Measuring early childhood development in multiple contexts: the internal factor structure and reliability of the early Human Capability Index in seven low and middle income countries.

BACKGROUND: The fourth year of the Sustainable Development Agenda era calls for countries to continue to invest not only in interventions and policies that will promote global equity and sustainability, but also in the monitoring systems required to track progress against these targets. A more pragmatic solution to measuring children's early development in low and middle income countries in particular, is required. This study explores the psychometric properties of the early Human Capability Index (eHCI), a population measure of holistic development for children aged 3-5 years, designed with the vision of being flexible and feasible for use in low resource and capacity settings. METHODS: Utilizing data from seven low and middle income countries: Brazil (n = 1810), China (n = 11,421), Kiribati (n = 8339), Lao People's Democratic Republic (n = 7493), Samoa (n = 12,191), Tonga (n = 6214), and Tuvalu (n = 549), analyses explored the internal factor structure and reliability of scores produced by the tool within each country. RESULTS: Confirmatory factor analyses and internal consistency coefficients demonstrated that after local adaptation, translation, and different implementation methods across countries, the eHCI maintained the same factor structure of nine theoretically-based developmental domains: Physical Health, Verbal Communication, Cultural Knowledge, Social and Emotional Skills, Perseverance, Approaches to Learning, Numeracy, Reading, and Writing. CONCLUSIONS: Findings support the aims of the eHCI in being adaptable and applicable for use within a range of low and middle income countries to facilitate measurement and monitoring of children's early development, as is required for the tracking of progress towards the Sustainable Development Agenda.

Endoplasmic reticulum stress is a target for therapy in Waldenstrom macroglobulinemia.

Waldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoma characterized by bone marrow (BM) involvement of IgM secreting lymphoplasmacytic cells. The induction of unfolded protein response (UPR) genes ("physiologic" UPR) enables cells to differentiate into professional secretory cells capable of production of high amounts of endoplasmic reticulum (ER)-processed proteins, such as immunoglobulins. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected, called proapoptotic/terminal UPR. We show that WM cells inherently express the physiologic UPR machinery compared with normal BM cells, and that increased ER stress leads to proapoptotic/terminal UPR in WM cells. We therefore examined tunicamycin, ER stress inducer, for potential antitumor effects in WM. Tunicamycin induced significant cytotoxicity, apoptosis and cell-cycle arrest, and inhibited DNA synthesis in WM cell lines and primary BM CD19(+) cells from patients with WM with an inhibitory concentration (IC(50)) of 0.5 microg/mL to 1 microg/mL, but not in healthy donor cells. Importantly, coculture of WM cells in the context of the BM microenvironment did not inhibit tunicamycin-induced cytotoxicity. Finally, we demonstrate that ER stress inducer synergizes with other agents used in the treatment of WM. These preclinical studies provide a framework for further evaluation of ER stress inducing agents as therapeutic agents in WM.

Measuring early child development in low and middle income countries: Investigating the validity of the early Human Capability Index.

Inclusion of early child development in the United Nations Sustainable Development Agenda raises issues of how this goal should be monitored, particularly in low resource settings. The aim of this paper was to explore the validity of the early Human Capability Index (eHCI); a population measure designed to capture the holistic development of children aged 3-5 years. Convergent, divergent, discriminant and concurrent validity were examined by exploring the associations between eHCI domains and child (sex, age, stunting status, preschool attendance) and family (maternal education, home learning environment) characteristics. Analyses were repeated using data from seven low and middle income countries: Brazil (n = 1810), China (n = 11421), Kiribati (n = 8339), Lao PDR (n = 7493), Samoa (n = 12191), Tonga (n = 6214), and Tuvalu (n = 549). Correlations and linear regressions provide evidence that within these country samples, the tool is capturing the aspects of early child development that it was designed to measure. Although the tool was intended to measure development of children aged 3-5 years, results suggest it can be validly applied to children aged 2-6 years. The eHCI is free, requires minimal implementation resources, captures development across domains and abilities, and is designed to allow cultural and contextual concepts to be included. The eHCI appears psychometrically robust in diverse country contexts and could enable evaluation of early years policies and programs, as well as monitoring of children's development to track progress towards the Sustainable Development Agenda.

Expression of regulatory genes for lymphoplasmacytic cell differentiation in Waldenstrom Macroglobulinemia.

Waldenstrom Macroglobulinemia (WM) is a B-cell malignancy characterized by excess bone marrow (BM) lymphoplasmacytic cells (LPC). The accumulation of LPC in WM may represent a failure of B-cells to properly differentiate into plasma cells. The present study investigated transcriptional expression of genes involved in late B-cell differentiation, including PRDM1, PAX5, XBP1 transcripts and ERN1, in BM B-cells from 31 patients with WM and six healthy donors. Real time reverse transcription polymerase chain reaction (RT-PCR) determined that approximately 80% of the patients had high XBP1 spliced mRNA expression, 80% of whom had high mRNA ERN1alpha expression. XBP1, PRDM1 and PAX5 mRNA was present in all patients studied. Using relative quantitative RT-PCR we isolated two groups with low and high expression of XBP1, XBP1 spliced and ERN1alpha. Sequence analysis showed germline polymorphisms in all genes studied. These data depict for the first time a heterogeneous expression pattern of the genes involved in late differentiation process of plasma cells in patients with WM and propose a role of XBP1-ERN1alpha in WM pathogenesis.

Novel agents in the treatment of Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia is a B-cell disorder characterized by bone marrow infiltration with lymphoplasmacytic cells and demonstration of an immunoglobulin M monoclonal gammopathy. Despite advances in therapy, Waldenström's macroglobulinemia remains incurable. As such, novel therapeutic agents are needed for the treatment of Waldenström's macroglobulinemia. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of Waldenström's macroglobulinemia so as to better target therapeutics for this malignancy. Importantly, as part of these efforts, we have prioritized the development of stem cell-sparing drugs because autologous stem cell transplantation remains a viable salvage option in Waldenström's macroglobulinemia. These efforts have led to the development of several novel agents for treating Waldenström's macroglobulinemia, including bortezomib; monoclonal antibodies and/or blocking protein targeting CD40, CD52, or CD70, a proliferation-inducing ligand and B-lymphocyte stimulator; the immunomodulator thalidomide as an enhancer of rituximab activity, as well as agents interfering with stem cell factor, phosphatidylinositol 3-kinase/Akt, phosphodiesterase, cholesterol, and protein kinase C beta signaling. This report provides an update on biologic studies and clinical efforts for the development of these novel agents in the treatment of Waldenström's macroglobulinemia.

Clinical responses to sildenafil in Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia (WM) is an incurable B-cell malignancy. Interestingly, an unusual response activity was observed in 5 patients with WM that appeared related to their use of sildenafil, a phosphodiesterase inhibitor used to treat erectile dysfunction. One patient demonstrated a complete remission, and 4 other patients demonstrated less dramatic, but also unexpected, responses associated with sildenafil. In view of these findings, WM tumor cells were culture-sorted with sildenafil at pharmacologically achievable levels and apoptosis was demonstrated in tumor cells from all 5 patients. These studies suggest that sildenafil may be an active agent in the treatment of WM.

Hepatitis C viral infection is not associated with Waldenström's macroglobulinemia.

While a familial predisposition may exist in up to 20% of patients with Waldenström's Macroglobulinemia (WM), the precipitating cause of this B-cell malignancy remains unknown in most patients. In previous studies, an association between hepatitis C virus (HCV) infection and WM has been suggested as etiological. This relationship has been the subject of debate, however, with some studies demonstrating increased incidence of HCV infection among WM patients and other studies showing no such association exists. This discordance might be attributable to the analytical method used, HCV antibody detection, which might be ineffective in patients with immunosuppression. We therefore analyzed the prevalence of HCV in a large population of WM patients utilizing both an HCV antibody detection immunoassay as well as qualitative polymerase chain reaction assay to directly detect HCV presence in serum samples. None of 100 randomly tested WM patients in this study tested positive for HCV by either analytical method. Our results therefore demonstrate a lack of association between HCV and WM.

Lúpus eritematoso sistêmico e infecção por CMV: descrição de casos / Systemic lupus erythematosus and cytomegalovirus infection: report of two cases

Este artigo descreve dois casos de associação entre lúpus eritematoso sistêmico (LES) e infecção por citomegalovírus (CMV). As principais dificuldades do diagnóstico diferencial discutidas, assim como a influência recíproca na fisiopatologia destas doenças.