronium Laser Cooling via the 1

We report on laser cooling of a large fraction of positronium (Ps) in free flight by strongly saturating the 1^{3}S-2^{3}P transition with a broadband, long-pulsed 243 nm alexandrite laser. The ground state Ps cloud is produced in a magnetic and electric field-free environment. We observe two different laser-induced effects. The first effect is an increase in the number of atoms in the ground state after the time Ps has spent in the long-lived 2^{3}P states. The second effect is one-dimensional Doppler cooling of Ps, reducing the cloud's temperature from 380(20) to 170(20) K. We demonstrate a 58(9)% increase in the fraction of Ps atoms with v_{1D}<3.7×10^{4} ms^{-1}.

Search for magnetic monopoles produced via the Schwinger mechanism.

Electrically charged particles can be created by the decay of strong enough electric fields, a phenomenon known as the Schwinger mechanism1. By electromagnetic duality, a sufficiently strong magnetic field would similarly produce magnetic monopoles, if they exist2. Magnetic monopoles are hypothetical fundamental particles that are predicted by several theories beyond the standard model3-7 but have never been experimentally detected. Searching for the existence of magnetic monopoles via the Schwinger mechanism has not yet been attempted, but it is advantageous, owing to the possibility of calculating its rate through semi-classical techniques without perturbation theory, as well as that the production of the magnetic monopoles should be enhanced by their finite size8,9 and strong coupling to photons2,10. Here we present a search for magnetic monopole production by the Schwinger mechanism in Pb-Pb heavy ion collisions at the Large Hadron Collider, producing the strongest known magnetic fields in the current Universe11. It was conducted by the MoEDAL experiment, whose trapping detectors were exposed to 0.235 per nanobarn, or approximately 1.8 × 109, of Pb-Pb collisions with 5.02-teraelectronvolt center-of-mass energy per collision in November 2018. A superconducting quantum interference device (SQUID) magnetometer scanned the trapping detectors of MoEDAL for the presence of magnetic charge, which would induce a persistent current in the SQUID. Magnetic monopoles with integer Dirac charges of 1, 2 and 3 and masses up to 75 gigaelectronvolts per speed of light squared were excluded by the analysis at the 95% confidence level. This provides a lower mass limit for finite-size magnetic monopoles from a collider search and greatly extends previous mass bounds.

First Search for Dyons with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions.

The MoEDAL trapping detector consists of approximately 800 kg of aluminum volumes. It was exposed during run 2 of the LHC program to 6.46 fb^{-1} of 13 TeV proton-proton collisions at the LHCb interaction point. Evidence for dyons (particles with electric and magnetic charge) captured in the trapping detector was sought by passing the aluminum volumes comprising the detector through a superconducting quantum interference device (SQUID) magnetometer. The presence of a trapped dyon would be signaled by a persistent current induced in the SQUID magnetometer. On the basis of a Drell-Yan production model, we exclude dyons with a magnetic charge ranging up to five Dirac charges (5g_{D}) and an electric charge up to 200 times the fundamental electric charge for mass limits in the range 870-3120 GeV and also monopoles with magnetic charge up to and including 5g_{D} with mass limits in the range 870-2040 GeV.

Magnetic Monopole Search with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions Interpreted in Photon-Fusion and Drell-Yan Production.

MoEDAL is designed to identify new physics in the form of stable or pseudostable highly ionizing particles produced in high-energy Large Hadron Collider (LHC) collisions. Here we update our previous search for magnetic monopoles in Run 2 using the full trapping detector with almost four times more material and almost twice more integrated luminosity. For the first time at the LHC, the data were interpreted in terms of photon-fusion monopole direct production in addition to the Drell-Yan-like mechanism. The MoEDAL trapping detector, consisting of 794 kg of aluminum samples installed in the forward and lateral regions, was exposed to 4.0 fb^{-1} of 13 TeV proton-proton collisions at the LHCb interaction point and analyzed by searching for induced persistent currents after passage through a superconducting magnetometer. Magnetic charges equal to or above the Dirac charge are excluded in all samples. Monopole spins 0, ½, and 1 are considered and both velocity-independent and-dependent couplings are assumed. This search provides the best current laboratory constraints for monopoles with magnetic charges ranging from two to five times the Dirac charge.

Lipid-core nanocapsules increase the oral efficacy of quercetin in cutaneous leishmaniasis.

New oral treatments are needed for all forms of leishmaniasis. Here, the improved oral efficacy of quercetin (Qc) and its penta-acetylated derivative (PQc) was evaluated in cutaneous leishmaniasis after encapsulation in lipid-core nanocapsules (LNCs) of poly(ε-caprolactone). Leishmania amazonensis-infected BALB/c mice were given 51 daily oral doses of free drugs (16 mg kg-1) or LNC-loaded drugs (0·4 mg kg-1). While treatment with free Qc reduced the lesion sizes and parasite loads by 38 and 71%, respectively, LNC-Qc produced 64 and 91% reduction, respectively. The antileishmanial efficacy of PQc was similar but not as potently improved by encapsulation as Qc. None of the treatments increased aspartate aminotransferase, alanine aminotransferase or creatinine serum levels. These findings indicate that when encapsulated in LNC, Qc and, to a lesser extent, PQc can safely produce an enhanced antileishmanial effect even at a 40-fold lower dose, with implications for the development of a new oral drug for cutaneous leishmaniasis.

Anti-parasitic effect of the diuretic and Na+-ATPAse inhibitor furosemide in cutaneous leishmaniasis.

Leishmania amazonensis promastigotes are known to express furosemide (Lasix®)-sensitive P-type membrane Na+-ATPase. In the present study, furosemide activity was studied in intracellular amastigotes and infected BALB/c mice to investigate its efficacy in cutaneous leishmaniasis (CL). Intracellular parasites, but not macrophages, were found to be sensitive to killing by furosemide (IC50 = 87 µ m vs CC50 ≫ 1000 µ m, respectively). Although furosemide did not induce nitric oxide production or intracellular pH changes in infected macrophages, it led to a significant reactive oxygen species (ROS) burst. Freshly isolated tissue parasites expressed a high degree of Na+-ATPase activity that decreased with culture, indicative of a higher enzyme expression in amastigotes than in promastigotes. Both intraperitoneal and oral treatment of L. amazonensis-infected mice with furosemide dosages equivalent to that prescribed as a diuretic significantly reduced the parasite's growth compared with the situation in untreated mice. Combination with oral furosemide increased the efficacy and safety of intraperitoneal treatment with sodium stibogluconate (SSG). To summarize, furosemide control of intracellular leishmanial growth by means of parasite Na+-ATPase inhibition, and macrophage ROS activation may help explain its sole and SSG-combined therapeutic effect against murine CL.

Search for Magnetic Monopoles with the MoEDAL Forward Trapping Detector in 13 TeV Proton-Proton Collisions at the LHC.

MoEDAL is designed to identify new physics in the form of long-lived highly ionizing particles produced in high-energy LHC collisions. Its arrays of plastic nuclear-track detectors and aluminium trapping volumes provide two independent passive detection techniques. We present here the results of a first search for magnetic monopole production in 13 TeV proton-proton collisions using the trapping technique, extending a previous publication with 8 TeV data during LHC Run 1. A total of 222 kg of MoEDAL trapping detector samples was exposed in the forward region and analyzed by searching for induced persistent currents after passage through a superconducting magnetometer. Magnetic charges exceeding half the Dirac charge are excluded in all samples and limits are placed for the first time on the production of magnetic monopoles in 13 TeV pp collisions. The search probes mass ranges previously inaccessible to collider experiments for up to five times the Dirac charge.

Breast reconstruction and revision surgery for implant-associated breast deformities using porcine acellular dermal matrix: a multicenter study of 156 cases.

BACKGROUND: Acellular dermal matrix is increasingly used as caudolateral coverage for breast implants in immediate breast reconstruction after skin-sparing mastectomy or in the correction of implant-associated breast deformities. Matrices of human, bovine, and porcine origin are available. The purpose of this retrospective multicenter study was to report experiences with porcine acellular dermal matrices, as only limited data can be found in the literature. METHODS: In the hospital databases of five institutions, 127 patients were identified who underwent breast reconstructions in 156 breasts using an acellular porcine dermal matrix. Medical records were reviewed. Patients were divided into three groups: immediate expander-implant or direct to implant reconstructions (n = 98), delayed expander-implant reconstructions (n = 14), and revision surgery for implant-associated breast deformities (n = 44). RESULTS: With a mean follow-up of 19.6 months, total major complication rate was 7.1 %: implant loss (3.2 %), skin flap necrosis (2.6 %), delayed skin healing (2.6 %), hematoma (1.9 %), seroma (1.3 %), infection (0.6 %), and capsular contracture (0.6 %). Total minor complication rate was 22.9 %, with seroma being the most frequent complication (19.2 %). In the group of immediate breast reconstructions, 20.4 % of the breasts had received radiotherapy in the past. These patients exhibited a significantly higher rate of seroma than patients without prior radiotherapy (35.0 vs. 14.9 %, p = 0.031). CONCLUSIONS: Complication rates using porcine acellular dermal matrix in breast reconstruction are comparable to complication rates reported in studies using human acellular dermal matrices. Thus, porcine acellular dermal matrices can safely be applied in breast reconstructive surgery.

Periodate-oxidized ATP modulates macrophage functions during infection with Leishmania amazonensis.

Previously, we showed that treating macrophages with ATP impairs the intracellular growth of Leishmania amazonensis, and that the P2X7 purinergic receptor is overexpressed during leishmaniasis. In the present study, we directly evaluated the effect of periodate-oxidized ATP (oATP) on parasite control in Leishmania-infected macrophages. We found that oATP impaired the attachment/entrance of L. amazonensis promastigotes to C57BL/6 mouse macrophages in a P2X7 receptor-independent manner, as macrophages from P2X7(-/-) mice were similarly affected. Although oATP directly inhibited the growth of axenic promastigotes in culture, promoted rapid ultrastructural alterations, and impaired Leishmania internalization by macrophages, it did not affect intracellular parasite multiplication. Upon infection, phagosomal acidification was diminished in oATP-treated macrophages, accompanied by reduced endosomal proteolysis. Likewise, MHC class II molecules expression and ectoATPase activity was decreased by oATP added to macrophages at the time of parasite infection. These inhibitory effects were not due to a cytotoxic effect, as no additional release of lactate dehydrogenase was detected in culture supernatants. Moreover, the capacity of macrophages to produce nitric oxide and reactive oxygen species was not affected by the presence of oATP during infection. We conclude that oATP directly affects extracellular parasite integrity and macrophage functioning.

Memory B cells in mouse models.

One of the principles behind vaccination, as shown by Edward Jenner in 1796, and host protection is immunological memory, and one of the cells central to this is the antigen-experienced memory B cell that responds rapidly upon re-exposure to the initiating antigen. Classically, memory B cells have been defined as progenies of germinal centre (GC) B cells expressing isotype-switched and substantially mutated B cell receptors (BCRs), that is, membrane-bound antibodies. However, it has become apparent over the last decade that this is not the only pathway to B cell memory. Here, we will discuss memory B cells in mice, as defined by (1) cell surface markers; (2) multiple layers; (3) formation in a T cell-dependent and either GC-dependent or GC-independent manner; (4) formation in a T cell-independent fashion. Lastly, we will touch upon memory B cells in; (5) mouse models of autoimmune diseases.

Kalanchoe pinnata inhibits mast cell activation and prevents allergic airway disease.

Aqueous extract of Kalanchoe pinnata (Kp) have been found effective in models to reduce acute anaphylactic reactions. In the present study, we investigate the effect of Kp and the flavonoid quercetin (QE) and quercitrin (QI) on mast cell activation in vitro and in a model of allergic airway disease in vivo. Treatment with Kp and QE in vitro inhibited degranulation and cytokine production of bone marrow-derived mast cells following IgE/FcɛRI crosslinking, whereas treatment with QI had no effect. Similarly, in vivo treatment with Kp and QE decreased development of airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and production of IL-5, IL-13 and TNF. In contrast, treatment with QI had no effect on these parameters. These findings demonstrate that treatment with Kp or QE is effective in treatment of allergic airway disease, providing new insights to the immunomodulatory functions of this plant.

Nanostructured polymer and lipid carriers for sunscreen. Biological effects and skin permeation.

The interest in developing new sunscreens is increasing due to the harmful effects of UV radiation on the skin, such as erythema, accelerated skin ageing (photoageing) and the induction of skin cancer. However, many molecular sunscreens penetrate into the skin causing photoallergies, phototoxic reactions and skin irritation. Thus, the aim of this work was the preparation and characterization of polymeric and solid lipid nanoparticles to act carriers of benzophenone-3 (BZ3), aiming to improve the safety of sunscreen products by increasing the sun protection factor (SPF), decreasing BZ3 skin penetration and decreasing BZ3 concentration in sunscreen formulation. BZ3 was encapsulated in poly(epsilon-caprolactone) (PCL) nanoparticles by the nanoprecipitation method and in solid lipid nanoparticles (SLN) by the hot high pressure homogenization method. The particles were stable for 40 days. The BZ3 encapsulated in PCL nanoparticles was released faster than BZ3 encapsulated in SLN. The sun protection factor increased when BZ3 was encapsulated in both nanostructures. However, BZ3 encapsulated in PCL nanoparticles decreased its skin permeation more than SLN-BZ3. Furthermore, BZ3 encapsulated in SLN did not exhibit cytotoxic or phototoxic effects in human keratinocytes (HaCaT cells) and BABL/c 3T3 fibroblasts, whereas PCL nanoparticles with BZ3 showed phototoxic potential in HaCaT cells. Nevertheless, BZ3 free and encapsulated in PCL nanoparticles or in SLN did not show allergic reactions in mice. Our results suggest that these nanostructures are interesting carriers for sunscreen.

Effectiveness of the immunomodulatory extract of Kalanchoe pinnata against murine visceral leishmaniasis.

Previously, we described the protective action of the immunomodulatory extract of Kalanchoe pinnata (Kp) in murine and human cutaneous leishmaniasis. In the present study, we investigated the effectiveness of Kp against visceral leishmaniasis, using the BALB/c mouse model of infection with Leishmania chagasi. Mice receiving oral daily doses of Kp (400 mg/kg) for 30 days displayed significantly reduced hepatic and splenic parasite burden, when compared with untreated animals. Protectiveness was accompanied by a reduction in parasite-specific IgG serum levels, and impaired capacity of spleen cells to produce IL-4, but not IFN-gamma and nitric oxide upon antigen recall in vitro. The reference drug Pentostam (72 mg/kg) given by the intra-peritoneal route on alternate days produced an anti-leishmanial effect similar to oral Kp. Our findings show that the oral efficacy of Kp, seen previously in murine cutaneous leishmaniasis, extends also to visceral leishmaniasis caused by L. chagasi, a difficult to treat and lethal disease of man.

Immunomodulatory pretreatment with Kalanchoe pinnata extract and its quercitrin flavonoid effectively protects mice against fatal anaphylactic shock.

Previously, we reported the immunosuppressive action of the aqueous extract of Kalanchoe pinnata (Kp) in mice. In the present study, we report on the protective effect of Kp in fatal anaphylactic shock, likewise a Th2-driven immunopathology, and the identification of its active component. Mice daily treated with oral Kp during hypersensitization with ovalbumin were all protected against death when challenged with the allergen, as compared with the 100% mortality in the untreated group. A single intraperitoneal dose 3 h prior to challenge was partially effective. Oral protection was accompanied by a reduced production of OVA-specific IgE antibodies, reduced eosinophilia, and impaired production of the IL-5, IL-10 and TNF-alpha cytokines. In vitro, Kp prevented antigen-induced mast cell degranulation and histamine release. Oral treatment with the quercitrin flavonoid isolated from Kp prevented fatal anaphylaxis in 75% of the animals. These findings indicate that oral treatment with Kp effectively downmodulates pro-anaphylactic inducing immune responses. Protection achieved with quercitrin, although not maximal, suggests that this flavonoid is a critical component of Kp extract against this extreme allergic reaction.

Prospective analysis of the long-term effect of teaching breast self-examination and breast awareness.

Breast cancer is the most common cancer in women in the industrialized world and a leading cause of death. Breast self-examination (BSE) is one of the methods for an early detection of breast cancer. In the present study the effectiveness of a campaign promoting BSE and breast awareness was analysed. Seminars were conducted in 2003 in Lower Saxony, Germany by a female gynaecologist and a social pedagogue and included a lecture, an individual training in BSE in a separate room and a talk about the importance of regular BSEs. Questionnaires were handed out immediately after the seminar and were sent by post 1 year later. Attendance of the seminar resulted in a significantly higher percentage of monthly BSEs (21.4% before vs. 61.9% after the teaching). Furthermore, 92.1% of the women who did not perform a monthly BSE stated that at least they examined their breasts more frequently after attending the seminar. The data demonstrate that the seminars in BSE had profound effects on the compliance of women in carrying out BSE regularly and correctly, without influence of age or education.

Cancer immunotherapy based on recombinant Salmonella enterica serovar Typhimurium aroA strains secreting prostate-specific antigen and cholera toxin subunit B.

Prostate cancer is the most common malignant tumor in men and is normally associated with increased serum levels of prostate-specific antigen (PSA). Therefore, PSA is one potential target for a prostate cancer vaccine. In this study we analyzed the functionality of new bacterial PSA vaccines, expressed and secreted via the hemolysin (HlyA) secretion system of Escherichia coli, the prototype of Type I secretion systems (T1SS) using an attenuated Salmonella enterica serovar Typhimurium aroA strain as carrier. The data demonstrate that a bacterial live vaccine encompassing T1SS in combination with cholera toxin subunit B can be successfully used for delivery of PSA to induce cytotoxic CD8+ T-cell responses resulting in an efficient prevention of tumor growth in mice.

High selective leishmanicidal activity of 3-hydroxy-2-methylene-3-(4-bromophenyl)propanenitrile and analogous compounds.

Sixteen not new aromatic compounds were prepared by one-pot reaction i.e. through Baylis-Hillman reaction and were the first time evaluated against promastigote Leishmania amazonensis and infected mammalian cells. Most of the compounds were selectively more active against amastigotes than the reference drug sodium stibogluconate (Pentostam, IC(50)=44.7 microM). We found that 3-hydroxy-2-methylene-3-(4-bromophenyl) propanenitrile (13) was the most active (IC(50)=12.5 microM) and safer compound (0.0 (0.9); % macrophage LDH release), being the lead compound.

[Dynamic decision making in emergency medicine. Example of paraplegia after a traffic accident]. / Dynamische Entscheidungsfindung in der Notfallmedizin. Beispiel einer Querschnittlähmung nach Verkehrsunfall.

Dynamic decision making is one of the key skills in crew resource management training in aviation. In emergency medicine it is important to practice this skill as a prerequisite for effective treatment of patients. We report a case of paraplegia after a road traffic accident and cervical spine injury. During the prehospital treatment the patient's state was re-evaluated at different times. Although the patient was initially unconscious the physician at the scene decided not to intubate the trachea as the level of consciousness improved during resuscitation. In the emergency room a C5 fracture and a prolapsed intervertebral disc were diagnosed and immediate decompression and stabilisation of the cervical spine were performed. Dynamic decision-making has been in practise for a long time in aviation, similarities to decisions in medicine and the psychological background are described on the basis of the case report.

Cissampelos sympodialis Eichl. (Menispermaceae): oral treatment decreases IgE levels and induces a Th1-skewed cytokine production in ovalbumin-sensitized mice.

The murine model of ovalbumin (OVA)-induced allergy was used to evaluate the effectiveness of oral treatment with the leaf extract of Cissampelos sympodialis Eichl. (Menispermaceae) (CS) in the modulation of immunoglobulin E (IgE) production and T cell activation. CS treatment with doses ranging from 200 to 600 mg/Kg/day for 15 days before and during OVA-sensitization promoted reduction in total and OVA-specific serum IgE. CS at 400 or 600 mg/Kg/day also reduced paw edema induced by local OVA challenge. Daily intake of up to 600 mg/Kg of oral CS by BALB/c mice did not reduce weight gain, which is indicative of a lack of systemic toxicity. To assess the effect of CS treatment on T cell proliferative response to stimuli in vitro, the mitogenic response of spleen cells of treated and control animals were evaluated. Cells from CS-treated animals showed an elevated background proliferative response to concanavalin-A (Con-A) when compared to those from control animals. Oral intake of CS increased the in vitro production of IFN-gamma and IL-10 by Con-A stimulated cells. Mice treated with 200 mg/Kg/day CS showed increasing levels of IFN-gamma. These results show that oral treatment with Cissampelos sympodialis extract has an immunomodulatory effect, reducing allergy-associated responses possibly by a preferential activation of Th1-type cytokines.

Different embryo-fetal toxicity effects for three VLA-4 antagonists.

BACKGROUND: VLA-4 (Very late antigen 4, integrin alpha4beta1) plays an important role in cell-cell interactions that are critical for development. Homozygous null knockouts of the alpha4 subunit of VLA-4 or VCAM-1 (cell surface ligand to VLA-4) in mice result in abnormal placental and cardiac development and embryo lethality. Objectives of the current study were to assess and compare the teratogenic potential of three VLA-4 antagonists. METHODS: IVL745, HMR1031, and IVL984 were each evaluated by the subcutaneous route in standard embryo-fetal developmental toxicity studies in rats and rabbits. IVL984 was also evaluated in mice. Fetuses were examined externally, viscerally, and skeletally. RESULTS: IVL745 did not cause significant maternal or fetal effects at doses up to 100 or 250 mg/kg/day in rats or rabbits, respectively. HMR1031 treatment resulted in marked maternal toxicity and slight fetal toxicity at the highest tested doses of 200 and 75 mg/kg/day in rats and rabbits, respectively. HMR1031 embryo-fetal effects consisted of slightly lower body weight and crown-rump length in rats and minor sternebral defects in rabbits. IVL984 treatment resulted in minimal maternal effects at doses up to 40, 15, and 100 mg/kg/day in rats, rabbits, and mice, respectively (excluding abortions in rabbits). However, marked developmental effects were observed at the lowest tested IVL984 doses, 1, 0.2, and 3 mg/kg/day in rats, rabbits, and mice, respectively. IVL984 embryo-fetal effects consisted of increased total post-implantation loss due to early resorptions and high incidences of cardiac malformations and skeletal malformations and/or variations. Notably, spiral septal defects were observed in up to 76% of rat fetuses and up to 58% of rabbit fetuses. CONCLUSIONS: Dramatic differences in teratogenic potential were observed: IVL745 was not teratogenic, HMR1031 caused slight embryo-fetal effects at maternally-toxic doses, and IVL984 was a potent teratogen at doses where direct maternal toxicity was limited to abortions in rabbits. Prominent effects of IVL984 included embryo lethality and cardiac malformations including spiral septal defects in three species.