Sachith Mettananda

Abdominal pain-predominant functional gastrointestinal diseases in children and adolescents: prevalence, symptomatology, and association with emotional stress

Background and Objective: Functional gastrointestinal disorders (FGD) are common among children, but little is known regarding their prevalence in developing countries. We assessed the prevalence of abdominal pain–predominant FGD, in addition to the predisposing factors and symptomatology, in Sri Lankan children. Patients and Methods: A cross-sectional survey was conducted among a randomly selected group of 10- to 16-year-olds in 8 randomly selected schools in 4 provinces in Sri Lanka. A validated, self-administered questionnaire was completed by children independently in an examination setting. FGD were diagnosed using Rome III criteria. Results: A total of 2180 questionnaires were distributed and 2163 (99.2%) were included in the analysis (1189 [55%] boys, mean age 13.4 years, standard deviation 1.8 years). Of them, 270 (12.5%) had at least 1 abdominal pain–predominant FGD. Irritable bowel syndrome (IBS) was seen in 107 (4.9%), functional dyspepsia in 54 (2.5%), functional abdominal pain in 96 (4.4%), and abdominal migraine (AM) in 21 (1.0%) (2 had AM and functional dyspepsia, 6 had AM and IBS). Extraintestinal symptoms were more common among affected children (P < 0.05). Abdominal pain–predominant FGD were higher in girls and those exposed to stressful events (P < 0.05). Prevalence negatively correlated with age (r = −0.05, P = 0.02). Conclusions: Abdominal pain–predominant FGD affects 12.5% of children ages 10 to 16 years and constitutes a significant health problem in Sri Lanka. IBS is the most common FGD subtype present. Abdominal pain–predominant FGD are higher in girls and those exposed to emotional stress. Prevalence of FGD decreased with age. Extraintestinal symptoms are more frequent in affected children.

Analysis of Effects of Meteorological Factors on Dengue Incidence in Sri Lanka Using Time Series Data

In tropical and subtropical regions of eastern and South-eastern Asia, dengue fever (DF) and dengue hemorrhagic fever (DHF) outbreaks occur frequently. Previous studies indicate an association between meteorological variables and dengue incidence using time series analyses. The impacts of meteorological changes can affect dengue outbreak. However, difficulties in collecting detailed time series data in developing countries have led to common use of monthly data in most previous studies. In addition, time series analyses are often limited to one area because of the difficulty in collecting meteorological and dengue incidence data in multiple areas. To gain better understanding, we examined the effects of meteorological factors on dengue incidence in three geographically distinct areas (Ratnapura, Colombo, and Anuradhapura) of Sri Lanka by time series analysis of weekly data. The weekly average maximum temperature and total rainfall and the total number of dengue cases from 2005 to 2011 (7 years) were used as time series data in this study. Subsequently, time series analyses were performed on the basis of ordinary least squares regression analysis followed by the vector autoregressive model (VAR). In conclusion, weekly average maximum temperatures and the weekly total rainfall did not significantly affect dengue incidence in three geographically different areas of Sri Lanka. However, the weekly total rainfall slightly influenced dengue incidence in the cities of Colombo and Anuradhapura.

α-Globin as a molecular target in the treatment of β-thalassemia.

The thalassemias, together with sickle cell anemia and its variants, are the worlds most common form of inherited anemia, and in economically undeveloped countries, they still account for tens of thousands of premature deaths every year. In developed countries, treatment of thalassemia is also still far from ideal, requiring lifelong transfusion or allogeneic bone marrow transplantation. Clinical and molecular genetic studies over the course of the last 50 years have demonstrated how coinheritance of modifier genes, which alter the balance of α-like and β-like globin gene expression, may transform severe, transfusion-dependent thalassemia into relatively mild forms of anemia. Most attention has been paid to pathways that increase γ-globin expression, and hence the production of fetal hemoglobin. Here we review the evidence that reduction of α-globin expression may provide an equally plausible approach to ameliorating clinically severe forms of β-thalassemia, and in particular, the very common subgroup of patients with hemoglobin E β-thalassemia that makes up approximately half of all patients born each year with severe β-thalassemia.

Human induced pluripotent stem cell derived erythroblasts can undergo definitive erythropoiesis and co‐express gamma and beta globins

Human induced pluripotent stem cells (hiPSCs), like embryonic stem cells, are under intense investigation for novel approaches to model disease and for regenerative therapies. Here, we describe the derivation and characterization of hiPSCs from a variety of sources and show that, irrespective of origin or method of reprogramming, hiPSCs can be differentiated on OP9 stroma towards a multi‐lineage haemo‐endothelial progenitor that can contribute to CD144+ endothelium, CD235a+ erythrocytes (myeloid lineage) and CD19+ B lymphocytes (lymphoid lineage). Within the erythroblast lineage, we were able to demonstrate by single cell analysis (flow cytometry), that hiPSC‐derived erythroblasts express alpha globin as previously described, and that a sub‐population of these erythroblasts also express haemoglobin F (HbF), indicative of fetal definitive erythropoiesis. More notably however, we were able to demonstrate that a small sub‐fraction of HbF positive erythroblasts co‐expressed HbA in a highly heterogeneous manner, but analogous to cord blood‐derived erythroblasts when cultured using similar methods. Moreover, the HbA expressing erythroblast population could be greatly enhanced (44·0 ± 6·04%) when a defined serum‐free approach was employed to isolate a CD31+ CD45+ erythro‐myeloid progenitor. These findings demonstrate that hiPSCs may represent a useful alternative to standard sources of erythrocytes (RBCs) for future applications in transfusion medicine.

Constipation During and After the Civil War in Sri Lanka: a Paediatric Study

Constipation is a common childhood disease. It is associated with exposure to stressful events. Sri Lanka was involved in three decades of civil war causing significant emotional stress. This study assessed the prevalence of childhood constipation during and after war. Data were collected from 10- to 16-year olds in five randomly selected schools, in three provinces (two schools from Eastern province), using a validated, self-administered questionnaire. Constipation was diagnosed using Rome III criteria. Phase I was conducted during the war to liberate Eastern province from separatist groups. Phase II was conducted 2 years after the war in same schools. During Phase I, prevalence of constipation was significantly higher in Eastern province (18.1%) compared with Western (14.2%) and Southern (12.6%) provinces (p = 0.009). Constipation was significantly lower in Eastern province in Phase II (10%) compared with Phase I (p < 0.0001). This study highlights the possible link between devastating emotional effects of civil war and childhood constipation.

Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia

Abstractβ-Thalassemia is one of the most common inherited anemias, with no effective cure for most patients. The pathophysiology reflects an imbalance between α- and β-globin chains with an excess of free α-globin chains causing ineffective erythropoiesis and hemolysis. When α-thalassemia is co-inherited with β-thalassemia, excess free α-globin chains are reduced significantly ameliorating the clinical severity. Here we demonstrate the use of CRISPR/Cas9 genome editing of primary human hematopoietic stem/progenitor (CD34+) cells to emulate a natural mutation, which deletes the MCS-R2 α-globin enhancer and causes α-thalassemia. When edited CD34+ cells are differentiated into erythroid cells, we observe the expected reduction in α-globin expression and a correction of the pathologic globin chain imbalance in cells from patients with β-thalassemia. Xenograft assays show that a proportion of the edited CD34+ cells are long-term repopulating hematopoietic stem cells, demonstrating the potential of this approach for translation into a therapy for β-thalassemia.β-thalassemia is characterised by the presence of an excess of α-globin chains, which contribute to erythrocyte pathology. Here the authors use CRISP/Cas9 to reduce α-globin expression in hematopoietic precursors, and show effectiveness in xenograft assays in mice.

Understanding α-globin gene regulation and implications for the treatment of β-thalassemia.

Over the past three decades, a vast amount of new information has been uncovered describing how the globin genes are regulated. This knowledge has provided significant insights into the general understanding of the regulation of human genes. It is now known that molecular defects within and around the α‐ and β‐globin genes, as well as in the distant regulatory elements, can cause thalassemia. Unbalanced production of globin chains owing to defective synthesis of one, and the continued unopposed synthesis of another, is the central causative factor in the cellular pathology and pathophysiology of thalassemia. A large body of clinical, genetic, and experimental evidence suggests that altering globin chain imbalance by reducing the production of α‐globin synthesis ameliorates the disease severity in patients with β‐thalassemia. With the development of new genetic‐based therapeutic tools that have a potential to decrease the expression of a selected gene in a tissue‐specific manner, the possibility of decreasing expression of the α‐globin gene to improve the clinical severity of β‐thalassemia could become a reality.

Neonatal mortality in sri lanka: timing, causes And distribution

Abstract Objective. To evaluate the timing, causes and distribution of neonatal deaths in Sri Lanka, to provide information for policy makers, to undertake appropriate measures to achieve the Millennium Development Goals. Methods. All neonatal deaths, reported to the Registrar Generals Office, Sri Lanka, from 1997 to 2001, were included in the analysis. Results. During this 5-year period, 17,946 neonatal deaths have occurred, of them 90.5% have occurred during the first week of life. The leading causes were preterm deliveries (33.2%), infections (19.8%) and cardiac anomalies (17.4%). The neonatal mortality rates (NMR) were higher in districts with specialised neonatal care facilities and high concentration of estates. Conclusions. Approximately 3600 neonates die in Sri Lanka annually, even though it has a lower NMR compared to rest of the South Asia. Neonatal deaths were higher in the major cities and in the estate sector. The majority of neonatal deaths were due to complications of preterm birth, neonatal sepsis and cardiac anomalies.

Posterior reversible encephalopathy syndrome in a survivor of valproate-induced acute liver failure: a case report

IntroductionPosterior reversible encephalopathy syndrome is an extremely rare radiological diagnosis that has not been reported previously in association with acute liver failure.Case presentationA 6-year-old Sri Lankan girl developed acute liver failure with severe hepatic encephalopathy due to sodium valproate. She was successfully treated medically with N-acetylcysteine and L-carnitine. During recovery she again developed features of encephalopathy and had repeated convulsions associated with moderate hypertension. The diagnosis of posterior reversible encephalopathy syndrome was made on clinical and radiological grounds and she showed a gradual improvement with control of blood pressure.ConclusionsThis report adds to the evidence behind treatment of valproate-induced acute liver failure with N-acetylcysteine and L-carnitine and illustrates a rare but interesting association between acute liver failure and posterior reversible encephalopathy syndrome.

Selective silencing of α-globin by the histone demethylase inhibitor IOX1: a potentially new pathway for treatment of β-thalassemia.

Thalassemia is the world’s most common form of inherited anemia, and in economically undeveloped countries still accounts for tens of thousands of premature deaths every year.[1][1] The accumulation of free excess α-globin chains in red blood cells and their precursors, as a result of the