The Role of Liposomal CpG ODN on the Course of L. major Infection in BALB/C Mice

"nBackground: Historically, leishmanization is the most effective protective measure against Cutaneous Leishmaniasis (CL), CL lesion induced by leishmanization sometimes takes a long time to heal. Ma­nipulation of leishmanization inoculums needed to induce a mild and acceptable CL lesion. The aim of this study was to explore if liposomal form of CpG ODN (Cytosin phosphate Guanin Oligodeoxynu­cleotides) mixed with Leishmania major   would induce a milder lesion size in Balb/c mice."nMethods: This study was performed in Biotechnology Research Center, Mashhad, and Center for Re­search and Training in Skin Diseases and Leprosy, Tehran, Iran during 2008-2009.  mice were subcutaneously (SC) inoculated with L. major mixed with liposomal form of CpG ODN, or L. major plus free CpG ODN, or L. major mixed with empty liposomes or L. major in PBS. The lesion onset and the size of lesion were recorded; the death rate was also monitored. "nResult: Footpad thickness was significantly (P<0.01) smaller, death rate was also significantly (P<0.05) lower in the mice received L. major mixed with liposomal CpG ODN or free CpG ODN than control groups received L. major in PBS or L. major plus liposomes, also mice which received L. ma­jor mixed with CpG ODN in soluble form showed a significantly (P < 0.001) smaller lesion size than control groups."nConclusion: CpG ODN seems to be an appropriate immunopotentiator mixed with Leishmania stabi­late in leishmanization

Les tumeurs glomiques de la main (à propos de 25 cas)

Introduction : Les tumeurs glomiques de la main sont des proliférations bénignes développées aux dépens du glomus neuromyoartériel du derme. Notre travail rappelle, à travers une revue de la littérature, les principales caractéristiques diagnostiques, évolutives et thérapeutiques de ces lésions. Matériels et méthodes : Notre étude est rétrospective étalée sur 20 ans. Elle a porté sur 25 cas de tumeurs glomiques de la main. Le groupe étudié se composait de 22 femmes et 3 hommes, dont la moyenne d’âge était de 40,7 ans. Il y avait 13 tumeurs sous unguéales, 09 pulpaires et 03 commissurales. Tous les patients ont bénéficiés d’une exérèse chirurgicale.Résultats : Au recul de 5 ans, il a été noté deux dystrophies unguéales et trois récidives tumorales.Discussion : La tumeur glomique de la main est une entité rare ; sa fréquence ne dépasse pas 5 % des tumeurs des parties molles de la main. Elle touche souvent les extrémités des doigts. Son diagnostic est surtout clinique basé sur la triade de Caroll. L’imagerie par résonnance magnétique peut être d’une aide précieuse dans les formes douteuses. Le traitement consiste en l’exérèse chirurgicale de la tumeur. L’examen anatomopathologique confirme le diagnostic. La récidive est rare si l’exérèse a été complète.Conclusion : La tumeur glomique est une tumeur bénigne qui touche surtout la phalange distale des doigts. Son traitement est exclusivement chirurgical, et ses résultats sont généralement excellents.

Liposome Circulation Time is Prolonged by CD47 Coating.

INTRODUCTION: Bio-degradable nano-particles have many applications as drug delivery vehicles because of their good bio-availability, controlled release, low toxicity and potential for encapsulation. However, the most important obstacle to nanoparticulate drug delivery is elimination by macrophages which reduces the residence time of nanoparticles in the blood. To overcome this problem, the surface of the nanoparticle can be passivated by coating with Polyethylene glycol (PEG). However, the use of PEG has its own disadvantages. CD47 receptor acts as a self marker on the surface of many cells and inhibits phagocytosis. This study used a CD47 mimicry peptide as a substitute for PEG to fabricate "stealth" nanoliposome with reduced macrophage clearance. METHODS: Doxorubibin was used as a model drug because of its inherent fluorescence. Doxorubicin-containing liposomes were coated with different percentages of CD47 mimicry peptide (0.5% and 1%). PEGfunctionalized doxorubicin-containing liposomes, were used as a comparator. The liposomal formulations were intravenously injected into mice. Serum was collected at pre-defined time points and tissue samples were taken at 24 hours. Fluorescence was used to determine the concentration doxorubicin in serum, heart, spleen, kidney, liver and lung tissues. RESULTS: Tissue biodistribution and serum kinetic studies indicated that compared with PEG, the use of CD47 mimicry peptide increased the circulation time of doxorubicin in the circulation. Moreover, unwanted accumulation of doxorubicin in the reticuloendothelial tissues (liver and spleen), kidney and heart was significantly decreased by the CD47 mimicry peptide. CONCLUSION: The use of a CD47 mimicry peptide on the surface of nanoliposomes improved the residence time of liposomal doxorubicin in the circulation. The accumulation of drug in non-target tissues was reduced, thereby potentially reducing toxicity

Potentiating Effects of MPL on DSPC Bearing Cationic Liposomes Promote Recombinant GP63 Vaccine Efficacy: High Immunogenicity and Protection

Visceral leishmaniasis (VL), a vector-transmitted disease caused by Leishmania donovani, is potentially fatal if left untreated. Vaccination against VL has received limited attention compared with cutaneous leishmaniasis, although the need for an effective vaccine is pressing for the control of the disease. Earlier, we observed protective efficacy using leishmanial antigen (Ag) in the presence of either cationic liposomes or monophosphoryl lipid A-trehalose dicorynomycolate (MPL-TDM) against experimental VL through the intraperitoneal (i.p.) route of administration in the mouse model. However, this route of immunization is not adequate for human use. For this work, we developed vaccine formulations combining cationic liposomes with MPL-TDM using recombinant GP63 (rGP63) as protein Ag through the clinically relevant subcutaneous (s.c.) route. Two s.c. injections with rGP63 in association with cationic liposomes and MPL-TDM showed enhanced immune responses that further resulted in high protective levels against VL in the mouse model. This validates the combined use of MPL-TDM as an immunopotentiator and liposomes as a suitable vaccine delivery system

Babassu aqueous extract (BAE) as an adjuvant for T helper (Th)1-dependent immune responses in mice of a Th2 immune response-prone strain

<p>Abstract</p> <p>Background</p> <p>The aqueous extract of a Brazilian palm-tree fruit - the babassu - (BAE) exerts a clear immunostimulative activity <it>in vivo</it>. In the present work, the possibility that BAE can promote Th1 immune responses in mice of a Th2 immune response-prone strain - the BALB/c was investigated. BAE itself, and preparations consisting of <it>Leishmania amazonensis </it>promastigote extract (LE), adsorbed or not to Al(OH)₃, and in the presence or not of BAE, were used as immunogens. LE and Al(OH)₃have been shown to preferentially elicit Th2 immune responses.</p> <p>Results</p> <p>The addition of BAE to LE-containing immunogenic preparations, adsorbed or not to Al(OH)₃, clearly promoted the <it>in vitro </it>production of interferon γ (IFN-γ), a major Th1-dependent cytokine, and not of interleukin (IL-)4 (a Th2-dependent cytokine), by LE-stimulated splenocytes of immunized BALB/c mice. It also promoted the <it>in vivo </it>formation of IgG2a anti-LE antibodies. However, immunization with LE by itself led to an increased production of IL-4 by LE-stimulated splenocytes, and this production, albeit not enhanced, was not reduced by the addition of BAE to the immunogen. On the other hand, the IL-4 production by LE-stimulated splenocytes was significantly lower in mice immunized with a preparation containing Al(OH)₃-adsorbed LE and BAE than in mice immunized with the control preparation of Al(OH)₃-adsorbed LE without BAE. Moreover, an increased production of IFN-γ, and not of IL-4, was observed in the culture supernatants of splenocytes, from BAE-immunized mice, which were <it>in vitro </it>stimulated with BAE or which received no specific <it>in vitro </it>stimulus. No differences in IL-10 (an immunoregulatory cytokine) levels in the supernatants of splenocytes from mice that were injected with BAE, in relation to splenocytes from control mice, were observed. The spontaneous <it>ex vivo </it>production of NO by splenocytes of mice that had been injected with BAE was significantly higher than the production of NO by splenocytes of control mice.</p> <p>Conclusions</p> <p>Based on the results described above, BAE, or biologically active molecules purified from it, should be further investigated as a possible adjuvant, in association or not with aluminium compounds, for the preferential induction of Th1-dependent immune responses against different antigens in distinct murine strains and animal species.</p

Evaluation of Leishmania donovani Protein Disulfide Isomerase as a Potential Immunogenic Protein/Vaccine Candidate against Visceral Leishmaniasis

In Leishmania species, Protein disulfide isomerase (PDI) - a redox chaperone, is reported to be involved in its virulence and survival. This protein has also been identified, through proteomics, as a Th1 stimulatory protein in the soluble lysate of a clinical isolate of Leishmania donovani (LdPDI). In the present study, the molecular characterization of LdPDI was carried out and the immunogenicity of recombinant LdPDI (rLdPDI) was assessed by lymphocyte proliferation assay (LTT), nitric oxide (NO) production, estimation of Th1 cytokines (IFN-γ and IL-12) as well as IL-10 in PBMCs of cured/endemic/infected Leishmania patients and cured L. donovani infected hamsters. A significantly higher proliferative response against rLdPDI as well as elevated levels of IFN-γ and IL-12 were observed. The level of IL-10 was found to be highly down regulated in response to rLdPDI. A significant increase in the level of NO production in stimulated hamster macrophages as well as IgG2 antibody and a low level of IgG1 in cured patient's serum was observed. Higher level of IgG2 antibody indicated its Th1 stimulatory potential. The efficacy of pcDNA-LdPDI construct was further evaluated for its prophylactic potential. Vaccination with this construct conferred remarkably good prophylactic efficacy (∼90%) and generated a robust cellular immune response with significant increases in the levels of iNOS transcript as well as TNF-α, IFN-γ and IL-12 cytokines. This was further supported by the high level of IgG2 antibody in vaccinated animals. The in vitro as well as in vivo results thus indicate that LdPDI may be exploited as a potential vaccine candidate against visceral Leishmaniasis (VL)

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10-14 and 50-54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings The global TFR decreased from 2.72 (95% uncertainty interval [UI] 2.66-2.79) in 2000 to 2.31 (2.17-2.46) in 2019. Global annual livebirths increased from 134.5 million (131.5-137.8) in 2000 to a peak of 139.6 million (133.0-146.9) in 2016. Global livebirths then declined to 135.3 million (127.2-144.1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2.1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27.1% (95% UI 26.4-27.8) of global livebirths. Global life expectancy at birth increased from 67.2 years (95% UI 66.8-67.6) in 2000 to 73.5 years (72.8-74.3) in 2019. The total number of deaths increased from 50.7 million (49.5-51.9) in 2000 to 56.5 million (53.7-59.2) in 2019. Under-5 deaths declined from 9.6 million (9.1-10.3) in 2000 to 5.0 million (4.3-6.0) in 2019. Global population increased by 25.7%, from 6.2 billion (6.0-6.3) in 2000 to 7.7 billion (7.5-8.0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58.6 years (56.1-60.8) in 2000 to 63.5 years (60.8-66.1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.Peer reviewe