Protective efficacy in a hamster model of a multivalent vaccine for human visceral leishmaniasis (Mulevaclin) consisting of the kmp11, leish-f3+, and ljl143 antigens in virosomes, plus gla-se adjuvant

Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, fatal if untreated. Vaccination is the most cost-effective approach to disease control; however, to date, no vaccines against human VL have been made available. This work examines the efficacy of a novel vaccine consisting of the Leishmania membrane protein KMP11, LEISH-F3+ (a recombinant fusion protein, composed of epitopes of the parasite proteins nucleoside hydrolase, sterol-24-c-methyltransferase, and cysteine protease B), and the sand fly salivary protein LJL143, in two dose ratios. The inclusion of the TLR4 agonist GLA-SE as an adjuvant, and the use of virosomes (VS) as a delivery system, are also examined. In a hamster model of VL, the vaccine elicited antigen-specific immune responses prior to infection with Leishmania infantum. Of note, the responses were greater when higher doses of KMP11 and LEISH-F3+ proteins were administered along with the GLA-SE adjuvant and/or when delivered within VS. Remarkably, hamsters immunized with the complete combination (i.e., all antigens in VS + GLA-SE) showed significantly lower parasite burdens in the spleen compared to those in control animals. This protection was underpinned by a more intense, specific humoral response against the KMP11, LEISH-F3+, and LJL143 antigens in vaccinated animals, but a significantly less intense antibody response to the pool of soluble Leishmania antigens (SLA). Overall, these results indicate that this innovative vaccine formulation confers protection against L. infantum infection, supporting the advancement of the vaccine formulation into process development and manufacturing and the conduction of toxicity studies towards future phase I human clinical trialsEuropean Community’s Seventh Framework Programme, grant number 603181 (Clinical Studies on a Multivalent Vaccine for Human Visceral Leishmaniasis [MuLeVaClin]), and by the RD16CIII/0003/0002 and RD16/0027/0008 Red de Investigación Cooperativa de Enfermedades Tropicales, Subprograma RETICS del Plan Estatal de I+D+I 2013–2016, co-funded by ERD

Protective Efficacy in a Hamster Model of a Multivalent Vaccine for Human Visceral Leishmaniasis (MuLeVaClin) Consisting of the KMP11, LEISH-F3+, and LJL143 Antigens in Virosomes, Plus GLA-SE Adjuvant

Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, fatal if untreated. Vaccination is the most cost-effective approach to disease control; however, to date, no vaccines against human VL have been made available. This work examines the efficacy of a novel vaccine consisting of the Leishmania membrane protein KMP11, LEISH-F3+ (a recombinant fusion protein, composed of epitopes of the parasite proteins nucleoside hydrolase, sterol-24-c-methyltransferase, and cysteine protease B), and the sand fly salivary protein LJL143, in two dose ratios. The inclusion of the TLR4 agonist GLA-SE as an adjuvant, and the use of virosomes (VS) as a delivery system, are also examined. In a hamster model of VL, the vaccine elicited antigen-specific immune responses prior to infection with Leishmania infantum. Of note, the responses were greater when higher doses of KMP11 and LEISH-F3+ proteins were administered along with the GLA-SE adjuvant and/or when delivered within VS. Remarkably, hamsters immunized with the complete combination (i.e., all antigens in VS + GLA-SE) showed significantly lower parasite burdens in the spleen compared to those in control animals. This protection was underpinned by a more intense, specific humoral response against the KMP11, LEISH-F3+, and LJL143 antigens in vaccinated animals, but a significantly less intense antibody response to the pool of soluble Leishmania antigens (SLA). Overall, these results indicate that this innovative vaccine formulation confers protection against L. infantum infection, supporting the advancement of the vaccine formulation into process development and manufacturing and the conduction of toxicity studies towards future phase I human clinical trials.This research was funded by the European Community’s Seventh Framework Programme, grant number 603181 (Clinical Studies on a Multivalent Vaccine for Human Visceral Leishmaniasis [MuLeVaClin]), and by the RD16CIII/0003/0002 and RD16/0027/0008 Red de Investigación Cooperativa de Enfermedades Tropicales, Subprograma RETICS del Plan Estatal de I+D+I 2013–2016, co-funded by ERDF “Una manera de hacer Europa” funds.S

Intraosseous foreign body granuloma in rotator cuff repair with bioabsorbable suture anchor

Biodegradable implants lead to problems such as cyst formation, soft-tissue inflammation, loose implant fragments or local osteolysis. This report represents the first published case of an intraosseous foreign body granuloma in the humeral head after arthroscopic rotator cuff tear fixation with a poly-l-lactide (PLLA) suture anchor. A 48-year-old female patient presented with pain in her right shoulder. A refixation of her right supraspinatus tendon with a biodegradable suture anchor was performed 11 months ago at an external hospital. Laboratory tests showed normal values for C-reactive protein, leukocytes and the erythrocyte sedimentation rate. No signs of infection or instability were noted. The visual analogue scale (VAS) was 8, the simple shoulder test (SST) was 4 and the American shoulder and elbow surgeons score (ASES) was 44. Plain radiographs showed high lucency in the area of the tuberculum majus. MRI showed an intra- and extraosseous mass surrounded by fluid in this area. Surgical care involved arthroscopic debridement and removal of the suture anchor. Histological examination revealed a foreign body granuloma. At the 18-month follow-up the patient was nearly pain-free. The VAS was 2, SST was 10 and ASES was 88. Foreign body granulomas are a well known but rarely described complication that arises after the use of biodegradable suture anchors in shoulder surgery. Every patient presenting with shoulder pain after usage of a biodegradable fixation material should be evaluated closely. Orthopaedic surgeons should be aware of the possibility of delayed foreign body reactions, especially after using PLLA anchors

Pre-clinical antigenicity studies of an innovative multivalent vaccine for human visceral leishmaniasis

The notion that previous infection by Leishmania spp. in endemic areas leads to robust anti-Leishmania immunity, supports vaccination as a potentially effective approach to prevent disease development. Nevertheless, to date there is no vaccine available for human leishmaniasis. We optimized and assessed in vivo the safety and immunogenicity of an innovative vaccine candidate against human visceral leishmaniasis (VL), consisting of Virus-Like Particles (VLP) loaded with three different recombinant proteins (LJL143 from Lutzomyia longipalpis saliva as the vector-derived (VD) component, and KMP11 and LeishF3+, as parasite-derived (PD) antigens) and adjuvanted with GLA-SE, a TLR4 agonist. No apparent adverse reactions were observed during the experimental time-frame, which together with the normal hematological parameters detected seems to point to the safety of the formulation. Furthermore, measurements of antigen-specific cellular and humoral responses, generally higher in immunized versus control groups, confirmed the immunogenicity of the vaccine formulation. Interestingly, the immune responses against the VD protein were reproducibly more robust than those elicited against leishmanial antigens, and were apparently not caused by immunodominance of the VD antigen. Remarkably, priming with the VD protein alone and boosting with the complete vaccine candidate contributed towards an increase of the immune responses to the PD antigens, assessed in the form of increased ex vivo CD4+ and CD8+ T cell proliferation against both the PD antigens and total Leishmania antigen (TLA). Overall, our immunogenicity data indicate that this innovative vaccine formulation represents a promising anti-Leishmania vaccine whose efficacy deserves to be tested in the context of the “natural infection”.The research leading to these results received funding from the European Community's Seventh Framework Programme under grant agreement No.603181 [Clinical Studies on a Multivalent Vaccine for Human Visceral Leishmaniasis (MuLeVaClin)] and from the project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Additionally, this study was funded in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (JGV, SK, FO). PC and BPC were supported by fellowships from the European Community's Seventh Framework Programme under grant agreements No. 603181 (Project MuLeVaClin) and No. 603240-2 (Project NMTryPI), respectively. PC was also supported by Foundation for Science and Technology (FCT), Portugal, through the individual grant SFRH/BD/121252/2016. JM and JMR are supported by a grant from Fondo de Investigaciones Sanitarias (ISCIII-RETICRD16/0027/0008-FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS)

PCOS, a heterogeneous disorder characterized by cystic ovarian morphology, androgen excess, and/or irregular periods, emerges during or shortly after puberty. Peri- and post-pubertal obesity, insulin resistance and consequent hyperinsulinemia are highly prevalent co-morbidities of PCOS and promote an ongoing state of excess androgen. Given the relationship of insulin to androgen excess, reduction of insulin secretion and/or improvement of its action at target tissues offer the possibility of improving the physical stigmata of androgen excess by correction of the reproductive dysfunction and preventing metabolic derangements from becoming entrenched. While lifestyle changes that concentrate on behavioral, dietary and exercise regimens should be considered as first line therapy for weight reduction and normalization of insulin levels in adolescents with PCOS, several therapeutic options are available and in wide use, including oral contraceptives, metformin, thiazolidenediones and spironolactone. Overwhelmingly, the data on the safety and efficacy of these medications derive from the adult PCOS literature. Despite the paucity of randomized control trials to adequately evaluate these modalities in adolescents, their use, particularly that of metformin, has gained popularity in the pediatric endocrine community. In this article, we present an overview of the use of insulin sensitizing medications in PCOS and review both the adult and (where available) adolescent literature, focusing specifically on the use of metformin in both mono- and combination therapy

Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence

background: Polycystic ovary syndrome (PCOS) is a common metabolic dysfunction and heterogeneous endocrine disorder in women of reproductive age. Although patients with PCOS are typically characterized by increased numbers of oocytes retrieved during IVF, they are often of poor quality, leading to lower fertilization, cleavage and implantation rates, and a higher miscarriage rate. methods: For this review, we searched the database MEDLINE (1950 to January 2010) and Google for all full texts and/or abstract articles published in English with content related to oocyte maturation and embryo developmental competence. results: The search showed that alteration of many factors may directly or indirectly impair the competence of maturating oocytes through endocrine and local paracrine/autocrine actions, resulting in a lower pregnancy rate in patients with PCOS. The extra-ovarian factors identified included gonadotrophins, hyperandrogenemia and hyperinsulinemia, although intra-ovarian factors included members of the epidermal, fibroblast, insulin-like and neurotrophin families of growth factors, as well as the cytokines. conclusions: Any abnormality in the extra- and/or intra-ovarian factors may negatively affect the granulosa cell-oocyte interaction, oocyte maturation and potential embryonic developmental competence, contributing to unsuccessful outcomes for patients with PCOS who are undergoing assisted reproduction.Obstetrics & GynecologyReproductive BiologySCI(E)PubMed49REVIEW117-331

Perceived spirituality, mindfulness and quality of life in psychiatric patients

There is some evidence of the relationship between spirituality and quality of life, but there are few bibliographic references on these constructs for patients suffering from mental illness; thus, this study was aimed at revealing the possible role of spiritual outlooks as a protective factor in these individuals. The sample consisted of 96 Portuguese psychiatric patients, selected from a psychiatric hospital and assessed based on parameters for quality of life, spirituality and mindfulness. The data support some theories about the nature of the spirituality. Spiritual beliefs are poorly correlated with the quality of life index, and there is a moderate association between these beliefs and some aspects of mindfulness. It is suggested that a spiritual outlook of psychiatric patients should be taken into account in psychological interventions