Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item GDF15 linked to maternal risk of nausea and vomiting during pregnancy(Nature Pub. Group, 2024) Fejzo, M.; Rocha, N.; Cimino, I.; Lockhart, S.M.; Petry, C.J.; Kay, R.G.; Burling, K.; Barker, P.; George, A.L.; Yasara, N.; Premawardhena, A.; Gong, S.; Cook, E.; Rimmington, D.; Rainbow, K.; Withers, D.J.; Cortessis, V.; Mullin, P.M.; MacGibbon, K.W.; Jin, E.; Kam, A.; Campbell, A.; Polasek, O.; Tzoneva, G.; Gribble, F.M.; Yeo, G.S.H.; Lam, B.Y.H.; Saudek, V.; Hughes, I.A.; Ong, K.K.; Perry, J.R.B.; Sutton, C.A.; Baumgarten, M.; Welsh, P.; Sattar, N.; Smith, G.C.S.; Charnock- Jones, D.S.; Coll, A.P.; Meek, C.L.; Mettananda, S.; Hayward, C.; Mancuso, N.; O'Rahilly, S.GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy (NVP) including its most severe form, Hyperemesis Gravidarum (HG), but a full mechanistic understanding is lacking [1-4]. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally-labelled GDF15 variant we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with beta-thalassemia, a condition where GDF15 levels are chronically high [5], report very low levels of NVP. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally-derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.Item Efficacy of hydroxyurea in reducing the erythropoietic stress of ineffective erythropoiesis in transfusion dependent beta thalassaemia: A randomised, double-blind placebo-controlled clinical trial(Sri Lanka Association for the Advancement of Science, 2021) Yasara, N.; Premawardhena, A.; Perera, P.; Manamperi, A.; Mettananda, S.The unbalanced synthesis and accumulation of a-globin chains due to impaired synthesis of 0- globin results in the destruction of red blood cells (RBC) and erythroid precursors of patients with P-thalassaemia. This leads to an increased erythropoietic activity and ineffective erythropoiesis in the bone marrow of these patients. Hydroxyurea is a licenced medication that decreases the RBC destruction of patients with p-thalassaemia. However, its effect on erythropoietic stress is unclear. In this study, our objective was to evaluate the effect of hydroxyurea on erythropoietic stress of ineffective erythropoiesis in transfusion-dependent (TD) p-thalassaemia. This experimental study was carried out at the Thalassaemia Unit of Colombo North Teaching Hospital as part of a randomised, double-blind placebo-controlled clinical trial that evaluates the efficacy of hydroxyurea. We recruited 24 patients with TD p-thalassaemia who were taking hydroxyurea IQ- 20 mg/kg/day and 16 patients who were receiving a placebo. The erythropoietic stress of ineffective erythropoiesis was assessed by measuring serum soluble transferrin receptor (sTfR) levels before and six months after taking either hydroxyurea or placebo. Levels of sTfR were measured using a validated enzyme-linked immunosorbent assay. Paired t-test was used in the statistical analysis. Nineteen (79%) out of 24 patients who received hydroxyurea showed a reduction in sTfR level, of which 8 (33%) and 6 (25%) showed >25% and 10-25% reductions, respectively. A significant reduction in mean sTfR level was observed after hydroxyurea treatment (72.3±SD25.9) compared to pre-treatment levels (89.6士SD22.9), (pv0.01). Conversely, no difference in sTfR levels was seen in patients who received the placebo pre・(91.9土SD24.7) and post-treatment (96.4±SD19.4), (p=0.17). In conclusion, oral hydroxyurea significantly reduced the erythropoietic stress of ineffective erythropoiesis in patients with TD p-thalassaemia showing a promise as a treatment modality.Item In vitro study to identify effects of fetal haemoglobin inducing agents on primary human erythroid cells(Sri Lanka Association for the Advancement of Science, 2021) Yasara, N.; Manamperi, A.; Mettananda, S.Beta-thalassemia is an autosomal, recessively inherited monogenic disorder characterized by defective beta-globin synthesis. Deposition of excess alpha-globin in erythrocytes and their precursors due to unbalanced globin synthesis is the main underlying pathophysiology. Clinical data show that induction of fetal haemoglobin (HbF) in erythroid cells ameliorates the disease severity and associated complications. Hence, improving HbF via up-regulating gamma-globin gene expression has been identified as a novel treatment. The aim of our in vitro study was to identify the effects of fetal haemoglobin inducing agents in human erythroid cells. Haematopoietic stem cells (HSC) from umbilical cord blood samples collected from three healthy human placentas were isolated. Firstly, mononuclear cells were separated from the interface after fractionation on Histopaque®-1077 Hybri-Max and CD34+ HSCs were isolated using positive selection by magnetic activated cell sorting. HSCs were then expanded and differentiated into mature erythroid cells using a three-phase liquid culture protocol. Primary human erythroid cells at day 7 of the culture were incubated with hydroxyurea (20 pM), butyric acid (10 ^M), 5-azacystidine (10 pM), decitabine (5 pM), busulfan (30 pM), vorinostat (2.5 pM) and valproic acid (1000 pM) for 72 hours. Effects of these compounds on cell expansion, viability, morphology, as well as a-, P- and y-globin mRNA levels were measured using standard laboratory methods. Negative controls were tested in parallel. Compared to other compounds, hydroxyurea and butyrate treated erythroid cells displayed a significantly high mean fold expansion and viability. Significantly higher gamma-globin mRNA levels were observed in hydroxyurea treated cells (Mean relative expression: 186 ± SEM16) compared to negative control cells (Mean relative expression: 137 ± SEM14). Highest y/p globin mRNA ratios were observed in busulfan (12.6 ± SEM2.9) and decitabine (12.1 ± SEM3.3) treated erythroid cells. In conclusion, hydroxyurea induces gamma-globin expression and decitabine and busulfan favourably alter the y/P-globin mRNA ratios in vitro in human erythroid cells.Item Association of GDF15 levels with body mass index and endocrine status in β-Thalassaemia(Blackwell Publishing, 2023) Karusheva, Y.; Petry, C.J.; Yasara, N.; Kottahachchi, D.; Premawardhena, A.; Barker, P.; Burling, K.; Sattar, N.; Welsh, P.; Mettananda, S.; O'Rahilly, S.S.OBJECTIVE: GDF15 has emerged as a stress-induced hormone, acting on the brain to reduce food intake and body weight while affecting neuroendocrine function. Very high GDF15 levels are found in thalassaemia, where growth, energy balance and neuroendocrine function are impaired. We examined the relationships between GDF15 and anthropometric measures and endocrine status in β-thalassaemia. DESIGN: Cross sectional study PATIENTS: All β-thalassaemia patients attending the thalassaemia unit of Colombo North Teaching Hospital for blood transfusions. MEASUREMENTS: Anthropometric data, appetite scores, circulating GDF15, IGF, thyroid and reproductive hormone levels in 103 β-thalassaemia patients were obtained. RESULTS: GDF15 levels were markedly elevated in thalassaemia patients (24.2 fold with β-thalassaemia major compared with healthy controls). Among patients with β-thalassaemia major, the relationship between GDF15 and Body Mass Index (BMI) was curvilinear with all individuals with GDF15 levels above 24,000 pg/ml having a BMI below 20 kg/m2 . After adjustment for BMI, age and Tanner stage, serum IGF1 concentrations correlated negatively with GDF15 in all thalassaemia patients (β=-0.027, p=0.02). We found a significant positive relationship between GDF15 and gonadotropin (in both sexes) and testosterone (in males). CONCLUSIONS: GDF15 levels were markedly elevated in patients with β-thalassaemia and its association with BMI is consistent with the known effect of GDF15 to reduce body weight. The inverse association between GDF15 with IGF1 levels may reflect a neuroendocrine impact of GDF15 or an indirect effect via impaired nutritional state. The positive association with testosterone in males and gonadotropins in both sexes, was surprising and should prompt further GDF15 studies on the hypothalamic pituitary gonadal axis. This article is protected by copyright. All rights reserved.Item Hydroxyurea for transfusion dependent β-thalassaemia: A randomized double-blind placebo-controlled clinical trial(Sri Lanka Medical Association, 2021) Yasara, N.; Wickramarathne, N.; Silva, I.; Hameed, N.; Attanayaka, A.M.K.R.; Jayasinghe, V.L.; Gunathilaka, P.A.C.K.; Wickramasinghe, N.; Rodrigo, R.; Perera, L; Perera, P.S.; Mettananda, K.C.D.; Manamperi, A.; Premawardhena, A.; Mettananda, S.Introduction and objectives Hydroxyurea induces fetal haemoglobin in vitro however, its clinical usefulness in β-thalassaemia is unclear. Here, we aim to assess the efficacy and safety of oral hydroxyurea in patients with transfusion dependent β-thalassaemia. Methods A phase 3 randomized double-blind placebo-controlled clinical trial was conducted at Colombo North Teaching Hospital in 2019/20. Sixty patients with transfusion dependent β-thalassaemia were randomized into hydroxyurea (10-20mg/kg/day) or placebo groups. Transfused blood volume, pre-transfusion haemoglobin, fetal haemoglobin and adverse effects were monitored during 6-month treatment and post-treatment periods. The study was approved by the ethics committee of University of Kelaniya and registered in Sri Lanka Clinical Trials Registry (SLCTR/2018/024). Results Fifty-four (hydroxyurea-27; placebo-27) patients completed the trial. Mean pre-transfusion haemoglobin (8.2±0.8g/ dLvs8.0±0.88g/dL, p=0.43) and fetal haemoglobin levels (7.9±11.2%vs4.6±4.3%, p=0.17) were higher in hydroxyurea group compared to placebo. Also, transfused blood volume was lower in the hydroxyurea group (94±29ml/kgvs102±28ml/kg, p=0.34). However, none were statistically significant. Based on elevation of fetal haemoglobin (>1.5% from baseline), we identified 12/27 patients who respond well to hydroxyurea (hydroxyurea-responders). Hydroxyurea-responders required significantly lower blood volume (77±27ml/kg) compared to non-responders (108±24ml/kg, p<0.01) and placebo group (102±28ml/kg, p<0.05). HbE β-thalassaemia sub-type (p<0.01) and Xmn1 polymorphism of γ-globin gene (p<0.05) were significant predictors of response to hydroxyurea. No serious side effects due to hydroxyurea were reported. Conclusion Over 40% of patients with transfusion dependent β-thalassaemia- specifically those with HbE β-thalassaemia and Xmn1 polymorphism of γ-globin gene- responded to hydroxyurea and required 25% less blood compared to controls. No serious adverse effects were reported following hydroxyurea treatment.Item Efficacy and Safety of Oral Hydroxyurea in Patients with Transfusion Dependent β Thalassaemia: a Randomized Double-Blind Placebo-Controlled Clinical Trial(Sri Lanka Medical Association, 2020) Yasara, N.; Wickramarathne, N.; Silva, I.; Hameed, N.; Attanayaka, A.M.K.R.; Jayasinghe, V.L.; Wickramasinghe, N.; Rodrigo, R.; Perera, L.; Mettananda, K.C.D.; Manamperi, A.; Premawardhena, A.; Mettananda, S.INTRODUCTION AND OBJECTIVES: Patients with β- thalassaemia require blood transfusions and iron chelation for life. Hydroxyurea is a licenced medication for sickle cell disease but its usefulness in transfusion dependent β-thalassaemia is unclear. Here, we aim to assess the efficacy and safety of oral hydroxyurea in patients with transfusion dependent β-thalassaemia. METHODS: A phase III randomized double-blind placebo-controlled clinical trial was conducted at Thalassaemia Unit of Colombo North Teaching Hospital in 2019. Forty-one patients with transfusion dependent β-thalassaemia were randomized into hydroxyurea (10-20mg/kg/day) or placebo (pharmaceutically inert capsule identical to hydroxyurea) groups. Transfused blood volume, pre-transfusion haemoglobin, haemoglobin F level and side effects were monitored monthly during 6- month treatment and 6-month follow-up periods. Adverse events were assessed by trained medical officers. The study was approved by ethics committee of University of Kelaniya and registered in Sri Lanka Clinical Trials Registry (SLCTR/ 2018/024). RESULTS: Of the 41 (hydroxyurea-20; placebo-21) patients, three discontinued treatment due to thrombocytopenia (hydroxyurea-2) and rash (placebo-1). Baseline characteristics of two groups were similar. Mean pre-transfusion haemoglobin (8.52+0.57 vs 8.38+0.55, p=0.45) and haemoglobin F levels (4.3+7.1% vs 3.1+1.9%, p=0.48) were higher in hydroxyurea group compared to placebo. Also, transfused blood volume was lower in hydroxyurea group (102+24ml/kg vs 111+27ml/kg, p=0.3). However, none were statistically significant. Based on elevation of haemoglobin F (>1.5% from baseline), we identified 6/18 patients as hydroxyurea responders. Hydroxyurea responders required significantly lower blood volume (87+13ml/kg) compared to non-responders (110+25ml/kg, p=0.05) and placebo group (111+27ml/kg, p<0.05) while maintaining higher pre-transfusion haemoglobin level (8.6+0.5 vs 8.4+0.5 and 8.3+0.5). No serious side effects were reported. CONCLUSIONS: One-third of patients with transfusion dependent β-thalassaemia responded to hydroxyurea treatment requiring 20% less blood compared to controls. No serious side effects were reported following hydroxyurea treatment.