A novel pathogenic mutation of the CYP27B1 gene in a patient with vitamin D-dependent rickets type 1: a case report

BACKGROUND: Rickets can occur due to Vitamin D deficiency or defects in its metabolism. Three rare genetic types of rickets with different alterations of genes have been reported, including: Vitamin D dependent rickets type 1, Vitamin D dependent rickets type 2 or also known as Vitamin D resistant rickets and 25 hydroxylase deficiency rickets. Vitamin D dependent rickets type 1 is inherited in an autosomal recessive pattern, and is caused by mutations in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. We report here a new mutation in CYP27B1, which lead to Vitamin D dependent rickets type 1. CASE PRESENTATION: We report on a 13-month-old Arabic Saudi girl with Vitamin D dependent rickets type 1 presented with multiple fractures and classic features of rickets. A whole exome sequencing identified a novel pathogenic missense mutation (CYP27B1:Homozygous c.1510C > T(p.Q504X)) which results in a protein truncating alteration. Both parents are heterozygous carriers of the mutation. Based on data search in Human Gene Mutation Database, 63 CYP27B1 alterations were reported: only 28.6% are protein truncating (5 nonsense, 13 frameshift insertions/deletions, 0 gross deletions), while 61.9% are non-truncating (38 missense, 1 small in-frame insertions/deletion), and 9.5% are possible protein-truncating (5 splice, 1 regulatory). CONCLUSION: The deleterious effect of this alteration, which was the only mutation detected in the CYP27B1 common gene of Vitamin D dependent rickets type 1 in the proband, and its autosomal recessive inheritance fashion, both support a pathogenic nature of this mutation as the cause of Vitamin D dependent rickets type 1

Exploring Sustainable Supply Chain Management in the Ethiopian coffee industry: an analysis of the critical factors, practices, and outcomes

Global agrifood supply chains are under increasing pressure from consumer organizations, environmental advocacy groups, and policymakers to address sustainability concerns. Similarly, the supply chains in developing countries, such as the Ethiopian coffee industry, are compelled to ensure the production of their agricultural products is environmentally and socially substantiable. Thus, there is a growing interest in adopting sustainable supply chain management (SSCM), however, the implementation of sustainability initiatives is challenging. As a result, many organizations are facing difficulty integrating sustainability initiatives into agrifood supply chains. Moreover, most of the empirical studies on SSCM are carried out in developed countries from the perspective of buyers. Hence, the perspectives of producers and suppliers in developing countries in literature are found to be limited. Due to the slow adoption pace of SSCM in emerging economies and developing countries, the field of study is still in its infancy stage. Even though there are some studies conducted in developing and emerging countries, more SSCM studies are needed in similar countries to identify trends and pathways and implement sustainable initiatives. As a result, a plethora of researchers are calling for more research concerning SSCM in developing countries to increase generalizability and inclusivity on a global scale. Consequently, to understand the changing aspects of SSCM more empirical research is required to be undertaken in developing countries such as Ethiopia. Therefore, this study intends to fill this gap, questioning how critical factors such as drivers, enablers, and barriers affect the adoption of SSCM practices. Moreover, the outcomes of environmental and social sustainability adoption have not been explored with respect to their associated drivers, enablers, and barriers constituting an additional knowledge gap. Consequently, this study was intended to accomplish two main objectives of determining the impact of critical factors in the adoption of SSCM practices and examining whether the adoption of SSCM practices can affect the performance of implementing firms. In light of the aim of research, this study intends to develop a comprehensive conceptual framework with a focus on the determinants, SSCM practices, and outcomes, relating theoretical linkages between critical factors to adopt SSCM initiatives, the implementation of SSCM practices, and corresponding performance outcomes. The determinant critical factors include drivers, enablers, and barriers to adopting SSCM initiatives; the SSCM practices encompass environmental and social sustainability practices, and the performance outcomes are measured using environmental, social, and economic indicators. To accomplish the main objective of the study and address the research questions, primary data was collected through delivery and collection questionnaires from 202 firms in the Ethiopian coffee industry. The reliability and validity of the proposed conceptual model were thoroughly assessed using relevant analytical statistical tools. In addition, to test the postulated hypotheses involving the theoretical relationship between critical factors, SSCM practices, and performance outcomes, Patial Least Square Structural Equation Modelling (PLS-SEM) was used. The set of critical factors, which includes drivers, enablers, and barriers, was found to have a significant impact on the adoption of SSCM practices. Furthermore, the empirical findings show that the implementation of SSCM practices has a significant effect on the environmental, social, and economic performance of firms implementing SSCM. This study is expected to contribute to the existing knowledge of SSCM by advocating that the driving forces can only take SSCM adoption to a limited extent; in addition, enablers are also vital to the successful implementation of SSCM practices. Moreover, it is crucial to understand that barriers pose challenges by obstructing the integration of SSCM practices. The study confirmed that the implementation of SSCM practices resulted in improved environmental, social, and economic performance. The study has developed and validated a comprehensive conceptual framework which is instrumental to integrate SSCM into the Ethiopian coffee industry and similar agrifood supply chains. This study offers helpful insights to regulators and policymakers who are interested in advancing the SSCM initiatives, as well as managers who want to implement SSCM practices. Business managers are offered a validated conceptual framework, which is very useful for assessing how the adoption of SSCM practices affects organizational performance in terms of environmental, social, and economic indicators

MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors

BACKGROUND MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers

HIV-related travel restrictions: trends and country characteristics

Introduction: Increasingly, HIV-seropositive individuals cross international borders. HIV-related restrictions on entry, stay, and residence imposed by countries have important consequences for this mobile population. Our aim was to describe the geographical distribution of countries with travel restrictions and to examine the trends and characteristics of countries with such restrictions. Methods: In 2011, data presented to UNAIDS were used to establish a list of countries with and without HIV restrictions on entry, stay, and residence and to describe their geographical distribution. The following indicators were investigated to describe the country characteristics: population at mid-year, international migrants as a percentage of the population, Human Development Index, estimated HIV prevalence (age: 15–49), presence of a policy prohibiting HIV screening for general employment purposes, government and civil society responses to having non-discrimination laws/regulations which specify migrants/mobile populations, government and civil society responses to having laws/regulations/policies that present obstacles to effective HIV prevention, treatment, care, and support for migrants/mobile populations, Corruption Perception Index, and gross national income per capita. Results: HIV-related restrictions exist in 45 out of 193 WHO countries (23%) in all regions of the world. We found that the Eastern Mediterranean and Western Pacific Regions have the highest proportions of countries with these restrictions. Our analyses showed that countries that have opted for restrictions have the following characteristics: smaller populations, higher proportions of migrants in the population, lower HIV prevalence rates, and lack of legislation protecting people living with HIV from screening for employment purposes, compared with countries without restrictions. Conclusion: Countries with a high proportion of international migrants tend to have travel restrictions – a finding that is relevant to migrant populations and travel medicine providers alike. Despite international pressure to remove travel restrictions, many countries continue to implement these restrictions for HIV-positive individuals on entry and stay. Since 2010, the United States and China have engaged in high profile removals. This may be indicative of an increasing trend, facilitated by various factors, including international advocacy and the setting of a UNAIDS goal to halve the number of countries with restrictions by 2015

Does the efficiency of a firm’s intellectual capital and working capital management affect its performance?

This study explores the efficiency of intellectual capital (ICE) and working capital management (WCME) in the GCC industrial sector and its potential impact on firm performance. The data were gathered from Standard & Poor's database from 2015 to 2019. This study uses data envelopment analysis (DEA), regression analysis, and robustness tests to accomplish its aims. The results indicate that most firms do not employ their intellectual and working capital investments well and need improvement actions to achieve the best practices. The regression model results reveal that ICE and WCME significantly and positively influence firms' performance. The results of this study support the resource-based, trade-off, and pecking order theories. The study findings have important implications for many stakeholders; for example, they would be helpful for firm decision-makers in managing their investments in intellectual and working capital to achieve the best practices and improve a firm's performance. In addition, the findings would be helpful for financiers, because high-performance firms are likely to have more reasonable valuations that facilitate debt financing. Moreover, the findings have noteworthy implications for trading procedures as investors aspire to attractive economic returns for their investments in corporations that pasture ICE and WCME issues. Additionally, these findings have important implications for employee job satisfaction and retention by improving IC management

How important is the context of an adolescent's first alcoholic drink? Evidence that parental provision may reduce later heavy episodic drinking

Objective: This study examined the extent to which a retrospective measure of parental provision of the first alcoholic beverage was related to current heavy episodic drinking and current responsible drinking practices. Sample: 608 14- to 17-year-olds from the 2007 Australian National Drug Strategy Household Survey. Measures: Source of first alcoholic beverage (friends/parents/others), source of current alcohol, age of onset of alcohol use, current responsible drinking practices, and proportion of current friends who drink. Results: Binary logistic and multiple regression procedures revealed that parental provision of an adolescent's first alcoholic beverage predicted lower current heavy episodic drinking, and responsible drinking mediated this association. Discussion: The results suggested that for adolescents who become alcohol users, parental provision of the first drink may reduce subsequent alcohol-related risks compared to introduction to alcohol by friends and other sources. Alcohol-related risks remain significant for adolescents who consume alcohol, independent of who is the provider. Copyright (C) 2012 S. Karger AG, Base

Accurate stationary densities with partitioned numerical methods for stochastic partial differential equations

We consider the numerical solution, by finite differences, of second-order-in-time stochastic partial differential equations (SPDEs) in one space dimension. New timestepping methods are introduced by generalising recently-introduced methods for second-order-in-time stochastic differential equations to multidimensional systems. These stochastic methods, based on leapfrog and Runge–Kutta methods, are designed to give good approximations to the stationary variances and the correlations in the position and velocity variables. In particular, we introduce the reverse leapfrog method and stochastic Runge–Kutta Leapfrog methods, analyse their performance applied to linear SPDEs and perform numerical experiments to examine their accuracy applied to a type of nonlinear SPDE

Ex vivo expansion of murine MSC impairs transcription factor-induced differentiation into pancreatic β-cells

© 2019 Dario Gerace et al. Combinatorial gene and cell therapy as a means of generating surrogate β-cells has been investigated for the treatment of type 1 diabetes (T1D) for a number of years with varying success. One of the limitations of current cell therapies for T1D is the inability to generate sufficient quantities of functional transplantable insulin-producing cells. Due to their impressive immunomodulatory properties, in addition to their ease of expansion and genetic modification ex vivo, mesenchymal stem cells (MSCs) are an attractive alternative source of adult stem cells for regenerative medicine. To overcome the aforementioned limitation of current therapies, we assessed the utility of ex vivo expanded bone marrow-derived murine MSCs for their persistence in immune-competent and immune-deficient animal models and their ability to differentiate into surrogate β-cells. CD45-/Ly6+ murine MSCs were isolated from the bone marrow of nonobese diabetic (NOD) mice and nucleofected to express the bioluminescent protein, Firefly luciferase (Luc2). The persistence of a subcutaneous (s.c.) transplant of Luc2-expressing MSCs was assessed in immune-competent (NOD) (n=4) and immune-deficient (NOD/Scid) (n=4) animal models of diabetes. Luc2-expressing MSCs persisted for 2 and 12 weeks, respectively, in NOD and NOD/Scid mice. Ex vivo expanded MSCs were transduced with the HMD lentiviral vector (MOI = 10) to express furin-cleavable human insulin (INS-FUR) and murine NeuroD1 and Pdx1. This was followed by the characterization of pancreatic transdifferentiation via reverse transcriptase polymerase chain reaction (RT-PCR) and static and glucose-stimulated insulin secretion (GSIS). INS-FUR-expressing MSCs were assessed for their ability to reverse diabetes after transplantation into streptozotocin- (STZ-) diabetic NOD/Scid mice (n=5). Transduced MSCs did not undergo pancreatic transdifferentiation, as determined by RT-PCR analyses, lacked glucose responsiveness, and upon transplantation did not reverse diabetes. The data suggest that ex vivo expanded MSCs lose their multipotent differentiation potential and may be more useful as gene therapy targets prior to expansion

Women’s health and well-being in low-income formal and informal neighbourhoods on the eve of the armed conflict in Aleppo

Objectives To explore how married women living in low-income formal and informal neighbourhoods in Aleppo, Syria, perceived the effects of neighbourhood on their health and well-being, and the relevance of these findings to future urban rebuilding policies post-conflict. Methods Semi-structured interviews were undertaken with eighteen married women living in informal or socioeconomically disadvantaged formal neighbourhoods in Aleppo in 2011, a year before the armed conflict caused massive destruction in all these neighbourhoods. Results Our findings suggest that the experience of neighbourhood social characteristics is even more critical to women’s sense of well-being than environmental conditions and physical infrastructure. Most prominent was the positive influence of social support on well-being. Conclusions The significance of this study lies, first, in its timing, before the widespread destruction of both formal and informal neighbourhoods in Aleppo and, second, and in its indication of the views of women who lived in marginalised communities on what neighbourhood characteristics mattered to them. Further research post-conflict needs to explore how decisions on urban rebuilding are made and their likely influence on health and well-being