Accountability and Generating Evidence for Global Health: Misoprostol in Nepal

Postpartum haemorrhage (PPH) is a major cause of maternal morbidity and mortality in Nepal. Compounded by the remote terrain, endemic poverty, and a lack of access to health facilities, the use of misoprostol has advantages over the standard use of oxytocin for PPH management. Drawing on our qualitative study of a pilot intervention managed by the Nepal Family Health Programme, we map the institutional relationships involved in the design, implementation, and practices for bringing misoprostol into national policy. In the intense and competitive global and national policy arena, sustained lobbying and getting the ‘right people’ on board were as powerful drivers as the quality of the intervention itself. The case study takes us to the heart of the debate around the politics of generation of evidence for interventions in global health programmes, and ultimately the question of accountability for health policy and practice.Open Society Foundations, Vozes Desiguais/Unequal Voices, Future Health Systems consortium, the Impact Initiative and Health Systems Globa

Societies, Social Inequalities and Marginalization: Marginal Regions in the 21st Century

Reviewed: Societies, Social Inequalities and Marginalization: Marginal Regions in the 21st Century. Edited by Raghubir Chand, Etienne Nel, and Stanko Pelc. Cham, Switzerland: Springer, 2017. xix + 311 pp. Hardcover: US$139.99, £ 99.99, ISBN 978-3-319-50997-6. E-book: US$ 109.00, £ 79.50, ISBN 978-3-319-50998-3

Response by the authors

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A comparative study of the use of the Istanbul Protocol amongst civil society organizations in low-income countries

The Istanbul Protocol (IP) is one of the great success stories of the global anti-torture movement, setting out universal guidelines for the production of rigorous, objective and reliable evidence about allegations of torture and ill-treatment. The IP is explicitly designed to outline ‘minimum standards for States’. However, it is all too often left to civil society organizations to investigate allegations of torture and ill-treatment. In this context, important questions remain as to how and where the IP can be used best by such organizations. These questions are particularly acute in situations where human rights groups may have limited institutional capacity. This paper explores the practical challenges faced by civil society in using the IP in Low-Income Countries. It is based on qualitative research in three case studies: Nepal, Kenya, and Bangladesh. This research involved over 80 interviews with human rights practitioners. The conclusions of the paper are that the Istanbul Protocol provides a useful framework for documentation, but more comprehensive forms of documentation will often be limited to a very small – albeit important - number of legal cases. In many cases, the creation of precise and standardized forms of evidence is not necessarily the most effective form of documentation for redress or accountability. In the absence of legal systems willing and able to respond effectively to allegations of torture and ill-treatment, there are severe limitations on the practical effectiveness of detailed and technical forms of documentation

Transcriptional regulation of murine natural killer cell development, differentiation and maturation.

Natural killer (NK) cells are innate cytotoxic effector cells that play important protective roles against certain pathogens as well as against pathogen-infected and transformed host cells. NK cells continuously arise from adult bone marrow-resident haematopoietic progenitors. Their generation can be sub-divided into three phases. The early NK cell development phase from multipotent common lymphoid progenitors occurs at least in part in common with that of additional members of a family of innate lymphoid cells, for which NK cells are the founding member. An intermediate phase of NK cell differentiation is characterized by the acquisition of IL-15 responsiveness and lineage-defining properties such as the transcription of genes coding for cytotoxic effector molecules. This is followed by a late maturation phase during which NK cells lose homeostatic expansion and increase effector capacity. These three phases are regulated by multiple stage-specific but not NK cell-specific transcription factors. This review summarizes the NK cell developmental and maturation processes and their transcriptional regulation with an emphasis on data derived from genetically modified mouse models

Adaptations of Natural Killer Cells to Self-MHC Class I.

Natural Killer (NK) cells use germ line encoded receptors to detect diseased host cells. Despite the invariant recognition structures, NK cells have a significant ability to adapt to their surroundings, such as the presence or absence of MHC class I molecules. It has been assumed that this adaptation occurs during NK cell development, but recent findings show that mature NK cells can also adapt to the presence or absence of MHC class I molecules. Here, we summarize how NK cells adjust to changes in the expression of MHC class I molecules. We propose an extension of existing models, in which MHC class I recognition during NK cell development sequentially instructs and maintains NK cell function. The elucidation of the molecular basis of the two effects may identify ways to improve the fitness of NK cells and to prevent the loss of NK cell function due to persistent alterations in their environment

Activation by SLAM Family Receptors Contributes to NK Cell Mediated "Missing-Self" Recognition.

Natural Killer (NK) cells attack normal hematopoietic cells that do not express inhibitory MHC class I (MHC-I) molecules, but the ligands that activate NK cells remain incompletely defined. Here we show that the expression of the Signaling Lymphocyte Activation Molecule (SLAM) family members CD48 and Ly9 (CD229) by MHC-I-deficient tumor cells significantly contributes to NK cell activation. When NK cells develop in the presence of T cells or B cells that lack inhibitory MHC-I but express activating CD48 and Ly9 ligands, the NK cells' ability to respond to MHC-I-deficient tumor cells is severely compromised. In this situation, NK cells express normal levels of the corresponding activation receptors 2B4 (CD244) and Ly9 but these receptors are non-functional. This provides a partial explanation for the tolerance of NK cells to MHC-I-deficient cells in vivo. Activating signaling via 2B4 is restored when MHC-I-deficient T cells are removed, indicating that interactions with MHC-I-deficient T cells dominantly, but not permanently, impair the function of the 2B4 NK cell activation receptor. These data identify an important role of SLAM family receptors for NK cell mediated "missing-self" reactivity and suggest that NK cell tolerance in MHC-I mosaic mice is in part explained by an acquired dysfunction of SLAM family receptors

Paratope plasticity in diverse modes facilitates molecular mimicry in antibody response

The immune response against methyl-α -D-mannopyranoside mimicking 12-mer peptide (DVFYPYPYASGS) was analyzed at the molecular level towards understanding the equivalence of these otherwise disparate Ags. The Ab 7C4 recognized the immunizing peptide and its mimicking carbohydrate Ag with comparable affinities. Thermodynamic analyses of the binding interactions of both molecules suggested that the mAb 7C4 paratope lacks substantial conformational flexibility, an obvious possibility for facilitating binding to chemically dissimilar Ags. Favorable changes in entropy during binding indicated the importance of hydrophobic interactions in recognition of the mimicking carbohydrate Ag. Indeed, the topology of the Ag-combining site was dominated by a cluster of aromatic residues, contributed primarily by the specificity defining CDR H3. Epitope-mapping analysis demonstrated the critical role of three aromatic residues of the 12-mer in binding to the Ab. Our studies delineate a mechanism by which mimicry is manifested in the absence of either structural similarity of the epitopes or conformational flexibility in the paratope. An alternate mode of recognition of dissimilar yet mimicking Ags by the anti-peptide Ab involves plasticity associated with aromatic/hydrophobic and van der Waals interactions. Thus, antigenic mimicry may be a consequence of paratope-specific modulations rather than being dependent only on the properties of the epitope. Such modulations may have evolved toward minimizing the consequences of antigenic variation by invading pathogens

Detection of Anti- Leptospira

Leptospirosis is a globally distributed zoonosis with varied clinical outcomes and multiorgan involvement in humans. In this study conducted from July 2011 to December 2011, 178 serum samples from patients suspected of leptospirosis were tested by Panbio IgM ELISA at National Public Health Laboratory, Kathmandu, out of which 51 (28.65%) were positive for anti-Leptospira IgM antibody. Leptospirosis was more common in people in their 2nd and 3rd decades of their life which together comprised 56.86% of the total positive cases. Most of those tested positive were farmers followed by students and housewives. Both animal contact and water contact seemed to play significant roles in disease transmission. Symptoms were vague with the most common being fever, headache, myalgia, abdominal pain, vomiting, jaundice, and diarrhoea. Life style heavily dominated by agronomical and farming activities in Nepal is conducive to leptospirosis transmission. Leptospirosis seems to be a significant public health problem in Nepal but is underestimated. In resource poor countries like Nepal where laboratories performing MAT or maintaining cultures are rarely available, serological test like ELISA could well depict the scenario of the disease prevalence