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β-Thalassaemia is caused by over 300 mutations in and around the β-globin gene that lead to impaired synthesis of β-globin. The expression of α-globin continues normally, resulting in an excess of α-globin chains within red blood cells and their precursors. These unpaired α-globin chains form unstable α-hemichromes that trigger cascades of events to generate reactive oxygen species, leading to ineffective erythropoiesis and haemolysis in patients with β-thalassaemia. The clinical genetic data reported over several decades have demonstrated how the coinheritance of α-thalassaemia ameliorates the disease phenotype of β-thalassaemia. Thus, it is evident that down-regulation of the α-globin gene expression in patients with β-thalassaemia could ameliorate or even cure β-thalassaemia. Over the last few years, significant progress has been made in utilising this pathway to devise a cure for β-thalassaemia. Most research has been done to alter the epigenetic landscape of the α-globin locus or the well-characterised distant enhancers of α-globin. In vitro, pre-clinical studies on primary human erythroid cells have unveiled inhibition of histone lysine demethylation and histone deacetylation as potential targets to achieve selective downregulation of α-globin through epigenetic drug targeting. CRISPR based genome editing has been successfully used in vitro to mutate α-globin genes or enhancers of α-goblin to achieve clinically significant knockdowns of α-globin to the levels beneficial for patients with β-thalassaemia. This review summarises the current knowledge on the regulation of human α-globin genes and the clinical genetic data supporting the pathway of targeting α-globin as a treatment for β-thalassaemia. It also presents the progress of epigenetic drug and genome editing approaches currently in development to treat β-thalassaemia.

ObjectivesTo describe the symptoms and pre-admission management of children presenting with febrile illness to the Colombo North Teaching Hospital, Ragama, Sri Lanka.MethodsA retrospective descriptive study was conducted at University Paediatric Unit of Colombo North Teaching Hospital, Ragama, Sri Lanka. Data on pre-admission management of all children admitted with febrile illness from July to December 2019 were extracted from patient records. Children who were transferred from other units, children with chronic illnesses and children developed fever following vaccinations were excluded. Ethical approval was obtained from Ethics Review Committee of Sri Lanka College of Paediatricians and data was analysed using SPSS version 22.ResultsA total of 366 children were admitted; 56% were males. Mean age was 53.5 ± 41.7 months and the majority were from Gampaha district. Mean duration of illness on admission was 3.6 ± 2.5 days. 236 (65.6%) patients had recorded fever spikes at home while 150 (60.7%) reported a contact history of fever. Common associated symptoms were cough (62.3%), cold (56%) and vomiting (39.6%). 199 (54.5%) underwent investigations prior to admission and full blood count was the commonest (47.5%) investigation. Although 357 (97.8%) had taken medication prior to admission, only 87.3% had consulted a doctor. 356 (97.3%) received paracetamol at home of which 24 (7.9%) and 123 (40.6%) received sub-therapeutic and supra-therapeutic doses respectively. Significantly higher proportion (44.9%) of children who consulted a doctor received appropriate dose of paracetamol compared to others (3.7%), (c2=11.9, p=0.003, p<001). Higher proportion children who had recorded fever spikes consulted a doctor (c2=3.99, p=0.046, p<0.05) and received therapeutic doses of paracetamol prior to admission (c2=4.94, p=0.026, p<0.05).ConclusionUse of sub- and supra-therapeutic doses of paracetamol was common before admission to the hospital. Recording temperature at home and medical consultation prior to admission were associated with appropriate dose paracetamol usage (p<005).

Erythropoietin is a hormone that stimulates erythropoiesis. The role of erythropoietin in the pathophysiology of HbE β-thalassaemia, a subtype of thalassaemia, is understudied. Here, we aim to evaluate the determinants and associations of erythropoietin in HbE β-thalassaemia patients. We conducted a cross-sectional study in Thalassaemia Centres of Colombo North Teaching Hospital, Sri Lanka, from September to December 2024. All patients with HbE β-thalassaemia were recruited. Clinical details were collected using an interviewer schedule. Haemoglobin, ferritin and erythropoietin were measured using standard laboratory methods. Serum samples of non-thalassaemia healthy volunteers were used as controls for erythropoietin measurements. Fifty-two patients (male-42.3%; mean age 24.5 ± 13.4 years) were recruited. The mean erythropoietin of HbE β-thalassaemia patients [137 (± 127) mIU/mL] was significantly higher than that of controls [21.2 (± SD16.3) mIU/mL, p < 0.001]. Among HbE β-thalassaemia patients, erythropoietin showed a gradual and significant decline with age (r = − 0.34, p < 0.05) irrespective of the haemoglobin level. Patients who underwent splenectomy had a significantly lower median erythropoietin level compared to those who did not (40 vs. 129 mIU/mL, p < 0.001). Patients with haemolysis and anaemia-related complications, especially gallstones, had significantly lower median erythropoietin level compared to those without (69.2 vs. 125.9 mIU/mL, p = 0.039). Erythropoietin response in HbE β-thalassaemia decreased gradually with age, irrespective of the degree of anaemia. Splenectomised patients had significantly lower erythropoietin levels compared to non-splenectomised patients. Lower erythropoietin level, which could be due to age-related decline or splenectomy, was positively associated with a high prevalence of haemolysis and anaemia-related complications.

Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10–20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p  < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p  < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p  < 0.01) and placebo-receivers (102 ± 28ml/kg; p  < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p  < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p  < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn 1 polymorphism of the γ-globin gene.

Background Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include β-thalassaemia and sickle cell disease. Despite this, many aspects of hydroxyurea are either unknown or understudied; specifically, its usefulness in β-thalassaemia major and haemoglobin E β-thalassaemia is unclear. However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with β-haemoglobinopathies. In this review, we aim to explore the available in vitro and in vivo mechanistic data and the clinical utility of hydroxyurea in β-haemoglobinopathies with a special emphasis on its usefulness during the COVID-19 pandemic. Main body Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. In human erythroid cells, it induces the expression of γ-globin, a fetal globin gene that is suppressed after birth. Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with β-haemoglobinopathies. Currently, it is recommended for sickle cell disease and non-transfusion dependent β-thalassaemia. A number of clinical trials are ongoing to evaluate its usefulness in transfusion dependent β-thalassaemia. During the COVID-19 pandemic, it was widely used as an adjunct to transfusion therapy due to limitations in the availability of blood and logistical disturbances. Thus, it has become clear that hydroxyurea could play a remarkable role in reducing transfusion requirements of patients with haemoglobinopathies, especially when donor blood is a limited resource. Conclusion Hydroxyurea is a well-tolerated oral drug which has been in use for many decades. Through its actions of reversible inhibition of ribonucleoside diphosphate reductase enzyme and fetal haemoglobin induction, it exerts many favourable effects on patients with β-haemoglobinopathies. It is currently approved for the treatment of sickle cell disease and non-transfusion dependent β-thalassaemia. Also, there are various observations to suggest that hydroxyurea is an important adjunct in the treatment of transfusion dependent β-thalassaemia which should be confirmed by randomised clinical trials.

Background Excessive use of screen devices and screen time are increasing health problems in children. We aim to describe the electronic screen device usage and determine the factors associated with their use among preschool-attending children in a suburban population in Sri Lanka. Methods A cross-sectional study was conducted in a suburban Medical Officer of Health area of Sri Lanka from January to March 2020. All children aged between 36–59 months attending ten randomly selected preschools were recruited. Data were collected using a parent-administered questionnaire and analysed using binary logistic regression in SPSS. The prevalence of electronic device usage, the average time spent on each device, and factors associated with individual device usage were analysed. Results A total of 340 children (Male-48%; mean age-50.1 ± 6.9 months) were recruited. Electronic devices were used by 96% of children. The most common devices were the television (87%) and the smartphone (63%). Of the children who used electronic devices, 60% exceeded the recommended screen time limit of one hour per day, 21% used devices for more than two hours per day, and 51% commenced using devices by two years of age. The higher education level of the father was independently associated with the use of smartphones and laptops and daily screen time of more than one hour ( p  < 0.05 for all). Male sex and being the only child were significantly associated with the use of smartphones, whereas maternal employment was associated with the use of laptops ( p  < 0.05 for all). Conclusions Electronic screen devices were used by 96% of preschool-attending children, and over 60% used them for more than the recommended daily upper limit of one hour. Higher paternal education, maternal employment and being the only child were significantly associated with electronic screen device use.

Background Transient memory loss with preserved consciousness needs precise diagnosis, as it could be owing to different causes requiring different management approaches. Differentiation between causes is difficult on first presentation, but it is important, as different causes have different management approaches and can have serious implications on a patient’s life, especially in regards to driving. Transient epileptic amnesia is a treatable condition if diagnosed correctly but can have major consequences when not treated. Transient epileptic amnesia is reported in literature, but reports on the temporal progression of partially treated transient epileptic amnesia are sparse; however, this knowledge could help someone diagnose the disease at least by the second encounter. Case presentation We report on a previously healthy, independent, right-handed 72-year-old Sinhalese Sri Lankan man, who had experienced five to seven brief periods of episodic memory loss since 2018, which were attributed to age, anxiety, and stress. He was involved in a car accident in 2000 and remained conscious but had retrograde amnesia. An extensive investigation conducted during his evaluation did not reveal a secondary cause for the accident. He later presented in 2022 with repeated generalized tonic–clonic seizures without secondary cause and an electroencephalogram showed epileptiform activity involving the left temporal lobe during the postictal period. He was diagnosed with transient epileptic amnesia and was started on carbamazepine. His seizures and amnestic episodes settled with the initiation of treatment, and now he is seizure-free after 6 years from the initial presentation of amnestic episodes. However, he has a mild degree of persistent interictal memory impairment. Conclusion Transient epileptic amnesia is difficult to diagnose on the first presentation, as it mimics several conditions where there is nonspecific memory loss, and there are often no involuntary movements. However, recurrent and brief amnestic episodes should lead to suspect transient epileptic amnesia over other causes. Transient epileptic amnesia requires a positive diagnosis, as it is treatable if diagnosed. A contraindication to driving and consequences of untreated disease could cause serious consequences, posing a risk to life. This case shows the temporal progression of the disease in a patient with partially treated transient epileptic amnesia.

Background Thalassaemia is a chronic disease without an effective cure in a majority. The clinical management has improved considerably during recent years; however, minimal attempts are made to up lift the quality of life among patients, especially in developing countries. Here we aim to describe and compare and to determine factors associated with health related quality of life among patients with transfusion dependent β-thalassaemia major and haemoglobin E β-thalassemia in Sri Lanka. Methods A case control study was conducted in the three largest thalassaemia centres of Sri Lanka. All patients with transfusion dependent β-thalassaemia (β-thalassaemia major and haemoglobin E β-thalassaemia) aged 5–18 years were recruited as cases whilst a randomly selected group of children without chronic diseases were recruited as controls. Socio-demographic and clinical data were collected using an interviewer-administered questionnaire and health related quality of life was measured using the validated Paediatric Quality of Life Inventory Version 4.0. Results Two hundred and seventy one patients with transfusion dependent β-thalassaemia (male-49.1%; mean age- 10.9 ± 3.6 years) and 254 controls (male-47.2%; mean age- 10.4 ± 3.5 years) were recruited. Mean health-related quality of life scores were significantly lower in patients compared to controls (72.9 vs. 91.5, p  < 0.001). Of the patients, 224 (84%) had β-thalassaemia major and 43 (16%) had haemoglobin E β-thalassaemia. Quality of life scores in psychological health ( p  < 0.05), emotional functioning ( p  < 0.05) and social functioning ( p  < 0.05) were significantly lower in patients with haemoglobin E β-thalassaemia compared to β-thalassaemia major. Splenectomy ( p  < 0.05), short stature ( p  < 0.05), under nutrition ( p  < 0.05) and longer hospital stays ( p  < 0.05) were significantly associated with lower quality of life scores. Conclusions Despite improvements in management, the quality of life among patients with β-thalassaemia still remains low. This is more pronounced in the subset of patients with haemoglobin E β-thalassaemia. Splenectomy, short stature, undernutrition and longer hospital stays were significantly associated with poor quality of life. It is timely, even in developing countries, to direct emphasis and to take appropriate steps to improve standards of living and quality of life of patients with β-thalassaemia.

Background Spinal fractures following seizures are reported but can be easily missed, as symptoms may be misinterpreted. Most seizure-induced spinal fractures occur in the thoracic and lumbar spine. Of all cervical spinal fractures, only 10% are odontoid fractures, making odontoid fractures following generalized convulsive seizures even rarer. Most odontoid fractures are unrecognized at the time of injury, as almost none are associated with neurological deficit at presentation. However, with time, it may result in incomplete or complete cervical cord compression owing to spinal instability, resulting in devastating neurological complications. Therefore, a high index of suspicion for early recognition and intervention is vital to prevent such sequelae. Case presentation. We report a previously healthy, independent, right-handed, 72-year-old South Asian man who presented with painful, weak shoulders with the inability to raise his arms above shoulder level following three generalized tonic–clonic convulsions. He did not have signs of lower limb or respiratory muscle weakness and had no difficulty in walking. His symptoms were attributed to postconvulsive muscle pain and spasm, for which he was managed conservatively. His shoulder pain and arm weakness resolved slowly over a month, but the restriction of neck movements persisted. Therefore, he was re-investigated 1 year later and was found to have a nonunited odontoid fracture with American Spinal Injury Association E impairment. Despite nonsurgical management, including neck immobilization with a soft cervical collar, he progressed to have impaired dexterity and diminished pain sensation in his hands, with sparing of legs (American Spinal Injury Association D impairment). He was diagnosed with central cord syndrome. He eventually underwent cranio-cervical fixation, after which he made a significant neurological recovery within 2 weeks. Conclusion Odontoid fracture without direct trauma, although uncommon, must be suspected when a patient complains of severe pain in the neck and shoulder following a generalized tonic–clonic convulsion. A high index of suspicion and anticipated cervical immobilization are required to avoid devastating neurological complications.

Background Emery-Dreifuss muscular dystrophy is a rare muscular dystrophy characterised by muscle weakness, joint contractures, and cardiac involvement. Among its subtypes, Emery-Dreifuss muscular dystrophy 5 typically presents with muscle weakness and cardiomyopathy during late childhood. Here, we report a Sri Lankan boy with Emery-Dreifuss muscular dystrophy 5 presenting with an unusual manifestation of persistent transaminitis detected during infancy. Case presentation A 21-month-old boy is admitted for further evaluation of high transaminases detected at nine months of age. He was the first-born child of healthy, non-consanguineous parents with an uncomplicated perinatal period. At nine months, he was found to have high transaminases (aspartate transaminase- 230IU/L and alanine transaminase- 234IU/L), which had persisted. He had marginal isolated gross motor developmental delay; however, he could walk unaided at 18 months. Examination revealed pseudohypertrophy of the calf and positive Gower’s sign. Lower limb tone and tendon reflexes were normal, and there were no joint contractions. He did not have dysmorphic features or peripheral stigmata of chronic liver disease. Investigations revealed persistently high aspartate and alanine transaminases and very high creatine phosphokinase of 15625 U/L. Abdominal ultrasonography and other liver function tests were normal. Based on normal liver function tests and high creatine phosphokinase, a muscular dystrophy was suspected. The electromyogram showed features of myopathy, and the muscle biopsy was compatible with congenital muscular dystrophy. The genetic analysis of the dystrophin gene by PCR-based amplification of 19 deletion-prone exons and copy number variation analysis did not reveal deletions in the dystrophin gene. The whole exome sequencing detected a missense splice region heterozygous variant of the SYNE2 gene, confirming Emery-Dreifuss muscular dystrophy 5. Conclusions Here, we report an extremely rare presentation of Emery-Dreifuss muscular dystrophy 5 during infancy with transaminitis. This case report highlights the importance of evaluating non-hepatic causes for elevated transaminases and the usefulness of whole exome sequencing in establishing an accurate diagnosis when relatively uncommon diseases are suspected.