Exploring ethical practice in NGOS on mental health research in Malawi.

In recent years, an increasing trend in mental health research has been to collaborate with non-governmental organizations [NGOs] and their constituents. However, ethical difficulties can arise as a result of such partnerships. Understanding the ethics-related practices of NGOs engaged in mental health research is therefore critical. This study addressed these questions in a Malawian context. The goal of this study was to investigate NGO's ethical practices in relation to mental health research by identifying characteristics that influence ethical practices and investigating staff conceptualization of ethics and mental health. Twenty individuals who work for different local NGOs took part in one-on-one interviews or a workshop about their engagement in diverse research initiatives. They pinpointed the areas that needed improvement, as well as the challenges and chances to create partnerships and increase research capability. The diversity in conceptualizing mental health was a key influence on research practices, with heterogeneity in definitions reflected in the use of cultural, spiritual, behavioural, or medical terms. Notably, there was also a greater emphasis on procedural ethics than ethics-in-practice. Collaboration dynamics and limited staffing capacity were cited as major ethical practice considerations. Each of these elements have an impact on NGOs' ethical behaviour when conducting mental health research. Participants in the study saw engagement with notions of both ethics and mental health as lacking or rudimentary in their institutions and felt that they needed to be improved through capacity building and stronger research involvement.

Un modelo para favorecer la ética y las buenas prácticas en investigación global e intercultural: aplicaciones en méxico y chile / A model to promote ethics and good practices in global and intercultural research: applications in méxico and chile / Um modelo para favorecer a ética e as boas práticas em pesquisa global e intercultural: aplicativos no méxico e no chile

Resumen La investigación intercultural plantea desafíos éticos complejos. Por ello, en el año 2019 se desarrolló un modelo de análisis de conflictos éticos en colaboración con más de 200 investigadores de más de 30 países. Este modelo parece pertinente para América Latina. El modelo propone que los desafíos éticos (y sus soluciones) dependen de cuatro factores presentes durante todo el proceso de investigación: el lugar donde se realiza la investigación, las personas involucradas, los principios éticos relevantes y los precedentes de investigaciones pasadas. En este artículo hacemos un análisis de la aplicabilidad de dicho modelo mediante dos análisis de casos referidos a la investigación con pueblos originarios en Chile y al trabajo con latinos migrantes en la frontera México-Estados Unidos.

Abstract Intercultural research poses critical ethical challenges. In 2019, in collaboration with more than 200 researchers from more than 30 countries, a group of researchers developed an ethical conflict analysis model that seems relevant for Latin America. The model proposes a flexible frame of reference where ethical challenges (and their solutions) depend on four factors present throughout the research process: the place where the research is carried out, the people involved, the relevant ethical principles, and the precedents from previous research. This article discusses the applicability of this model through two case analyses: one study with Indigenous peoples in Chile and the other with Latin-American migrants on the border between Mexico and US.

Resumo A pesquisa intercultural apresenta desafios éticos complexos. Por isso, em 2019, foi desenvolvido um modelo de análise de conflitos éticos em colaboração com mais de 200 pesquisas de mais de 30 países. Esse modelo parece pertinente para a América Latina, pois propõe que os desafios éticos (e suas soluções) dependem de quatro fatores presentes durante todo o processo de pesquisa: o lugar onde a pesquisa é realizada, as pessoas envolvidas, os princípios éticos relevantes e os precedentes de pesquisa passadas. Neste artigo, fazemos uma análise da aplicabilidade desse modelo mediante duas análises de casos referidos à pesquisa com povos originários no Chile e ao trabalho com latinos migrantes na fronteira México-Estados Unidos.

Online sexual harassment and depression in Chilean adolescents: Variations based on gender and age of the offenders.

BACKGROUND: Online sexual harassment in adolescence is associated with depressive symptoms. There is, however, a dearth of research investigating variability of symptom profiles in this population in relation to offender gender and age. OBJECTIVE: To identify the proportion of adolescents reporting online harassment by different types of offenders and compare their levels of depression. PARTICIPANTS AND SETTING: Participants were 18,872 Chilean students aged 12 to 17 years (3.063 of them online sexually harassed). METHODS: The study involved a secondary analysis of self-report data on online sexual harassment, poly-victimization, and depression collected as part of the National Poly-victimization Survey. RESULTS: In 37.6% of the cases the offender was male under 18, in 22.4% an adult male, in 14.5% a female under 18, and in 2.9% an adult female. In 22.5% of cases the offender could not be identified. An ANCOVA demonstrated levels of poly-victimization across the lifespan and frequency of online sexual harassment in the last year to predict depressive symptomatology. In females, higher levels of depressive symptoms were observed among those sexually harassed by either a female under 18, an offender whose age and gender the victim could not identify, or an adult male. In males, higher levels of depression were observed among those harassed by either an adult male, an offender whose age and gender the victim could not identify, or a male under 18. CONCLUSIONS: The current study highlights the importance of offender's age and gender in predicting depression levels in adolescent victims of online sexual harassment.

Bis-enoxacin blocks rat alveolar bone resorption from experimental periodontitis.

Periodontal diseases are multifactorial, caused by polymicrobial subgingival pathogens, including Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. Chronic periodontal infection results in inflammation, destruction of connective tissues, periodontal ligament, and alveolar bone resorption, and ultimately tooth loss. Enoxacin and a bisphosphonate derivative of enoxacin (bis-enoxacin) inhibit osteoclast formation and bone resorption and also contain antibiotic properties. Our study proposes that enoxacin and/or bis-enoxacin may be useful in reducing alveolar bone resorption and possibly bacterial colonization. Rats were infected with 10(9) cells of polymicrobial inoculum consisting of P. gingivalis, T. denticola, and T. forsythia, as an oral lavage every other week for twelve weeks. Daily subcutaneous injections of enoxacin (5 mg/kg/day), bis-enoxacin (5, 25 mg/kg/day), alendronate (1, 10 mg/kg/day), or doxycycline (5 mg/day) were administered after 6 weeks of polymicrobial infection. Periodontal disease parameters, including bacterial colonization/infection, immune response, inflammation, alveolar bone resorption, and systemic spread, were assessed post-euthanasia. All three periodontal pathogens colonized the rat oral cavity during polymicrobial infection. Polymicrobial infection induced an increase in total alveolar bone resorption, intrabony defects, and gingival inflammation. Treatment with bis-enoxacin significantly decreased alveolar bone resorption more effectively than either alendronate or doxycycline. Histologic examination revealed that treatment with bis-enoxacin and enoxacin reduced gingival inflammation and decreased apical migration of junctional epithelium. These data support the hypothesis that bis-enoxacin and enoxacin may be useful for the treatment of periodontal disease.

Multifunctional role of osteopontin in directing intrafibrillar mineralization of collagen and activation of osteoclasts.

Mineralized collagen composites are of interest because they have the potential to provide a bone-like scaffold that stimulates the natural processes of resorption and remodeling. Working towards this goal, our group has previously shown that the nanostructure of bone can be reproduced using a polymer-induced liquid-precursor (PILP) process, which enables intrafibrillar mineralization of collagen with hydroxyapatite to be achieved. This prior work used polyaspartic acid (pASP), a simple mimic for acidic non-collagenous proteins, to generate nanodroplets/nanoparticles of an amorphous mineral precursor which can infiltrate the interstices of type-I collagen fibrils. In this study we show that osteopontin (OPN) can similarly serve as a process-directing agent for the intrafibrillar mineralization of collagen, even though OPN is generally considered a mineralization inhibitor. We also found that inclusion of OPN in the mineralization process promotes the interaction of mouse marrow-derived osteoclasts with PILP-remineralized bone that was previously demineralized, as measured by actin ring formation. While osteoclast activation occurred when pASP was used as the process-directing agent, using OPN resulted in a dramatic effect on osteoclast activation, presumably because of the inherent arginine-glycine-aspartate acid ligands of OPN. By capitalizing on the multifunctionality of OPN, these studies may lead the way to producing biomimetic bone substitutes with the capability of tailorable bioresorption rates.

Enoxacin directly inhibits osteoclastogenesis without inducing apoptosis.

Enoxacin has been identified as a small molecule inhibitor of binding between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments. It inhibits bone resorption by calcitriol-stimulated mouse marrow cultures. We hypothesized that enoxacin acts directly and specifically on osteoclasts by disrupting the interaction between plasma membrane-directed V-ATPases, which contain the osteoclast-selective a3-subunit of V-ATPase, and microfilaments. Consistent with this hypothesis, enoxacin dose-dependently reduced the number of multinuclear cells expressing tartrate-resistant acid phosphatase (TRAP) activity produced by RANK-L-stimulated osteoclast precursors. Enoxacin (50 µM) did not induce apoptosis as measured by TUNEL and caspase-3 assays. V-ATPases containing the a3-subunit, but not the "housekeeping" a1-subunit, were isolated bound to actin. Treatment with enoxacin reduced the association of V-ATPase subunits with the detergent-insoluble cytoskeleton. Quantitative PCR revealed that enoxacin triggered significant reductions in several osteoclast-selective mRNAs, but levels of various osteoclast proteins were not reduced, as determined by quantitative immunoblots, even when their mRNA levels were reduced. Immunoblots demonstrated that proteolytic processing of TRAP5b and the cytoskeletal protein L-plastin was altered in cells treated with 50 µM enoxacin. Flow cytometry revealed that enoxacin treatment favored the expression of high levels of DC-STAMP on the surface of osteoclasts. Our data show that enoxacin directly inhibits osteoclast formation without affecting cell viability by a novel mechanism that involves changes in posttranslational processing and trafficking of several proteins with known roles in osteoclast function. We propose that these effects are downstream to blocking the binding interaction between a3-containing V-ATPases and microfilaments.

Rational identification of enoxacin as a novel V-ATPase-directed osteoclast inhibitor.

Binding between vacuolar H+-ATPases (V-ATPases) and microfilaments is mediated by an actin binding domain in the B-subunit. Both isoforms of mammalian B-subunit bind microfilaments with high affinity. A similar actinbinding activity has been demonstrated in the B-subunit of yeast. A conserved "profilin-like" domain in the B-subunit mediates this actin-binding activity, named due to its sequence and structural similarity to an actin-binding surface of the canonical actin binding protein profilin. Subtle mutations in the "profilin-like" domain eliminate actin binding activity without disrupting the ability of the altered protein to associate with the other subunits of V-ATPase to form a functional proton pump. Analysis of these mutated B-subunits suggests that the actin-binding activity is not required for the "housekeeping" functions of V-ATPases, but is important for certain specialized roles. In osteoclasts, the actin-binding activity is required for transport of V-ATPases to the plasma membrane, a prerequisite for bone resorption. A virtual screen led to the identification of enoxacin as a small molecule that bound to the actin-binding surface of the B2-subunit and competitively inhibited B2-subunit and actin interaction. Enoxacin disrupted osteoclastic bone resorption in vitro, but did not affect osteoblast formation or mineralization. Recently, enoxacin was identified as an inhibitor of the virulence of Candida albicans and more importantly of cancer growth and metastasis. Efforts are underway to determine the mechanisms by which enoxacin and other small molecule inhibitors of B2 and microfilament binding interaction selectively block bone resorption, the virulence of Candida, cancer growth, and metastasis.

Identification of enoxacin as an inhibitor of osteoclast formation and bone resorption by structure-based virtual screening.

An interaction between the B2 subunit of vacuolar H(+)-ATPase (V-ATPase) and microfilaments is required for osteoclast bone resorption. An atomic homology model of the actin binding site on B2 was generated and molecular docking simulations were performed. Enoxacin, a fluoroquinolone antibiotic, was identified and in vitro testing demonstrated that enoxacin blocked binding between purified B2 and microfilaments. Enoxacin dose dependently reduced the number of osteoclasts differentiating in mouse marrow cultures stimulated with 1,25-dihydroxyvitamin D(3), as well as markers of osteoclast activity, and the number of resorption lacunae formed on bone slices. Enoxacin inhibited osteoclast formation at concentrations where osteoblast formation was not altered. In summary, enoxacin is a novel small molecule inhibitor of osteoclast bone resorption that acts by an unique mechanism and is therefore an attractive lead molecule for the development of a new class of antiosteoclastic agents.