scholarly journals INFLUENCE OF SICKLE CELL GENE ON THE ALLELIC DIVERSITY AT THE MSP-1 LOCUS OF PLASMODIUM FALCIPARUM IN ADULT PATIENTS WITH SEVERE MALARIA

2015 ◽  
Vol 7 ◽  
pp. e2015050 ◽  
Author(s):  
Dilip Kumar Patel ◽  
Ranjeet Singh Mashon ◽  
Prasanta Purohit ◽  
Siris Patel ◽  
Satyabrata Meher ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Falciparum Malaria ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Allelic Diversity ◽  
Adult Patients ◽  
Medical Sciences ◽  
Hemoglobin Variants ◽  
Biology Laboratory ◽  
Severe Falciparum Malaria

Although several studies have supported that sickle cell trait (HbAS) protects against falciparum malaria, the exact mechanism by which sickle gene confers protection is unclear. Further, there is no information on the influence of sickle gene on parasitic diversity of P. falciparum population in severe symptomatic malaria.  This study was undertaken to assess the effect of the sickle gene on the parasite densities and diversities in hospitalized adult patients with severe falciparum malaria. The study was carried out in 166 adult hospitalized subjects with severe falciparum malaria at Sickle Cell Clinic and Molecular Biology Laboratory, Veer Surendra Sai Institute of Medical Sciences and Research, Burla, Odisha, India . They were divided into three groups on the basis of hemoglobin variants HbAA (n=104), HbAS (n=30) and HbSS (n=32). The msp-1 loci was genotyped using a PCR based methodology. The parasite densities were significantly high in HbAA compared to HbAS and HbSS. The multiplicity of infection (MOI) and multiclonicity for msp-1 were significantly low in HbSS and HbAS compared to HbAA. The prevalence of K1 (p<0 .0001) and MAD20 (p=0.0003) alleles were significantly high in HbAA. The RO33 allele was detected at a higher frequency in HbSS and HbAS, compared to K1 and MAD20. Sickle gene was found to reduce both the parasite densities and diversity of P. falciparum in adults with severe malaria.

A Novel β Globin Gene Mutation, Reported As An α Chain Hemoglobin Variant By High Performance Liquid Chromatography (HPLC) & As Sickle Cell Trait On New Born Screening: A case Report

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 954-954
Author(s):  
Kranthi Nandan Seelaboyina ◽  
Jennifer Alison Busse ◽  
Sandeep Malik ◽  
Thomas Moulton
Keyword(s):  
Sickle Cell ◽  
Copy Number ◽  
Sickle Cell Trait ◽  
Globin Gene ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Thalassemia Intermedia ◽  
Exon 2 ◽  
Alpha Globin ◽  
Hemoglobin Variants

Abstract Introduction There are 827 variants of β thalassemia reported to the registry of human hemoglobin variants and thalassemias registry 1. Genetic mutations of β thalassemia are very diverse but can be broadly divided in to non deletion forms and deletion forms. The new mutation is a frame shift insertion in exon 2 of the β globin gene. To the best of our knowledge this mutation has never been described before and presents as a mild form β thalassemia intermedia. Objective To describe the phenotypic presentation of the new β globin variant, due to insertion of 9 nucleotides (AAAGTGCTC) between nucleotides c.207 and c.208. Case report A 22 months-old Hispanic boy who was referred for evaluation of persistent anemia. The new born screening for the child was positive for sickle cell trait. Initial hemoglobin (Hb) was 8.8, hematocrit was 27 and MCV was 65.5, which were decreased. RDW was 25.2, which was increased. Hemoglobin evaluation by acid and alkaline electrophoresis and HPLC revealed a HbS 0%, HbF 6.5% HbA 78.4%, HbA2 4.9% and a Hb variant 10.2%. The interpretation of the results was an α globin variant suggestive of Hb Montefiore and β thalassemia trait. Alpha thalassemia PCR for the 7 most common deletions in the α globin chain was negative. Subsequent α globin gene sequencing revealed no α globin gene mutations. On physical exam there were no bony changes or hepatosplenomegaly. Family History The mother is 29-year-old with HbAA. The father is 39-years-old with the same mutation on beta globin gene analysis. Hb electrophoresis also suggested an α and β globin mutation. Alpha thalassemia PCR was negative and he had a normal α globin gene copy number. At age 19 he had a splenectomy secondary to splenomegaly and hypersplenism. He is consistently anemic with Hb< 9 and MCV < 70. The child has a paternal half brother, who is 21 years old and has similar problems as father. He had a splenectomy at the age of 17 after admission for abdominal pain. The patient has a 5-year-old sibling, who is normal with HbAA and another paternal half sibling reported as no anemia. Discussion Though β thalassemia intermedia is most commonly homozygous or compound heterozygous, less frequently it can be due to single locus mutation. DNA sequencing of the α globin gene of the index case was completely normal and there was normal copy number of the α globin gene in the father. No Hb S was found on Hb electrophoresis. The new mutation adds 9 base pairs to exon 2 and 3 amino acids (Lys-Val-Leu) between amino acid 68 and 69 of the protein. This elongates the beta chain which can lead to instability and precipitation of Hb as well as hemolysis and anemia2. Further studies like short time incubation and pulse chase globin chain synthesis experiments are needed to know the stability of the β globin protein3. In addition, an increase of α globin gene copy number can also be a reason for increasing the severity of β thalassemia trait2. However the α gene copy was normal in the father. Conclusion We present a case of a child with a false positive abnormal newborn screen suggestive of sickle cell trait, as well as a Hb electrophoresis suggestive of an alpha globin mutation. As the father and paternal brother have had a splenectomy in their teen years with noted hepatosplenomegaly, suggestive of increased hemolysis, and the anemia is more severe than usual for β thalassemia trait, this suggests that phenotypically the c.199_207dup variant presents as a mild β thalassemia intermedia. In addition, there does not seem to be any bony abnormalities associated with marrow hyperplasia. As both our patients are heterozygous for this novel mutation with normal α globin gene copy number and alpha globin sequencing, we suspect that elongation of the β globin produces an unstable hemoglobin with a mild β thalassemia intermedia phenotype2. References 1. Databases of human hemoglobin variants and other resources at the globin gene server. Hemoglobin. 25(2):183-93, 2001 May. 2. Galanello R, Cao A. Relationship between genotype and phenotype. Thalassemia intermedia. Annals of the New York Academy of Sciences 1998; 850:325-33. 3. Is hemoglobin instability important in the interaction between hemoglobin E and beta thalassemia? Blood September 15, 1998 vol. 92 no. 6 2141-2146. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hemoglobin Variants and Disease Manifestations in Severe Falciparum Malaria

JAMA ◽  
2007 ◽  
Vol 297 (20) ◽  
pp. 2220 ◽  
Author(s):  
Jürgen May ◽  
Jennifer A. Evans ◽  
Christian Timmann ◽  
Christa Ehmen ◽  
Wibke Busch ◽  
...  
Keyword(s):  
Falciparum Malaria ◽  
Hemoglobin Variants ◽  
Severe Falciparum Malaria

Falciparum malaria in a patient with sickle cell trait with hemophagocytosis and secondary pancytopenia

2012 ◽  
Vol 91 (8) ◽  
pp. 1329-1330 ◽  
Author(s):  
Jalil Ur Rehman ◽  
Nezar Bhabri ◽  
Ahmed Waleed ◽  
A. Maulawi ◽  
M. Aslam
Keyword(s):  
Falciparum Malaria ◽  
Sickle Cell ◽  
Sickle Cell Trait

scholarly journals Cord blood screening for hemoglobin abnormalities by thin layer isoelectric focusing

Blood ◽  
1980 ◽  
Vol 56 (6) ◽  
pp. 1068-1071 ◽  
Author(s):  
F Galacteros ◽  
K Kleman ◽  
J Caburi-Martin ◽  
Y Beuzard ◽  
J Rosa ◽  
...  
Keyword(s):  
Thin Layer ◽  
Cord Blood ◽  
Sickle Cell ◽  
Isoelectric Focusing ◽  
Sickle Cell Trait ◽  
Cell Disease ◽  
Abnormal Hemoglobin ◽  
Excellent Method ◽  
Hemoglobin Variants ◽  
Blood Screening

Hemoglobin variants can be successfully identified in cord blood samples. The methods most commonly used include cellulose acetate (CAC) and citrate agar (CAG) electrophoresis. Recently thin layer isoelectric focusing (TLIF) has been shown to be an excellent method for identifying hemoglobin variants. To determine the applicability of TLIF for cord blood screening, we compared the results of 835 samples obtained by TLIF with that obtained by CAC, CAG, and the combination of both CAC and CAG. In 100 of these samples we detected an abnormal hemoglobin pattern using TLIF. In contrast, we detected only 80 abnormal samples by CAC, 70 by CAG, and 80 by using the combination of CAC and CAG. Due to the increased resolution provided by TLIF, we correctly diagnosed two sickle cell trait samples by TLIF that were incorrectly suspected to be homozygous for sickle cell disease by CAC and CAG. We identified 41 samples containing Bart's hemoglobin by TLIF in contrast to only 21 using CAC and 14 using CAG. The time and cost of TLIF was comparable to that using the combination of both methods. We, therefore, conclude that TLIF is the method of choice for cord blood screening.

scholarly journals Red blood cell tension controlsPlasmodium falciparuminvasion and protects against severe malaria in the Dantu blood group

2018 ◽  
Author(s):  
Silvia N. Kariuki ◽  
Alejandro Marin-Menendez ◽  
Viola Introini ◽  
Benjamin J. Ravenhill ◽  
Yen-Chun Lin ◽  
...  
Keyword(s):  
Protective Effect ◽  
Severe Malaria ◽  
Blood Group ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Surface Protein ◽  
Major Effect ◽  
Similar Degree ◽  
Parasite Invasion ◽  
Degree Of Protection

Malaria has had a major effect on the human genome, with many protective polymorphisms such as sickle cell trait having been selected to high frequencies in malaria endemic regions1, 2. Recently, we showed that a novel blood group variant, Dantu, provides 74% protection against all forms of severe malaria in homozygous individuals3-5. This is a similar degree of protection to sickle cell trait and considerably greater than the most advanced malaria vaccine, but until now the mechanism of protection has been unknown. In the current study, we demonstrate a significant impact of Dantu on the ability ofPlasmodium falciparummerozoites to invade RBCs. The Dantu variant was associated with extensive changes to the RBC surface protein repertoire, but unexpectedly the malaria protective effect did not correlate with specific RBC-parasite receptor-ligand interactions. By following invasion using video microscopy, we found a strong link between RBC tension and parasite invasion and, even in non-Dantu RBCs, identified a tension threshold above which RBC invasion did not occur. Dantu RBCs had higher average tension, meaning that a higher proportion of Dantu RBCs could not be invaded. These findings not only provide an explanation for the protective effect of Dantu against severe malaria, but also provide fresh insights into the essential process ofP. falciparumparasite invasion, and how invasion efficiency varies across the heterogenous populations of RBCs that are present both within and between individuals.

scholarly journals Cord blood screening for hemoglobin abnormalities by thin layer isoelectric focusing

Blood ◽  
1980 ◽  
Vol 56 (6) ◽  
pp. 1068-1071 ◽  
Author(s):  
F Galacteros ◽  
K Kleman ◽  
J Caburi-Martin ◽  
Y Beuzard ◽  
J Rosa ◽  
...  
Keyword(s):  
Thin Layer ◽  
Cord Blood ◽  
Sickle Cell ◽  
Isoelectric Focusing ◽  
Sickle Cell Trait ◽  
Cell Disease ◽  
Abnormal Hemoglobin ◽  
Excellent Method ◽  
Hemoglobin Variants ◽  
Blood Screening

Abstract Hemoglobin variants can be successfully identified in cord blood samples. The methods most commonly used include cellulose acetate (CAC) and citrate agar (CAG) electrophoresis. Recently thin layer isoelectric focusing (TLIF) has been shown to be an excellent method for identifying hemoglobin variants. To determine the applicability of TLIF for cord blood screening, we compared the results of 835 samples obtained by TLIF with that obtained by CAC, CAG, and the combination of both CAC and CAG. In 100 of these samples we detected an abnormal hemoglobin pattern using TLIF. In contrast, we detected only 80 abnormal samples by CAC, 70 by CAG, and 80 by using the combination of CAC and CAG. Due to the increased resolution provided by TLIF, we correctly diagnosed two sickle cell trait samples by TLIF that were incorrectly suspected to be homozygous for sickle cell disease by CAC and CAG. We identified 41 samples containing Bart's hemoglobin by TLIF in contrast to only 21 using CAC and 14 using CAG. The time and cost of TLIF was comparable to that using the combination of both methods. We, therefore, conclude that TLIF is the method of choice for cord blood screening.

scholarly journals The prognostic and diagnostic value of intraleukocytic malaria pigment: an individual patient data pooled meta-analysis of 32,000 patients with severe falciparum malaria in Africa and Asia

2021 ◽  
Author(s):  
Ketsanee Srinamon ◽  
James A Watson ◽  
Kamolrat Silamut ◽  
Benjamas Intharabut ◽  
Nguyen Hoan Phu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Severe Malaria ◽  
Falciparum Malaria ◽  
Peripheral Blood ◽  
Prognostic Value ◽  
Individual Patient Data ◽  
Risk Of Death ◽  
African Children ◽  
Malaria Pigment ◽  
Severe Falciparum Malaria

AbstractBackgroundSevere falciparum malaria is a major cause of death in tropical countries, particularly in African children. Accurate diagnosis and prognostic assessment are critical to clinical management.MethodsThe prognostic value of the malaria parasite count, and the proportions of polymorphonuclear leukocytes (PMNs) and monocytes (PMMs) containing malaria pigment in peripheral blood films were assessed in three randomized controlled trials conducted in severe malaria patients; two in Southeast Asia (AQ Vietnam; n=483 and SEAQUAMAT; n=1,330) and one in Africa (AQUAMAT; n=4,211). Following a systematic review of the literature, we incorporated these data into an individual patient data meta-analysis including published data from the Severe Malaria in African children (SMAC) network (n=25,845) and a study from Mali (n=166).FindingsThe proportion of pigment containing PMNs on peripheral blood films was strongly positively correlated with prognosis (odds-ratio for in-hospital mortality for a tenfold increase: 2.53 [95% CI: 2.13-3.00], p = 10−26). The meta-analytic odds-ratio estimate for in-hospital death in patients with >5% pigment containing PMNs compared with lower values was 2.67 (95% CI: 2.08-3.42; p = 10−14). Particularly in African children, the proportion of pigment containing PMNs added substantially to the prognostic assessment from simple bedside examination, and also to the conventional parasite count. In all analyses, the proportion of pigment containing monocytes had a lower prognostic value.InterpretationMicroscopy assessment of the proportion of pigment containing PMNs in a blood film is simple and rapid, and should be performed in all patients hospitalised with suspected severe malaria. Patients with >5% pigment containing PMNs have more than double the risk of death.OtherFunded by Wellcome. The systematic review was registered prospectively on PROS-PERO, number CRD42021284527Research in contextEvidence before this studySevere falciparum malaria remains a major cause of preventable childhood mortality in sub-Saharan Africa. In 2019 there were an estimated 274,000 deaths in children under 5 years. Rapidly identifying patients at the greatest risk of death and providing effective treatment is essential to saving lives. Based on data from our prospective studies of strictly defined severe falciparum malaria in Vietnamese adults, the proportions of peripheral blood neutrophils and monocytes containing malaria pigment (haemozoin) was proposed as a prognostic factor for mortality. We carried out a systematic review on PubMed of all articles published between database inception and October 11, 2021, using search terms “intraleukocytic pigment” and “severe malaria”. In addition to papers published by our research group, we found two other studies that reported the prognostic value of intraleukocytic pigment counts in severe malaria cohorts of at least 100 patients: the SMAC network study, the largest published cohort study conducted in over 25,000 African children with suspected severe malaria, and a cohort of 172 children from Mali. The SMAC study reported that intraleukocytic malaria pigment counts were not a useful predictor of outcome in African children diagnosed with severe malaria. This differed from the results from the Malian study and our original study in Vietnamese adults.Added value of this studyWe provide new data on the prognostic value of intraleukocytic malaria pigment counts in over 6,000 adults and children with a strict diagnosis of severe falciparum malaria studied prospectively in Asia and Africa. These patients were enrolled in three of the largest randomised controlled trials in severe malaria. These randomised trials have provided the main evidence base for current global therapeutic recommendations. Our data show that there is substantial prognostic value in counting intraleukocytic malaria pigment. This was significantly greater for neutrophil rather than monocyte associated pigment. Pooling all the individual patient data showed that the prognostic value was consistent across studies and countries, despite the substantial differences in study populations and study designs. Having more than 5% pigment containing neutrophils was associated with over double the risk of death from severe falciparum malaria.Implications of all the available evidenceIntraleukocytic malaria pigment counts have sub-stantial prognostic value in severe falciparum malaria. The proportion of neutrophils containing malaria pigment should be counted in thin blood films in all patients with suspected severe malaria. Patients with over 5% of pigment containing neutrophils have a high risk of death.

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