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Tavares-Neto, J., Paulo C. Naoum, José Adorno, et al. "Hemoglobinopatias no Distrito Federal, Brasil." Revista da Sociedade Brasileira de Medicina Tropical 19, no. 1 (1986): 13–19. http://dx.doi.org/10.1590/s0037-86821986000100004.
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Em uma amostra de 3137 pessoas, residentes no Distrito Federal, foram detectadas as seguintes hemoglobinas: em 3009(95,92%) HbAA; em 91 (2,90%) HbAS; em 20(0,64%) HbAC; em 8 (0,26%) talassemia beta minor; em 5(0,16%) HbAJ alfa; em 3 (0,09%) HbAM e em 1 (0,03%) talassemia major associada com HbAS. A HbAS têm as seguintes freqüências, quanto ao grupo racial: branco - 1,84%; mulato claro 2,55%; mulato médio-3,68%; mulato escuro - 6,80%; negro -10,43% e mestiço de índio -3,85%.
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Kreuels, Benno, Christina Kreuzberg, Robin Kobbe, et al. "Differing effects of HbS and HbC traits on uncomplicated falciparum malaria, anemia, and child growth." Blood 115, no. 22 (2010): 4551–58. http://dx.doi.org/10.1182/blood-2009-09-241844.
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Abstract The high prevalence of hemoglobin S (HbS) in Africa and hemoglobin C (HbC) in parts of West Africa is caused by the strong protection against severe falciparum malaria during childhood. Much less is known about the effect of HbS and especially HbC on Plasmodium falciparum infection, uncomplicated malaria, and anemia. A total of 1070 children from the Ashanti Region, Ghana, were enrolled at the age of 3 months and visited monthly until 2 years of age. The effects of the β-globin genotype on the age-dependent incidence of malaria, levels of parasitemia, and hemoglobin as well as physical development were analyzed by population-averaged models. Infants with HbAS were protected from uncomplicated malaria (P < .005) and anemia (P < .001), had lower age-adjusted parasite densities (P < .001), and higher age-adjusted hemoglobin levels compared with children with the HbAA genotype (P = .004). In contrast, HbAC carriers had lower hemoglobin levels (P < .033) and were not protected against malaria or anemia. Notably, infants with HbAS were also significantly protected against stunting compared with carriers of HbAA or HbAC. This indicates differing mechanisms of protection against malaria of HbAS and HbAC and might help to understand why HbC is restricted to distinct areas of West Africa.
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Dikwa, K. B., D. B. Maikaje, U. A. Yahaya, and A. B. Suleiman. "Differences in haematological parameters and haemoglobin phenotypes in symptomatic and asymptomatic subjects with Plasmodium falciparum infection in parts of Kaduna metropolis, Nigeria." African Journal of Clinical and Experimental Microbiology 22, no. 3 (2021): 407–14. http://dx.doi.org/10.4314/ajcem.v22i3.12.
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Background: Plasmodium falciparum is the leading cause of malaria morbidity and mortality in Nigeria with varied symptoms and haematological consequences. The objective of this study is to assess the differences in haematological parameters and haemoglobin phenotypes in symptomatic P. falciparum infected and apparently healthy asymptomatic individuals in parts of Kaduna metropolis.Methodology: A total of 1000 subjects; 500 symptomatic and 500 apparently healthy subjects asymptomatic for malaria, were recruited from selected hospitals and National Blood Bank in Kaduna metropolis. Blood samples were collected for thick and thin film microscopy to determine malaria parasitaemia and parasite species identification respectively. Haematological parameters were determined using automated blood analyser (KX-21N, Sysmex, Japan) and haemoglobin phenotypes by alkaline cellulose acetate electrophoresis.Results: Of the 1000 subjects recruited, 347 (34.7%) were positive for P. falciparum on blood film, which included 226 (45.2%) of 500 symptomatic and 121 (24.2%) of 500 asymptomatic subjects (p<0.00001). Of the 347 P. falciparum infected subjects, 275 (79.3%) had HbAA, 61 (17.6%) had HbAS, 1 (0.3%) had HbAC, 8 (2.3%) had HbSS, and 2 (0.6%) had HbSSf phenotypes. One hundred and sixty-three (72.1%) of the 226 symptomatic subjects had HbAA while 112 (92.6%) of the 121 asymptomatic subjects had HbAA, which indicated a significantly higher frequency of asymptomatic malaria in subjects with HbAA (p<0.00001). Conversely, 53 (23.5%) of the 226 symptomatic subjects had HbAS while 8 (6.6%) of 121 asymptomatic subjects had HbAS, indicating a significantly higher frequency of symptomatic malaria in subjects with HbAS (p=0.000086). The frequency of parasitaemia > 3,000 parasites/μL of blood was 100% for HbSSf, 25% for HbSS, 8.2% for HbAS and 2.2% for HbAA, which showed significantly higher frequency in subjects with HbSS (X2=7.5989, p=0.0054) and HbAS (X2=3.9627, p=0.046519) compared to HbAA. In symptomatic subjects, only MCHC value was significantly higher in subjects with HbAS (33.21±2.430) compared to those with HbAA (32.09 ±2.315) (p=0.003), while all other haematological parameters were not significantly different (p>0.05). In asymptomatic subjects, none of the haematological parameters was significantly different between subjects with HbAS and HbAA (p>0.05).Conclusion: Although the frequency of P. falciparum infection in this study is generally higher in subjects with HbAA, symptomatic infection and higher parasite density are associated with HbAS, HbSS and HbSSf. Effective utilisation of personal preventive measures by inhabitants, in addition to current malaria control and intervention strategies should be adequately implemented in Kaduna metropolis.
 Keywords: Haematological parameters, haemoglobin, electrophoresis, Plasmodium falciparum, malaria
 
 Différences dans les paramètres hématologiques et les phénotypes d'hémoglobine chez les sujets symptomatiques et asymptomatiques atteints d'une infection à Plasmodium falciparum dans certaines parties de la métropole de Kaduna, Nigéria
 
 Contexte: Plasmodium falciparum est la principale cause de morbidité et de mortalité liées au paludisme au Nigéria avec des symptômes et des conséquences hématologiques variés. L'objectif de cette étude est d'évaluer les différences de paramètres hématologiques et de phénotypes d'hémoglobine chez des individus symptomatiques infectés par P. falciparum et asymptomatiques apparemment en bonne santé dans certaines parties de la métropole de Kaduna.
 Méthodologie: Un total de 1000 sujets; 500 sujets symptomatiques et 500 sujets apparemment sains asymptomatiques pour le paludisme ont été recrutés dans certains hôpitaux et dans la Banque nationale du sang de la métropole de Kaduna. Des échantillons de sang ont été prélevés pour la microscopie à couche épaisse et mince afin de déterminer respectivement la parasitémie du paludisme et l'identification des espèces de parasites. Les paramètres hématologiques ont été déterminés à l'aide d'un analyseur sanguin automatisé (KX-21N, Sysmex, Japon) et des phénotypes d'hémoglobine par électrophorèse sur acétate de cellulose alcaline.
 Résultats: Sur les 1000 sujets recrutés, 347 (34,7%) étaient positifs pour P. falciparum sur frottis sanguin, qui comprenait 226 (45,2%) de 500 sujets symptomatiques et 121 (24,2%) de 500 sujets asymptomatiques (p<0,00001). Sur les 347 sujets infectés par P. falciparum, 275 (79,3%) avaient HbAA, 61 (17,6%) avaient HbAS, 1 (0,3%) avaient HbAC, 8 (2,3%) avaient HbSS et 2 (0,6%) avaient des phénotypes HbSSf. Cent soixante-trois (72,1%) des 226 sujets symptomatiques avaient une HbAA tandis que 112 (92,6%) des 121 sujets asymptomatiques avaient une HbAA, ce qui indiquait une fréquence significativement plus élevée de paludisme asymptomatique chez les sujets avec HbAA (p<0,00001). À l'inverse, 53 (23,5%) des 226 sujets symptomatiques avaient une HbAS tandis que 8 (6,6%) des 121 sujets asymptomatiques avaient une HbAS, indiquant une fréquence significativement plus élevée de paludisme symptomatique chez les sujets avec HbAS (p=0,000086). La fréquence de parasitémie> 3000 parasites / μL de sang était de 100% pour l'HbSSf, 25% pour l'HbSS, 8,2% pour l'HbAS et 2,2% pour l'HbAA, ce qui a montré une fréquence significativement plus élevée chez les sujets atteints d'HbSS (X2=7,5989, p=0,0054) et HbAS (X2=3,9627, p=0,046519) par rapport à l'HbAA. Chez les sujets symptomatiques, seule la valeur MCHC était significativement plus élevée chez les sujets avec HbAS (33,21±2,430) par rapport à ceux avec HbAA (32,09±2,315) (p=0,003), tandis que tous les autres paramètres hématologiques n'étaient pas significativement différents (p>0,05). Chez les sujets asymptomatiques, aucun des paramètres hématologiques n'était significativement différent entre les sujets avec HbAS et HbAA (p>0,05).
 Conclusion: Bien que la fréquence des infections à P. falciparum dans cette étude soit généralement plus élevée chez les sujets atteints d'HbAA, une infection symptomatique et une densité parasitaire plus élevée sont associées à l'HbAS, l'HbSS et l'HbSSf. Une utilisation efficace des mesures de prévention personnelle par les habitants, en plus des stratégies actuelles de lutte antipaludique et d'intervention, devrait être mise en oeuvre de manière adéquate dans la métropole de Kaduna.
 Mots clés: Paramètres hématologiques, hémoglobine, électrophorèse, Plasmodium falciparum, paludisme
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Martina, W. V., E. G. Martijn, M. van der Molen, J. G. Schermer, and F. A. Muskiet. "Beta-N-terminal glycohemoglobins in subjects with common hemoglobinopathies: relation with fructosamine and mean erythrocyte age." Clinical Chemistry 39, no. 11 (1993): 2259–65. http://dx.doi.org/10.1093/clinchem/39.11.2259.
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Abstract Amounts of beta-N-terminal glycohemoglobins (HbX1c), serum fructosamine, and erythrocyte polyamines were determined in nondiabetic adults with HbAA, HbAC, HbAS, HbCC, HbSC, HbSS, and HbS/hereditary persistent HbF (HPFH). The groups did not differ in fructosamine concentrations. Mean (95% confidence limits) HbX1c percentages were: 4.4 (4.1-4.8) for HbA1c in HbAA, 4.3 (3.9-4.8) for HbA1c in HbAC, 4.1 (3.6-4.6) for HbC1c in HbAC, 4.4 (4.0-4.7) for HbA1c in HbAS, 2.6 (range: 2.3-3.8) for HbC1c in HbCC, 2.0 (1.5-2.4) for HbS1c in HbSC, 0.9 (0.6-1.3) for HbS1c in HbSS, and 1.3 (range: 0.8-2.4) for HbS1c in HbS/HPFH. There was a nonlinear inverse relation between HbX1c and erythrocyte polyamines, indicating that HbX1c percentage decreases with decreasing mean erythrocyte age. We conclude that amounts of HbX1c in subjects with heterozygous hemoglobinopathies should be expressed as a percentage of HbX0 + HbX1c, not total hemoglobin. Interpretation of HbX1c in subjects with a decreased erythrocyte half-life is difficult; measurement of fructosamine seems a suitable alternative.
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Pattillo, Robin E., and L. Bruce Gladden. "Red blood cell lactate transport in sickle disease and sickle cell trait." Journal of Applied Physiology 99, no. 3 (2005): 822–27. http://dx.doi.org/10.1152/japplphysiol.00235.2005.
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This study determined and compared rates and mechanisms of lactate transport in red blood cells (RBCs) of persons with 1) sickle cell disease (HbSS), 2) sickle cell trait (HbAS), and 3) a control group (HbAA). Blood samples were drawn from 30 African-American volunteers (10 HbSS, 10 HbAS, 10 HbAA). Lactate influx into RBCs was measured by using [14C]lactate at six (2, 5, 10, 15, 25, and 40 mM) unlabeled lactate concentrations. The monocarboxylate transporter pathway was blocked by p-chloromercuriphenylsulfonic acid to determine its percent contribution to total lactate influx. Generally, total lactate influx into RBCs from the HbSS group was significantly greater than influx into RBCs from HbAS or HbAA, with no difference between HbAS and HbAA. Faster influx into HbSS RBCs was attributed to increased monocarboxylate transporter activity [increased apparent Vmax( V′max)]. V′max(4.7 ± 0.6 μmol·ml−1·min−1) for HbSS RBCs was significantly greater than V′maxof HbAS RBCs (2.9 ± 1.5 μmol·ml−1·min−1) and HbAA RBCs (2.0 ± 0.5 μmol·ml−1·min−1). Km(42.8 ± 8 mM) for HbSS RBCs was significantly greater than Km(27 ± 12 mM) for HbAA RBCs. We suspect that elevated erythropoietin levels in response to chronic anemia and/or pharmacological treatment (erythropoietin injections, hydroxyurea ingestion) is the underlying mechanism for increased lactate transport capacity in HbSS RBCs.
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Patel, Dilip Kumar, Ranjeet Singh Mashon, Prasanta Purohit, et al. "INFLUENCE OF SICKLE CELL GENE ON THE ALLELIC DIVERSITY AT THE MSP-1 LOCUS OF PLASMODIUM FALCIPARUM IN ADULT PATIENTS WITH SEVERE MALARIA." Mediterranean Journal of Hematology and Infectious Diseases 7 (August 24, 2015): e2015050. http://dx.doi.org/10.4084/mjhid.2015.050.
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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.
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Chatel, Benjamin, Laurent A. Messonnier, Christophe Vilmen, Monique Bernard, Vincent Pialoux, and David Bendahan. "Exacerbated metabolic changes in skeletal muscle of sickle cell mice submitted to an acute ischemia–reperfusion paradigm." Clinical Science 132, no. 19 (2018): 2103–15. http://dx.doi.org/10.1042/cs20180268.
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Sickle cell disease (SCD) is characterized by painful vaso-occlusive crisis. While there are several metabolic abnormalities potentially associated with muscular ischemia–reperfusion cycles that could be harmful in the context of SCD, the metabolic consequences of such events are still unknown. Ten controls (HbAA), thirteen heterozygous (HbAS), and ten homozygous (HbSS) SCD mice were submitted to a standardized protocol of rest–ischemia–reperfusion of the left leg during which adenosine triphosphate, phosphocreatine, and inorganic phosphate concentrations as well as intramuscular pH were measured using phosphorous magnetic resonance spectroscopy (MRS). Forty-eight hours later, skeletal muscles were harvested. Oxidative stress markers were then measured on the tibialis anterior. At the end of the ischemic period, HbSS mice had a lower pH value as compared with the HbAA and HbAS groups (P<0.01). During the reperfusion period, the initial rate of phosphocreatine resynthesis was lower in HbSS mice as compared with HbAA (P<0.05) and HbAS (P<0.01) animals. No significant difference among groups was observed regarding oxidative stress markers. HbSS mice displayed a higher intramuscular acidosis during the ischemic period while their mitochondrial function was impaired as compared with their HbAA and HbAS counterparts. These metabolic abnormalities could worsen the complications related to the pathology of SCD.
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Mooberry, Micah J., Robert Bradford, Robin Kellerman, et al. "An Exploratory Study of the Effects of Strenuous Exercise On Markers of Activation of Coagulation, Inflammation and Endothelial Activation: Possible Implications for Exercise-Related Morbidity in Sickle Cell Trait." Blood 120, no. 21 (2012): 3224. http://dx.doi.org/10.1182/blood.v120.21.3224.3224.
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Abstract Abstract 3224 The acute physiological response to strenuous exercise is characterized by a transient hypercoagulable state as well as an acute inflammatory response. Despite these well-recognized findings, the mechanisms involved in these exercise-induced effects are not well understood. To further evaluate the effect of exercise on multiple hematologic parameters, subjects underwent an exercise protocol with blood samples obtained at several time points. Fifteen healthy male African-American subjects [10 normal hemoglobin (HbAA), 5 sickle cell trait (HbAS)], ages 18–35, exercised at 65% of VO2max × 30 min followed by an increase in treadmill grade of 2.5% every 3 min until volitional exhaustion. Blood was collected at baseline, immediately post-exercise, and at 1 and 2 hours post-exercise. Analyses included CBC, D-dimer, sVCAM, LDH, haptoglobin, plasma free hemoglobin (PF Hb), RBC phosphatidylserine (PS) exposure (by flow cytometry), microparticle (MP) procoagulant activity (Zymuphen MP-activity assay measuring ‘PS equivalents’), and MP-tissue factor (MP-TF) activity (in-house chromogenic assay). Flow cytometric enumeration of MPs in platelet poor plasma was performed using a standardized ISTH protocol, and included platelet MP (PMP: AnnV+/CD41+), endothelial MP (EMP: CD31+/CD41−), red cell MP (RBC MP: AnnV+/CD235a+), leukocyte MP (LMP: AnnV+/CD45+), and monocyte MP (MMP: AnnV+/CD14+) analyses. As previously reported, increases in total WBC count, monocyte count, and sVCAM occurred immediately after exercise, with return towards baseline thereafter. A similar transient increase was seen with both MP procoagulant activity and MP-TF activity (Fig. 1), with a 2.5- (p<0.01) and 3-fold (p<0.01) increase, respectively. Acute increases were also observed for PMPs, EMPs, LMPs and MMPs, which peaked immediately post-exercise. No significant changes were noted for D-dimer, Hb, LDH, or haptoglobin; however, a modest increase in PF Hb was noted following exercise. Interestingly, some unique differences were seen in HbAS compared to HbAA subjects; specifically, EMPs peaked later (at 2 hrs) and were more elevated in HbAS subjects, although the difference was not statistically significant (HbAS 138.2 +/−162.3 EMPs/uL vs. HbAA 65.4 +/− 29.3 EMPs/uL; p=0.26). Additionally, there was a trend towards increased RBC MPs in HbAS subjects (HbAS: 291 +/− 284 RBC MPs/uL at baseline vs. 975 +/− 1033 RBC MPs/uL at 2 hrs; p=0.13). A trend towards increased RBC PS exposure immediately post-exercise in HbAS subjects compared to HbAA was also apparent (Fig. 2), with almost 3× more RBC PS exposure in the HbAS group (post exercise % PS+ RBCs: HbAS 1.28 +/− 1.05% vs. HbAA 0.22 +/− 0.10%; p=0.09, n=4). We also observed a trend towards lower haptoglobin and increased D-dimer in HbAS subjects compared to HbAA subjects at all time points. These data confirm previous observations reporting systemic activation of coagulation occurring after strenuous exercise, and demonstrate a transient increase in MP-TF activity. Interestingly, the time course and magnitude of this activity differs from that seen in the human endotoxemia model (data not shown), in which there is a 5–7 fold increase in MP-TF activity that peaks much later (4 hours) post LPS exposure. The much earlier peak and lower magnitude (∼ 3-fold increase) with exercise suggest a mechanism that does not involve cellular synthesis of TF but is instead likely due to a release of pre-formed TF stores. Other findings in this study may also be relevant to the pathophysiology of the well-documented risk of exertional sudden death with sickle cell trait. In particular, we speculate that the increased RBC PS exposure, elevated RBC MPs and a relative increase in EMPs may contribute to increased activation of coagulation and occlusion of the microvasculature during exercise that may result in DIC, rhabdomyolysis and sudden death. Disclosures: No relevant conflicts of interest to declare.
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Weykamp, C. W., T. J. Penders, F. A. Muskiet, and W. van der Slik. "Influence of hemoglobin variants and derivatives on glycohemoglobin determinations, as investigated by 102 laboratories using 16 methods." Clinical Chemistry 39, no. 8 (1993): 1717–23. http://dx.doi.org/10.1093/clinchem/39.8.1717.
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Abstract Influences of hemoglobin (Hb) variants (HbSS, HbCC, beta-thalassemia, HbAE, HbAS, HbAC, hereditary persistent HbF) and Hb derivatives (carbamylated- and acetylated-Hbs, Schiff base, and those formed in stored blood) on results of glyco-Hb assays by 102 laboratories using 16 different methods were investigated. Affinity chromatography shows deviating results only with homozygous Hb S and C. Correct interpretation of results from patients with decreased erythrocyte half-lives requires previous knowledge on this condition. Measurements of HbA1c by HPLC and electrophoresis are obviously unsuitable for homozygous hemoglobinopathies; for heterozygous hemoglobinopathies and Hb synthesis variants, HbA1c should be expressed as percentage of HbA0 + HbA1c; abnormal Hbs are usually recognized; both carbamylated- and acetylated-Hbs interfere and Schiff base must be eliminated. Except for stored blood, all Hb variants and derivatives gave erroneous results with disposable ion-exchange columns. Dako's immunoassay is not affected by Hb derivatives; glycated Hb variants are not recognized as glyco-Hb and percentages are consequently too low. Glyco-Hb by the immunoassay of Bayer (performed by one laboratory) is not affected by Hb variants and derivatives.
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Cataldo, Giuseppe, Mary M. Lunzer, Donald A. Simone, et al. "Targeting Putative Mu Opioid/Chemokine Receptor Type 5 Heteromers Potently Attenuates Nociception in a Murine Model of Sickle Cell Disease." Blood 126, no. 23 (2015): 277. http://dx.doi.org/10.1182/blood.v126.23.277.277.
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Abstract Background: Sickle cell disease (SCD) is one of the world's most common inherited diseases, due to a point mutation in hemoglobin that leads to the polymerization of hemoglobin S, giving red blood cells (RBCs) their sickle shape. The hallmarks of SCD are hemolysis and vaso-occlusion. Vaso-occlusive crises (VOC) frequently occur in response to inflammatory and hypoxic conditions such as infections, surgery, etc. Pain is a major defining characteristic of SCD starting early in life and continuing throughout adulthood. VOC-induced pain can be chronic or episodic and unpredictable, requiring frequent hospitalizations and analgesics. Opioids, predominantly morphine, have been the mainstay treatment for pain management of SCD but pose a serious challenge attributed to the many adverse side effects, including tolerance, respiratory depression, sedation, nausea, constipation, pruritus, and dependence. Given that analgesics characteristically used to treat pain appear to be relatively ineffective in alleviating pain associated with SCD as well as display their own dose-limiting adverse effects, there exists a requisite need for superior pharmacological agents in its treatment. Here we reveal that the bivalent ligand MCC22, is highly effective as an analgesic in a murine model of SCD. MCC22 (MW=1255) contains both mu agonist and chemokine CCR5 antagonist pharmacophores that are linked through a 22-atom-spacer. It was designed specifically to target the mu opiate receptor (MOR)-CCR5 heteromer, as there is evidence for crosstalk between MOR and CCR5 in cultured cells that reduces the efficacy of opioid analgesics employed in SCD. Intrathecal (i.t.) MCC22 was potent in reducing the mechanical and heat hyperalgesia in Complete Freund's Adjuvant (CFA) and lipopolysaccharide (LPS) inflammatory pain assays. ED50s for the i.t. administration were 0.019 and 0.015 pmol/mouse, respectively. MCC22 when given intraperitoneally (i.p.) to LPS pretreated mice had an ED50 of 5.6 µmol/kg. We next investigated whether MCC22 would be effective in alleviating pain in SCD mice. Methods:Townes transgenic humanized mice expressing sickle hemoglobin (HbSS / HbAS) and normal human hemoglobin (HbAA) controls (4-12 weeks of age, 20-25g) were used in this study. Mice were characterized for hyperalgesia by quantifying cutaneous mechanical sensitivity of the hind paw and forelimb grip force. Mechanical sensitivity of the hind paw was evaluated by determining the frequency of withdrawal responses and paw withdrawal threshold. The frequency of paw withdrawal evoked by a standard von Frey monofilament with a bending force of 9.3 mN applied to the plantar surface of the hind paws was determined from 10 trials on each paw. Withdrawal threshold was determined using an electronic von Frey anesthesiometer pressed against the plantar surface with increasing force until withdrawal occurred. To assess deep tissue hyperalgesia, the tensile force of peak forelimb exertion was measured using a computerized grip force meter. To evaluate the analgesic effects of MCC22, paw withdrawal frequency was determined before and at various times after administration of 8.0 µmol/kg i.p. Results: Pain Characterization: HbSS sickle mice exhibited robust mechanical hyperalgesia as shown by a significant increase in paw withdrawal frequency compared to HbAS and HbAA controls (Figure1A, p<0.001). Paw withdrawal frequency in HbAS mice was also greater than those for HbAA mice (p<0.001), but less than HbSS mice. HbSS mice had lower mechanical withdrawal thresholds compared to both HbAS and HbAA mice (Figure 1B, p<0.001), while HbAS did not differ from HbAA mice. HbSS and HbAS mice also displayed lower forelimb grip force compared to HbAA mice (Figure 1C, p<0.001), although grip force in HbSS was lower than HbAS mice (p<0.001). Administration of MCC22 (8.0 µmol/kg i.p.) reduced hyperalgesia within 30 minutes as evidenced by a decrease in paw withdrawal frequency in both HbSS and HbAS mice (Figure 1D, p<0.001). Conclusions: Hyperalgesia was demonstrated in both HbAS and HbSS mice. MCC22 potently attenuated mechanical hyperalgesia in these SCD mice. The use of bivalent ligands that target heteromers involved in signaling pain may offer novel and effective treatments for pain in patients with SCD. We speculate that an analgesic with potential anti-inflammatory and mu-agonist activity may provide a novel approach to sickle pain. Figure 1. Figure 1. Disclosures Belcher: CSL Behring: Research Funding; Seattle Genetics: Research Funding; Biogen Idec: Research Funding. Vercellotti:Biogen Idec: Research Funding; CSL Behring: Research Funding; Cydan: Research Funding; Seattle Genetics: Research Funding.
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Maffo, Christelle Ngou, Antoine Berry, Isabelle Morlais, et al. "PO 8290 INFLUENCE OF THE SICKLE CELL TRAIT ON PLASMODIUM FALCIPARUM TRANSMISSION IN ASYMPTOMATIC CHILDREN." BMJ Global Health 4, Suppl 3 (2019): A27.2—A27. http://dx.doi.org/10.1136/bmjgh-2019-edc.69.
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BackgroundThe sickle cell trait is associated with protection against severe malaria. Recently, it has been shown that the genetic protection conferred by the sickle cell trait has no effect on the transmission of Plasmodium species from humans to vectors. Our study aimed to investigate the putative association between the sickle cell trait AS and the susceptibility to malaria infection of both the human host and the insect vector.MethodsThe study was conducted from June to November 2017 among asymptomatic children living in Cameroon. The samples were collected on microscopy slides, Whatman FTA and grade 17 paper for the selection of gametocyte carriers by microscopy, the molecular diagnosis of Plasmodium species, and sickle cell trait (PCR- RFLP), respectively. Infectivity of the mosquito was measured by experimental infections on gametocyte-containing blood from naturally infected carrier. Genetic diversity was measured using microsatellite markers.ResultsA total of 1557 children were recruited; the prevalence of Plasmodium infection among this group was 58% and the AS sickle cell trait 20%. No significant difference in the prevalence of P. falciparum infection was observed according to the sickle cell trait carriage and this irrespective of the parasite stage (p>0.05). The level of infectivity of the mosquito was higher when feedings were performed on blood from HbAS genotypes compared to HbAA genotype blood, and the difference was even more significant when the blood pellet was resuspended with non-immune AB plasma (p<0.0001). No significant difference was observed in the infection complexity between HbAS and HbAA genotypes (p>0.05).ConclusionPlasmodium infection is not influenced by HbAS genotype regardless of parasite stage; the risk of anopheles infection is higher with blood from gametocyte carriers with sickle cell trait (HbAS). The sickle cell trait does not affect the multiplicity of infection.
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Chatel, Benjamin, Laurent A. Messonnier, Christophe Hourdé, Christophe Vilmen, Monique Bernard, and David Bendahan. "Moderate and intense muscular exercises induce marked intramyocellular metabolic acidosis in sickle cell disease mice." Journal of Applied Physiology 122, no. 5 (2017): 1362–69. http://dx.doi.org/10.1152/japplphysiol.01099.2016.
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Sickle cell disease (SCD) is associated with an impaired oxygen delivery to skeletal muscle that could alter ATP production processes. The present study aimed to determine the effects of sickle hemoglobin (HbS) on muscle pH homeostasis in response to exercise in homozygous (HbSS, n = 9) and heterozygous (HbAS, n = 10) SCD (Townes) mice in comparison to control (HbAA, n = 10) littermates. Magnetic resonance spectroscopy of phosphorus 31 enabled to measure intramuscular pH and phosphocreatine (PCr) concentration during rest-stimulation-recovery protocols at two different intensities. Maximal activity of some enzymes involved in muscle energetics and content of proteins involved in pH regulation were also investigated. HbSS mice presented a more pronounced exercise-induced intramuscular acidosis, whatever the intensity of exercise. Moreover, the depletion of PCr was also exacerbated in HbSS mice in response to intense exercise as compared with both HbAA and HbAS mice ( P < 0.01). While no difference was observed concerning proteins involved in muscle pH regulation, the activity of enolase (a glycolytic enzyme) was higher in both HbSS and HbAS mice as compared with controls ( P < 0.05). Interestingly, HbAS mice presented also metabolic impairments as compared with their control counterparts. This study has identified for the first time an exacerbated exercise-induced intramuscular acidosis in SCD mice.NEW & NOTEWORTHY The main finding of the present study was that the exercise-induced intramuscular acidosis was systematically more pronounced in sickle cell disease (SCD) mice as compared with their control counterparts. This result is important since it has been demonstrated in vitro that acidosis can trigger hemoglobin polymerization. From that point of view, our results tend to support the idea that high-intensity exercise may increase the risk of hemoglobin polymerization in SCD.
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Izuwa, G., J. O. Akpotuzor, D. C. Okpokam, P. A. Akpan, N. A. Ernest, and J. Asuquo. "Haemorrheologic and Fibrinolytic Activities of HbSS, HbAS and HbAA Subjects in Abuja, Nigeria." Journal of Medical Sciences 16, no. 1-2 (2015): 32–37. http://dx.doi.org/10.3923/jms.2016.32.37.
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Díaz-Castillo, Alber, Neyder Contreras-Puentes, Ciro Alvear-Sedán, Carlos Moneriz-Pretell, Erika Rodríguez-Cavallo, and Darío Mendez-Cuadro. "Sickle Cell Trait Induces Oxidative Damage on Plasmodium falciparum Proteome at Erythrocyte Stages." International Journal of Molecular Sciences 20, no. 22 (2019): 5769. http://dx.doi.org/10.3390/ijms20225769.
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The presence of hemoglobin A-S (HbAS) in erythrocytes has been related to the high production of reactive oxygen species (ROS) and an increased in intracellular oxidative stress that affects the progress of Plasmodium erythrocytic cycle life and attenuates its serious clinical symptoms. Nevertheless, oxidative effects on P. falciparum proteome across the intraerythrocytic cycle in the presence of HbAS traits have not been described yet. Here, an immune dot-blot assay was used to quantify the carbonyl index (C.I) on P. falciparum 3D7 proteome at the different asexual erythrocytic stages. Protein carbonylation on parasites cultivated in erythrocytes from two donors with HbAS increased 5.34 ± 1.42 folds at the ring stage compared to control grown in hemoglobin A-A (HbAA) red blood cells. Whereas at trophozoites and schizonts stages were augmented 2.80 ± 0.52 and 3.05 ± 0.75 folds, respectively. Besides proteins involved in processes of the stress response, recognition and invasion were identified from schizonts carbonylated bands by combining SDS-PAGE with MALDI-TOF-TOF analysis. Our results reinforce the hypothesis that such oxidative modifications do not appear to happen randomly, and the sickle cell trait affects mainly a small fraction of parasite proteins particularly sensitive to ROS.
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Kumari, Namita, Javed Khan, Tatiana Ammosova, et al. "Restriction of HIV-1 Infection in Sickle Cell Disease Trait." Blood 130, Suppl_1 (2017): 940. http://dx.doi.org/10.1182/blood.v130.suppl_1.940.940.
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Abstract We recently showed that in Sickle Cell Disease (SCD), activation of anti-viral restriction factor SAMHD1 and NF-κB inhibitor, IkBα prevented ex vivo HIV-1 infection. SAMHD1 activation was due to its reduced phosphorylation by CDK2, whose activity was inhibited by reduced intracellular iron levels in SCD peripheral blood mononuclear cells (PBMC). We also found that a hazard ratio associated with HIV infection among 11,412 SCD trait subjects was 1.0% comparing to &gt;2% HIV-1 infection among African-Americans in USA. We compared 9 HbAS HIV-1 infected individuals with 107 HbAA or HbAC HIV-1 infected individuals who were enrolled at Howard University clinic. While hemoglobin levels in these two groups were not significantly different, HIV-1 viral load was significantly lower in HbAS group as well the number of HIV-1 associated complications (Hospitalization) were reduced. In the present study, we analyzed ex vivo HIV-1 infection of SCD trait PBMC and determined the expression of iron and hypoxia-regulated host factors including HO-1, NFκB, IKK, IKBα that are implicated in HIV-1 replication. We also analyzed CDK2 activity, SAMHD1 phosphorylation and RNR2 expression in SCD trait PBMCs. One round HIV-1 infection was significantly reduced in in SCD trait PBMC. Expression of HO-1 and IKBα was upregulated in SCD trait whereas IKK and NF-κB expression was downregulated. While CDK2 activity and SAMHD1 phosphorylation were not changed, RNR2 expression was reduced. Expression levels of HIV-1 env and gag mRNA were significantly lower in HIV-1 infected SCD trait subjects. In the same patients, HO-1 and IKBα mRNA levels were upregulated comparing to HIV-1+ HbAA or HbAC subjects. Our findings suggest that HIV-1 infection might be deregulation in SCD trait and that iron metabolism and hypoxia might play a role in this deregulation. This work was supported by NIH Research Grants 1P50HL118006, 1R01HL125005, and 5G12MD007597. The content is solely the responsibility of the authors and does not necessarily represent the official view of NHLBI, NIMHD or NIH. Disclosures No relevant conflicts of interest to declare.
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John, Tami D., Madeleine Lu, Celeste K. Kanne, et al. "Rheological Assessments of Sickle Cell Patients Post Allogeneic Hematopoietic Cell Transplant." Blood 134, Supplement_1 (2019): 996. http://dx.doi.org/10.1182/blood-2019-128946.
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Introduction: Mixed donor chimerism (MDC) occurs in nearly 35% of patients with sickle cell disease (SCD) post allogeneic hematopoietic cell transplant (alloHCT). Donor myeloid engraftment of &gt;20% is considered necessary to support disease resolution. However, in a disease known for its clinical variability, we hypothesize that patients (pts) with a severe pre-HCT phenotype may have abnormal RBC rheology at a level of chimerism and %HbS believed to be consistent with a cure. RBC rheology is markedly abnormal in SCD; these abnormalities are associated with SCD related clinical complications. Even fully oxygenated, sickle RBC are less deformable than those of HbAA or HbAS individuals; upon deoxygenation, deformability further declines. Sickle RBC morphology reflects the tendency to polymerize, with characteristic sickle forms. Sickle RBC are more adherent to the endothelial cell lining of the vasculature than HbAA or HbAS RBCs. The goal of any cell-based therapy of curative intent should be normalize the red cell rheology. To determine if the rheology of blood from SCD pts post-HCT with varying degrees of donor chimerism fall into the HbSS range of values, we propose to functionally assess the peripheral blood from a series of 6 post alloHCT SCD patients using a battery of rheological tests measuring deformability, sickling, adherence, percent dense cells (%DRBC), and RBC morphology. Methods: Peripheral blood samples (EDTA) from 6 SCD pts post alloHCT with a matched sibling donor were collected and immediately analyzed using oxygenscan (Lorrca), artificial microvascular network (AMVN), microfluidic image acquisition, and an ADVIA hematology analyzer. The Lorrca with oxygenscan measures RBC deformability (elongation index EI), under a range of pO2 (150-0 mmHg). EImax is the deformability of the oxygenated sickle RBC; EImin is the deformability of deoxygenated RBCs. The point of sickling (PoS) is the pO2 at which RBC deformability rapidly declines. RBC adhesiveness is measured by the difference in rate of perfusion of RBC through the AVMN coated with adhesive proteins (adherent AVMN) and a non-adherent, uncoated AVMN. %DRBC was measured by an ADVIA hematology analyzer. Microscopic RBC images were acquired and classified to determine the fraction of sickled RBCs in well-oxygenated samples. Additional clinical data including Hb profile, donor chimerism, and symptoms were obtained via chart review. Reference ranges were generated as described above using n=45 HbSS samples ages 2-21, on hydroxyurea, chronic transfusion, or untreated; n=14 HbAS, and n=43 HbAA. Results: In Figure 1, we show the measurements obtained by the Lorrca with oxygenscan on 5 pts post-alloHCT with a range of donor chimerism, as well as typical values for HbAA, HbAS, and HbSS patients. Patient 1 and 3 exhibit normal rheology; both were transplanted with a HbAA donor, with high chimerism and no detectable HbS. Patient 2 has 40% whole blood chimerism, well above the 20% threshold described with myeloid chimerism, and a HbS less than 50%, yet their plot resembles that of an untransplanted HbSS pt; the donor to Patient 2 exhibits the expected HbAA deformability. Patients 5 and 6 exhibit rheology in the HbAS range; they have intermediate chimerism from a HbAS donor. Clinical details and biomarker panel values for all 6 pts analyzed are in Table 1, as well as ranges of values for HbSS and HbAS subjects generated in the Sheehan and Shevkoplyas labs. Patient 2 is the only subject with values in the HbSS range, and the only subject with SCD symptoms. Conclusions: Our rheological tests identified a pt with values consistent with a HbSS pt of moderate severity or treated with hydroxyurea despite variable donor chimerism above the 20% threshold and HbS &lt;50% thought to be sufficient for cure. The pt reported pain events beginning two years prior, indicating a clinical correlation supporting the validity of the rheological tests we propose to use to distinguish cure from persistent SCD. Current post-HCT evaluation depends on chimerism and hemoglobin profiles, and would not detect the significant functional abnormalities visible by Lorrca with oxygenscan biomarkers that indicate that Patient 2 is at risk for SCD related complications. Our results suggest that this functional analysis may help with management of post alloHCT SCD pts, and may be even more essential to assessing new gene-based therapy approaches to curing patients with SCD. Disclosures Rab: RR Mechatronics: Research Funding. van Wijk:Agios Pharmaceuticals: Consultancy, Research Funding; RR Mechatronics: Research Funding. Shevkoplyas:SSS: Research Funding; New Health Sciences: Consultancy.
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Tatfeng, Y. M., and D. E. Agbonlahor. "Citocinas Th1 e Th2 em crianças com hemoglobinopatias e infecção por malária não complicada." Revista de Ciências Médicas e Biológicas 9, no. 1 (2010): 13. http://dx.doi.org/10.9771/cmbio.v9i1.4634.
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<div>O relativo equilíbrio entre as citocinas Th1 e Th2 parece crucial para o resultado das infecções. Foram avaliados os</div><div>níveis de citocinas pró-inflamatórias Th1, interleucina 2 (IL2) e interferon gama (IFNγ) e as citocinas antiinflamatórias</div><div>Th2, IL4 e IL10 em indivíduos homizigotos para hemoglobina (Hb) AA, SS e heterozigotos AS com malária não</div><div>complicada por P. falciparum, na cidade de Benin, na Nigéria. Os níveis de citocinas Th1 e Th2 de 111 crianças com</div><div>malária não complicada e 89 controles saudáveis foram determinados por método imunoenzimático. Células CD4 e</div><div>CD8 foram contadas utilizando o protocolo T4T8 Dynabeads Quantification, enquanto os parâmetros hematológicos</div><div>foram estimados através de técnicas hematológicas. Níveis de citocinas Th1 e Th2 foram significativamente maiores</div><div>em pacientes HbAA, HBAs e HbSS do que os respectivos controles (P <0,05). Citocinas Th1 e Th2 foram significativamente</div><div>elevadas em indivíduos HbAA (IFNγ: 57,31 ± 77.79pg/ml, IL2: 108,75 ± 63.53pg/ml, IL10: 18,39 ± 15.08pg/ml) do que</div><div>em HbAS (IFNγ: 32,48 ± 24,83 pg / ml, IL2: 64,16 ± 56,0 pg / ml, IL10: pg / ml) e HbSS (IFNγ: 23,36 ± 14,73 pg/ml, IL2:</div><div>76,74 ± 39,99 pg / ml, IL10: 7,19 ± 4,50 pg/ml) (P <0,05). A média do parâmetros hematológicos (contagem total de</div><div>leucócitos, monócitos) HbSS de crianças infectadas foram significativamente maiores do que HbAA e indivíduos HbAS</div><div>(P <0,05), porém, o volume corpuscular médio foi significativamente menor do que os outros (P <0,05). Finalmente,</div><div>é importante reconhecer que o papel das citocinas na resposta imune ainda está para ser totalmente compreendido.</div>
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Snider, D. P., A. Kaubisch, and D. M. Segal. "Enhanced antigen immunogenicity induced by bispecific antibodies." Journal of Experimental Medicine 171, no. 6 (1990): 1957–63. http://dx.doi.org/10.1084/jem.171.6.1957.
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The binding of protein antigens to APC with heterocrosslinked bispecific antibodies (HBAs) enhances their processing and presentation to Th cells in vitro. Here we have asked whether HBAs could also increase immune responses in vivo. We immunized mice with hen egg lysozyme (HEL) in the presence or absence of HBA, and followed antibody production after the primary challenge and after a secondary boost. We found that HBAs that bind antigen to MHC class I or II molecules, to Fc gamma R, but not to surface IgD, enhance the immunogenicity of HEL. HBAs that bound HEL to MHC class II molecules, for examples, decreased the amount of antigen required to elicit a primary anti-HEL antibody response in mice by 300-fold, and the amount required to prime for a secondary response by 10(3)- to 10(4)-fold. In fact, HBAs were as effective as IFA in generating antibody responses. Since adjuvants cannot be used in humans, HBAs could prove useful for immunizing people, especially in cases where, due to scarcity or toxicity, minute doses of antigen must be used.
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Olaniyan, MathewFolaranmi, and Akerele Cletus. "PLASMA LEVEL OF TOTAL ANTIOXIDANT AND FREQUENCY OF HBSC, HBSS,HBAA, HBAS, HBAC AND G6PD DEFICIENCY IN ICTERIC CHILDREN PRESENTING WITH ANAEMIA." International Journal of Advanced Research 4, no. 10 (2016): 138–48. http://dx.doi.org/10.21474/ijar01/1770.
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Hasan, Muhammad Noman, Arwa Fraiwan, Priyaleela Thota, et al. "Clinical Testing of Hemechip in Nigeria for Point-of-Care Screening of Sickle Cell Disease." Blood 132, Supplement 1 (2018): 1095. http://dx.doi.org/10.1182/blood-2018-99-115355.
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Abstract In sub-Saharan Africa, nearly a quarter of a million babies are born with sickle cell disease (SCD) each year. An estimated 50-90% of these babies die before age 5 due to lack of early diagnosis and timely treatment. The World Health Organization estimates that more than 70% of SCD related deaths are preventable with simple, cost-effective interventions, such as early screening followed by affordable and widely available treatment regimens. Here, we present the early clinical testing results of HemeChip, which is the first single-use cartridge-based microchip electrophoresis hemoglobin screening platform. HemeChip was developed by Hemex Health, Inc., based on technology licensed from Case Western Reserve University. HemeChip allows affordable, objective, quantitative screening of hemoglobin variants at the point-of-care. HemeChip works with a drop of finger or heel-prick blood and separates hemoglobin variants on a piece of cellulose acetate paper that is housed in an injection molded plastic cartridge with a precisely controlled electric field. HemeChip works with a portable reader to produce easily understandable, objective, and quantitative descriptions of the hemoglobin types and percentages present in a blood sample. The HemeChip reader guides the user step-by-step through the test procedure with animated on-screen instructions to minimize user errors. Hemoglobin identification and quantification is automatically done with a custom software on the reader. HemeChip reader records and analyzes the hemoglobin electrophoresis real-time, and it can wirelessly transmit the test results to a central electronic database, if needed. HemeChip prototype units have been clinically tested and benchmarked against the clinical standard technique in Kano, Nigeria, where the SCD prevalence is the highest in the world. We tested a total of 248 subjects (228 children aged 6 weeks to 5 years in Kano, Nigeria; and 20 adults in Cleveland, Ohio, United States) under institutional review board approval, using both HemeChip and the clinical standard laboratory method, High Performance Liquid Chromatography (HPLC, VARIANT™ II, Bio-Rad Laboratories, Inc., Hercules, California). HemeChip tests were done on eHealth Africa campus in Kano, Nigeria, by trained local healthcare workers using blood samples collected at the nearby Aminu Kano Teaching Hospital. Clinical standard (HPLC) testing was done independently by the International Foundation Against Infectious Disease in Nigeria (IFAIN, Abuja, Nigeria) for the blood samples obtained in Kano or by the University Hospitals Cleveland Medical Center Clinical Laboratories (Cleveland, Ohio) for the blood samples obtained in Cleveland. Test results included the following: homozygous SCD (HbSS), heterozygous sickle hemoglobin C disease (HbSC), heterozygous sickle trait (HbAS), and normal (HbAA). HemeChip identified the subjects with HbSS with 100% accuracy, HbSC with 100% accuracy, HbAS with 98.2% accuracy, and HbAA with 96.4% accuracy in comparison to HPLC (Table 1). Overall accuracy of HemeChip was 97.2% in comparison to HPLC for the subjects tested. HemeChip sensitivity was 100% for all hemoglobin variants tested (Table 2), and specificity was 96.4% for HbSS vs. HbAA, 98.2% for HbSS vs. HbAS, 100% for HbSC vs. HbAS, and 100% for HbAS vs. HbAA. Bland-Altman analysis indicated strong agreement between the quantitative HPLC and HemeChip results for hemoglobin percentages, with a mean bias of -3.2%. HemeChip enables, for the first time, accurate, cost-effective identification and quantification of hemoglobin variants at the point-of-need. HemeChip has been developed based on a versatile, mass-producible microchip electrophoresis platform technology that may address other unmet needs in biology and medicine that require rapid, decentralized hemoglobin or protein analysis, identification, and/or quantification. Disclosures Thota: Hemex Health Inc: Employment. Little:PCORI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; NHLBI: Research Funding; Doris Duke Charitable Foundations: Research Funding.
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Vincent, Lucile, Léonard Féasson, Samuel Oyono-Enguéllé та ін. "Remodeling of skeletal muscle microvasculature in sickle cell trait and α-thalassemia". American Journal of Physiology-Heart and Circulatory Physiology 298, № 2 (2010): H375—H384. http://dx.doi.org/10.1152/ajpheart.00812.2009.
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The influence of sickle cell trait and/or α-thalassemia on skeletal muscle microvascular network characteristics was assessed and compared with control subjects [hemoglobin (Hb) AA] in 30 Cameroonian residents [10 HbAA, 5 HbAA α-thalassemia (α-t), 6 HbAS, and 9 HbASα-t] matched for maximal work capacity and daily energy expenditure. Subjects performed an incremental exercise to exhaustion and underwent a muscle biopsy. Muscle fiber type and surface area were not different among groups. However, sickle cell trait (SCT) was associated with lower capillary density ( P < 0.05), lower capillary tortuosity ( P < 0.001), and enlarged microvessels ( P < 0.01). SCT carriers had reduced counts of microvessels <5-μm diameter, but a higher percentage of broader microvessels, i.e., diameter >10 μm ( P < 0.05). α-Thalassemia seemed to be characterized by a higher capillary tortuosity and unchanged capillary density and diameter. Thus, while SCT is a priori clinically benign, we demonstrate for the first time that significant remodeling of the microvasculature occurs in SCT carriers. These modifications may possibly reflect protective adaptations against hemorheological and microcirculatory dysfunction induced by the presence of HbS. The remodeling of the microvascular network occurs to a lesser extent in α-thalassemia. In α-thalassemic subjects, increased capillary tortuosity would promote oxygen supply to muscle tissues and might compensate for the lower Hb content often reported in those subjects.
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Harrison, Ewen M., Eva Sharpe, Christopher O. Bellamy, et al. "Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia-reperfusion injury." American Journal of Physiology-Renal Physiology 295, no. 2 (2008): F397—F405. http://dx.doi.org/10.1152/ajprenal.00361.2007.
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Heat shock proteins (Hsps) are protective in models of transplantation, yet practical strategies to upregulate them remain elusive. The heat shock protein 90-binding agent (HBA) geldanamycin and its analogs (17-AAG and 17-DMAG) are known to upregulate Hsps and confer cellular protection but have not been investigated in a model relevant to transplantation. We examined the ability of HBAs to upregulate Hsp expression and confer protection in renal adenocarcinoma (ACHN) cells in vitro and in a mouse model of kidney ischemia-reperfusion (I/R) injury. Hsp70 gene expression was increased 30-40 times in ACHN cells treated with HBAs, and trimerization and DNA binding of heat shock transcription factor-1 (HSF1) were demonstrated. A three- and twofold increase in Hsp70 and Hsp27 protein expression, respectively, was found in ACHN cells treated with HBAs. HBAs protected ACHN cells from an H2O2-mediated oxidative stress, and HSF1 short interfering RNA was found to abrogate HBA-mediated Hsp induction and protection. In vivo, Hsp70 was upregulated in the kidneys, liver, lungs, and heart of HBA-treated mice. This was associated with a functional and morphological renal protection from I/R injury. Therefore, HBAs mediate upregulation of protective Hsps in mouse kidneys which are associated with reduced I/R injury and may be useful in reducing transplant-associated kidney injury.
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Yates, Robin, George R. Buchanan, Howard Ginsburg, et al. "Splenic Infarction Due to Concomitant Hereditary Spherocytosis and Sickle Cell Trait." Blood 108, no. 11 (2006): 3741. http://dx.doi.org/10.1182/blood.v108.11.3741.3741.
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Abstract The occurrence of hereditary spherocytosis (HS) and sickle cell trait (HbAS) in the same patient is rare, with just 21 cases reported in the literature. Although six of these cases had splenic infarction or sequestration, none were reported as having a precipitating event. However, in persons with HbAS, splenic sequestration or infarction has been reported following exposure to high altitudes, including pressurized commercial aircraft. The interaction of these 2 (HS and HbAS) disorders can be explained by the hypoxic and acidic environment in the spleen. This environment causes spherocytes containing HbAS to be both less deformable and more prone to sickling, which promotes sluggish blood flow within the spleen and leads to sequestration and infarction. We have encountered a 10-year-old Caucasian girl with both HS and HbAS who experienced left upper quadrant pain during and following a flight on a commercial aircraft. Past medical history included episodes, although less severe, of left upper quadrant pain after traveling to high altitudes on automobile trips or on commercial aircraft. Family history included the dual diagnoses of HbAS and HS in the patient’s mother, for which she underwent splenectomy as a teenager, and a diagnosis of HS in her 9-year-old brother. At presentation, she had significant left upper quadrant tenderness upon palpation that was associated with voluntary guarding. There was no rebound or involuntary guarding. The spleen was noted to span 3–4cm below the left costal margin. Laboratory values included a hemoglobin of 10.8 (g/dl), reticulocyte count of 7.5%, total bilirubin of 3.0 (mg/dl), and lactate dehydrogenase of 1160 (U/L), all of which were similar to her baseline values. Abdominal ultrasound and cat scan demonstrated infarction in the inferior pole of her spleen. Despite supportive medical treatment, she required immediate splenectomy to relieve her symptoms and prevent recurrence. Her operative and post-operative courses were uneventful. This first report of a patient with both HS and HbAS who suffered splenic infarction after traveling on a commercial aircraft demonstrates how two different inherited red blood cell abnormalities can interact and lead to clinically significant complications.
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Ahmad, Maliha Maryam, Laxminath Tumburu, Chunyu Liu, Mehdi Pirooznia, and Swee Lay Thein. "Mitochondrial DNA Variation in Individuals with Sickle Cell Disease." Blood 136, Supplement 1 (2020): 11. http://dx.doi.org/10.1182/blood-2020-138518.
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Background: Sickle cell disease (SCD) is a complex multi-system disorder that predominantly affects individuals of African heritage. While the sickle pathology is initiated by polymerization of HbS, multiple end-organ damage is inflicted by years of on-going inflammation and vasculopathy. An emerging marker of inflammation is the accumulation of mutations in mitochondrial DNA (mtDNA), the phenotypic effect of which will depend on the nature of the gene that harbors the mutation, the mutant allele fraction, and the pathogenicity of the mutant allele. A mutation in mtDNA is heteroplasmic when it is present in only a proportion of mtDNA, and homoplasmic, when it is present in all mtDNA molecules. Mitochondrial heteroplasmy can also occur at different tissue or cell levels, even within the same individual. Given the underlying chronic inflammation in SCD, we hypothesize that SCD patients display increased rates of mtDNA mutations. Methods: We analyzed and compared whole genome sequencing (WGS) data from the cohort of 683 SCD patients (SCD cohort) of African ancestry with that of 621 individuals of African ancestry from the 1000 Genomes Project (1KG). The SCD cohort included 561 HbSS & HbSβ0 thalassemia (combined), 90 HbSC, and 25 HbSβ+ thalassemia. The 1KG cohort included 516 HbAA and 105 sickle carriers (HbAS). mtDNA sequences of SCD and 1KG cohorts were initially aligned to the revised Cambridge Reference Sequence (rCRS NC_012920), and subsequently base recalibrated and deduplicated. Mitochondrial sequences extracted from the cleaned WGS data of both cohorts were analyzed for heteroplasmic and homoplasmic variants using mitoCaller from the package mitoAnalyzer. Results: The average depth per locus is ~6,828X for the SCD cohort and ~2,879X for the 1KG cohort. We performed a locus by locus comparison between the mtDNA sequences of both cohorts. No homoplasmic variants unique to the SCD cohort were found when compared to the 1KG cohort. In contrast, there were several "hotspots" of heteroplasmic variants that were unique to the SCD cohort, and largely shared amongst the SCD patient population (Figure 1A). To identify these unique variants, we used MITOMASTER and Ensembl VEP to annotate the heteroplasmic variants that had above 40% population frequency within the SCD cohort and below 10% population frequency in the 1KG cohort. Several heteroplasmic variants were non-synonymous and the selected variants originated from the Control Region (D-loop), RNR1, RNR2, ND1, ND4, and ND5. One of the heteroplasmic variants, 2623 A&gt;G, was found to be age linked for HbSS & HbSβ0 (Figure 1B), with its minor allele frequency (MAF) increasing with age. Further analysis needs to be done in order to determine if more variants unique to the SCD cohort are age-linked. We then compared the quantity of heteroplasmic variants across the different SCD genotypic groups with the 1KG HbAA and the 1KG HbAS groups. The median number of heteroplasmic variants per individual increased progressively from HbAA, HbAS, HbSβ+ thalassemia, and HbSC with the highest median number of 119 in HbSS & HbSβ0 (Figure 1C). Mitochondrial heteroplasmy for 1KG HbAA and 1KG HbAS were statistically significant when tested against each other and against every SCD sub-group; however, the difference was not statistically significant between the different SCD genotypes (Table insert in Fig 1C). It is important to note that we did not apply a MAF threshold, thus many of the heteroplasmic variants may be present at very low levels. Conclusion: Our findings suggest that there is an increased prevalence of heteroplasmic variants in SCD compared to ethnic-matched healthy populations. Within the SCD genotypes, the heteroplasmic burden increased progressively (HbAS &lt; HbSβ+ thalassemia &lt; HbSC &lt; HbSS & HbSβ0) with genotypic groups that are associated with increasing phenotypic severity. mtDNA heteroplasmic burden for one variant also increased with age in HbSS & HbSβ0 individuals, but further studies are needed to explore if mtDNA heteroplasmic burden correlates with the degree of organ damage and disease severity within the same genotypic group. Although it is not clear if the variants are a cause or effect of the sickle inflammatory pathology, our data suggest that mtDNA heteroplasmic burden is a potential biomarker of SCD severity. Disclosures No relevant conflicts of interest to declare.
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Nguyen, Julia, Fuad Abdulla, Chunsheng Chen, et al. "Phenotypic Characterization the Townes Sickle Mice." Blood 124, no. 21 (2014): 4916. http://dx.doi.org/10.1182/blood.v124.21.4916.4916.
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Abstract The HbSS-Townes mouse model, developed in Dr. Tim Townes laboratory, University of Alabama, Birmingham (and kindly provided by him to our laboratory) were created on a mixed genetic background in which the murine adult α-globin genes were replaced with the human α-globin gene (genotype: Hba hα/hα) and the murine adult β-globin genes were replaced with human sickle βS- and fetal Aγ-globin gene fragments linked together (genotype: Hbb hAγβS/hAγβS) (Wu LC et al. Blood 2006;108: 1183-1188). HbSS-Townes mice have anemia, a shortened RBC half-life of 2.5 days and a severe disease phenotype. Control HbAA-Townes mice were created by replacing the murine globin genes with human α-globin gene (genotype: Hba hα/hα) and linked human βA- and fetal Aγ-globins (genotype: Hbb hAγβA/hAγβA), while HbAS-Townes heterozygous mice were developed by breeding HbAA and HbSS mice. Many laboratories are utilizing these mice but complete phenotypic description of these three models has not been described including: hematology, kidney and liver function, inflammatory markers, haptoglobin and hemopexin levels, red cell half-lives, organ histopathology and vascular responses to vaso-occlusive stimuli. Table 1 summarizes our findings. There was a clear difference in histopathology between the HbSS and other groups (HbAA and HbAS). HbSS mice had hepatic necrosis, increased erythropoiesis and increased hemosiderin within the liver and some subtle lesions involving the glomeruli in the kidneys. Additional findings were a marked increase in size of spleen (7.0-7.6 x by % body weights) attributed to severe congestion and increased erythropoiesis. No lesions were observed in the lungs and other tissues. The tissues evaluated in the HbAS and HbAA groups were essentially normal. In contrast, HbSS mice had multifocal irregular areas of necrosis within the liver, with reactive leukocyte infiltrates (mainly neutrophils in the more acute lesions with a greater proportion of mononuclear cells (macrophages etc.) in more chronic lesions. MPO immunohistochemistry confirmed the presence of neutrophils in the liver. There was a substantial increase in iron (and hemosiderin) in the livers of HbSS mice, confirmed by a Prussian Perls stain and low, but detectable, levels of iron in the proximal convoluted tubules of the kidney. This is consistent with increased red cell turnover in the HbSS mice. Total iron mass in the markedly enlarged spleen is very high. There is a somewhat subtle glomerulopathy present in the kidney, with enlarged glomeruli with variable ectasia of vessels, and mesangial derangement. In conclusion the Townes mouse models provide a spectrum of severe hemolytic disease that in many ways mimic the human disease albeit imperfectly. TableTable 1 HbAAHbASHbSSHb (g/dL)12.0 ± 0.610.6 ± 0.59.5 ± 1.4*Hematocrit (%)49.6 ± 2.345.0 ± 4.2*29.2 ± 0.9*#WBC (K/µL)10.8 ± 1.213.2 ± 4.038.2 ± 4.9*#Platelet Counts (K/uL)854 ± 78889 ± 1421004 ± 179Monocytes (%)8.0 ± 1.17.6 ± 1.77.4 ± 1.0Lymphocytes (%)60 ± 3.063.8 ± 5.667.5 ± 9.1Neutrophils (%)28.6 ± 5.926.1 ± 8.727.8 ± 2.2Reticulocytes (%)7.8 ± 1.78.6 ± 4.556.8 ± 2.6*#RBC Half-Life (days)15.710.62.4Expired CO (nmoles/h/g)0.92 ± 0.241.27 ± 0.236.33 ± 1.08*Serum Bilirubin (mg/dl)3.5 ± 0.94.3 ± 0.65.6 ± 0.4*Urine Creatinine (mg/dL)44.1 ± 3.845.9 ± 3.856.2 ± 7.0*Urine Osmolality (mOsm/kg H2O)2147 ± 761707 ± 2651361 ± 32*Serum Haptoglobin (µg/ml)39.3 ± 3.80.5 ± 0.2*2.3 ± 1.4*Serum Hemopexin (µg/ml)802 ± 266169 ± 51*124 ± 35*Serum SAP (µg/ml)20.9 ± 7.214.1 ± 12.086.7 ± 20.2*#Stasis at 1h in Response to Hb (%)10.0 ± 3.219.8 ± 2.7*30.0 ± 3.4*#Mortality at 24h in Response to Heme (%)00100*#Liver % of Body Weight4.95 ± 0.484.39 ± 0.356.22 ± 0.21*#Spleen % of Body Weight0.79 ± 0.140.87 ± 0.396.61 ± 0.75*#Kidney % of Body Weight0.65 ± 0.270.72 ± 0.190.73 ± 0.24Liver Necrosis Score0.0 ± 0.00.25 ± 0.502.38 ± 0.25*Liver Fe Score0.0 ± 0.00.25 ± 0.53.0 ± 0.0*Lung Fe Score0.0 ± 0.00.0 ± 0.0*1.0 ± 0.0*#Spleen Fe Score3.0 ± 0.03.0 ± 0.02.0 ± 0.0*#Kidney Fe Score0.0 ± 0.00.25 ± 0.51.75 ± 0.5*#Liver Gr1 Score1.0 ± 0.01.25 ± 0.52.25 ± 0.5*Lung Gr1 Score1.0 ± 0.01.0 ± 0.01.25 ± 0.5Spleen Gr1 Score1.5 ± 0.62.0 ± 0.02.0 ± 0.0Kidney Gr1 Score0.25 ± 0.50.25 ± 0.50.75 ± 0.5* p<0.05 vs HbAA; # p<0.05 vs HbAS Disclosures No relevant conflicts of interest to declare.
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Nankanja, Ruth, Charles Kiyaga, Mark Geisberg, Erik Serrao, and Stephen Balyegyusa. "Implementation of a Sickle Cell Disease Screening Initiative in Uganda with HemoTypeSCTM." Blood 132, Supplement 1 (2018): LBA—3—LBA—3. http://dx.doi.org/10.1182/blood-2018-120839.
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Abstract Sickle Cell Disease (SCD) is a widely prevalent hemoglobinopathy in sub-Saharan Africa that is frequently deadly in early life, killing 70-80% of afflicted children before their fifth birthday. SCD accounts for ~20% of annual childhood deaths in Uganda - one of the first African countries surveyed for SCD prevalence. This health danger is currently addressable: prophylactic intervention programs including hydroxyurea, antibiotics, and immunizations have drastically reduced SCD mortality in developed areas and could be implemented in sub-Saharan Africa in a cost-effective manner. However, the cornerstone of such programs, newborn diagnostic screening, has not been widely implemented in Uganda, or elsewhere in Africa. This dilemma springs from the cost and logistical problems with accepted diagnostic methodologies, which require laboratory equipment, highly-trained operating personnel, uninterrupted electrical supply, and sample transport away from the point-of-care (POC). Clearly, a low-cost, low-complexity, POC diagnostic test for SCD could help diminish this public health crisis. HemoTypeSCTM is an inexpensive competitive lateral-flow immunoassay that uses monoclonal antibodies to detect hemoglobins (Hbs) A, S, and C in a 1.5-μL droplet of whole blood. In this study we conducted a field validation of HemoTypeSC accuracy in children of southeastern Uganda, aimed at providing evidence for the applicability of the test in widespread newborn screening programs in the region. This study was designed as a blinded, prospective diagnostic accuracy trial of HemoTypeSC as an investigational test compared to Hb electrophoresis as a reference method. Jinja Regional Referral Hospital was selected as a low-resource study center due to its relatively high daily patient volume, as well as its suitability as a prototype center for organized newborn SCD screening within Uganda. Exactly 1,000 children five years old and younger were prospectively recruited from the hospital wards and outpatient clinics. HemoTypeSC was compared to Hb electrophoresis for detection of the Hb phenotypes HbAA (normal), HbAS (sickle cell trait), and HbSS (SCD). Initial data analysis indicated that HemoTypeSC correctly identified 998 out of 1,000 phenotypes, for an overall accuracy of 99.8%. This included 720/720 (100%) specimens correctly identified as HbAA, 182/182 (100%) correctly identified as HbAS, and 96/98 (98%) correctly identified as HbSS. The two discordant samples were both identified as HbSS by electrophoresis and HbAS by HemoTypeSC. To resolve these discrepancies, the patients with the discordant HbSS/HbAS results were recalled for repeat testing. During the ensuing phone contact for scheduling, it was discovered that both individuals were in fact previously diagnosed with SCD, and both had been recently transfused. The previous diagnostic result reports for these participants were subsequently viewed and confirmed as HbSS. Because HbA was indeed present in the blood of these two patients at the time of sampling, the HbAS result was determined to be true. A secondary data analysis was therefore conducted, in which these two specimens were included as true positives for HbSS and true negatives for HbAS. It was ultimately determined that HemoTypeSC correctly identified 1,000 out of 1,000 phenotypes across all patients screened, including 96/96 HbSS specimens, for an overall sensitivity, specificity, positive predictive value, and negative predictive value of 100%. These results indicate that HemoTypeSC performs at least as accurately as the gold-standard method of Hb electrophoresis in detecting SCD and sickle cell trait at the POC in a resource-limited setting. This to our knowledge represents the first ever report of a rapid test for SCD displaying 100% sensitivity and specificity in a field validation study. In summary, HemoTypeSC represents a promising tool that can presently enable newborn and general population screening. Widespread combination of HemoTypeSC newborn and population screening programs with appropriate treatment, prophylaxis, and health counseling systems in countries most affected by the disease could save the lives of millions of children over the coming decades. A separate abstract regarding a HemoTypeSC field validation trial in Nigeria has also been submitted as a late-breaking abstract. We would be open to sharing a presentation slot with this group. Disclosures No relevant conflicts of interest to declare.
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Kanne, Celeste K., Danielle Guffey, Charles Minard, et al. "Red Cell Rheology Biomarkers to Assess Cure in Gene-Based Therapies." Blood 136, Supplement 1 (2020): 11–12. http://dx.doi.org/10.1182/blood-2020-138989.
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Introduction Red cell rheology is abnormal in sickle cell disease (SCD); red blood cells (RBC) are rigid, dense, and the sickle hemoglobin (HbS) polymerizes with deoxygenation. There are several devices commercially available and under development to assess RBC rheology. One is an oxygen gradient ektacytometer (Lorrca with Oxygenscan, RR Mechatronics) which measures RBC deformability under oxygenated conditions (EImax) and deoxygenated conditions (EImin), and the oxygen concentration at which deformability begins to worsen, point of sickling (PoS). A commercially available hematology analyzer, the ADVIA (Siemens), measures hemoglobin (Hb) by flow and colorimetric methods, permitting automated calculation of the percent dense red blood cells (%DRBC). Allogeneic hematopoietic stem cell transplant (alloHSCT) can provide a cure for SCD, and viable gene-based therapy options are under investigation to serve the many patients without a matched related donor. However, the level of HbS correction or functional Hb induction necessary to achieve a cure is still unknown. Clinical endpoints such as prevention of pain events are important, but it is possible to be pain free for several years while still experiencing organ damage. As gene-based therapy clinical trials move forward, we must assess the level of functional improvement beyond Hb profile and conventional clinical labs. We propose that the goal of any gene-based SCD therapy should be to normalize blood rheology to the level of an individual with sickle cell trait (HbAS), and that EImax, EImin, PoS, and %DRBC may be used to distinguish between HbAS and HbSS/Sβ0 genotypes. Methods Subjects: Blood samples were collected from 257 unique patients (17 HbAS, and 240 HbSS/Sβ0) under IRB-approved protocols at Texas Children's Hospital and University Medical Center Utrecht. Patients were 56% male, ages 9 months to 22 years. Some HbSS/Sβ0 subjects were on transfusion and hydroxyurea (HU) (Table 1). Fetal hemoglobin (HbF) levels ranged from 0-41%. Oxygen gradient ektacytometry: Blood collected in EDTA and standardized to a fixed RBC count was suspended in 5 mL polyvinylpyrrolidone at room temperature. 1.5 mL of the sample solution was injected into test cup. Each sample was run in duplicate. ADVIA: 250µL of blood collected in EDTA at room temperature was aspirated to measure the %DRBC, defined as the percentage of RBCs with a Hb concentration &gt;1.11 mg/mL. Analysis: Patient characteristics were summarized using median with 25th and 75th percentiles, and frequency with percentage. Characteristics and labs were compared by group with t-test, Wilcoxon rank sum test, or Fisher's exact test. Receiver operating characteristics (ROC) analyses were performed to identify HbAS versus HbSS/Sβ0 for each biomarker. All analyses were performed using Stata 15. Results The EImin, EImax, PoS, and %DRBC differed significantly between the HbAS and HbSS/Sβ0 groups, despite including transfused, very young, and HU-treated samples in the HbSS/Sβ0 cohort (p&lt;0.001, p=0.002, p&lt;0.001, and p&lt;0.001, respectively; Table 1). ROC analysis showed that a threshold Elmin greater than or equal to 0.453 identified HbAS with 94.12% sensitivity and 95.43% specificity. EImax greater or equal to 0.569 identified HbAS with 94.12% sensitivity and 81.57% specificity. PoS less than 21.38 mmHg identified HbAS with 93.87% sensitivity and 93.33% specificity. %DRBC less than 1.6% identified HbAS with 88.13% sensitivity and 88.00% specificity (Table 2). Conclusion Conventional laboratory testing may not be able to establish if gene-based therapy has achieved a cure. We propose to define a cure as achievement of an HbAS level of RBC quality in a gene-based therapy edited RBC population. We show that rheological biomarkers EImin, EImax, PoS, and %DRBC differ significantly between individuals with HbAS and HbSS/Sβ0 of all spectrums of severity and treatment regimens. Not only are the rheological biomarker values significantly different, but there is little to no overlap in ranges of values obtained from the different genotypes, even in heavily transfused HbSS patients, with HbS as low as 31%. EImin, EImax, PoS, and %DRBC functionally identify genotype with high sensitivity and specificity; we propose that they be used not to diagnose SCD, but to determine if a HbSS or HbSS/Sβ0 individual who has undergone successful gene-based therapy has achieved the RBC functionality of a HbAS individual. Disclosures van Beers: Novartis: Research Funding; Pfizer: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; RR mechatronics: Research Funding. Wijk:Agios Pharmaceuticals Inc.: Research Funding; RR mechatronics: Research Funding. Rab:RR Mechatronics: Research Funding. Sheehan:Global Blood Therapeutics: Research Funding; Novartis: Research Funding; Emmaus: Research Funding.
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Bowers, A. S., D. J. Pepple, and H. L. Reid. "Oxygen delivery index in subjects with normal haemoglobin (HbAA), sickle cell trait (HbAS) and homozygous sickle cell disease (HbSS)." Clinical Hemorheology and Microcirculation 40, no. 4 (2008): 303–9. http://dx.doi.org/10.3233/ch-2008-1142.
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Bowers, A. S., D. J. Pepple, and H. L. Reid. "Optimal haematocrit in subjects with normal haemoglobin genotype (HbAA), sickle cell trait (HbAS), and homozygous sickle cell disease (HbSS)." Clinical Hemorheology and Microcirculation 47, no. 4 (2011): 253–60. http://dx.doi.org/10.3233/ch-2011-1387.
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Fye, Haddy KS, Paul Mrosso, Frédéric B. Piel, et al. "Proteomics Pathways of Sickle Cell Anemia (P2SCA): A Comprehensive Analysis By Liquid Chromatography Mass Spectrometry of Erythrocyte Membrane Proteins Characterized from the Muhimbili Sickle Cell Programme, Tanzania." Blood 132, Supplement 1 (2018): 3653. http://dx.doi.org/10.1182/blood-2018-99-114650.
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Abstract Annually, there are 312 000 births with Sickle Cell Anemia (SCA), which has been recognized as one of the most common inherited conditions in Africa and is currently emerging as a condition of prominence in much of the developed world due to migration patterns. Despite its growing importance, there has been a significant lag in the application of emerging methodologies to its research, in particular to support the discovery of disease-associated markers of potential implication in therapeutics and informing a more comprehensive understanding of the condition. To bring SCA in line with cutting-edge 'omics research, we conducted a study applying advanced mass spectrometry methods for the comprehensive characterization of the protein profiles of erythrocyte membranes. One hundred and twenty participants of confirmed Hemoglobin (Hb) phenotypes HbAA (18), HbAS (21) and HbSS (81) were enrolled from the Muhimbili Sickle Cell Programme in Tanzania. All consented individuals were confirmed to not be on hydroxyurea treatment and not having received a blood transfusion in the preceding 3 months. Whole blood was collected and mixed in 10 ml EDTA vials sent within 72 hours to the Target Discovery Institute (TDI), University of Oxford, UK. Once received, packed erythrocyte fractions were isolated and underwent a series of wash steps followed by erythrocyte lysis and the isolation of the ghost membranes by ultracentrifugation. The ghost cells were then prepared for liquid chromatography mass spectrometry (LCMS) analysis using a novel published method. Proteomics analysis on a Thermo Scientific Q-Exactive High Field MS identified 2,288 membrane or membrane associated proteins of which 1,605 showed significant difference between at least two of the Hb phenotypes with fold changes of up to 22. Specific comparisons identified 1,286 proteins showing significant (p value cut-off, 0.05) changes in expression between the HbAA and HbSS groups; 1,248 between the HbAS and HbSS groups and 278 between the HbAA and HbAS groups. A summary of 30 markers have been presented including a range of proteins of potential therapeutic impact. These were selected based on their ranked significance following statistical analysis, the overall distinction seen between the controls and the HbSS group and the robustness of their identification. The results obtained show significant changes in the presence or absence as well as levels of numerous proteins in the HbSS population compared to controls. This research is a significant contribution to the field of SCA research and forms the foundation to direct further study on the sickle erythrocyte membrane. The large number of proteins identified to be of association to individuals' Hb genotypes represents a significant breakthrough and could contribute to a better understanding of the pathophysiological mechanisms involved in the disease. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Gbessi, Eric A., Offianan A. Toure, Albert Gnondjui, et al. "Artemisinin derivative-containing therapies and abnormal hemoglobin: Do we need to adapt the treatment?" Parasite 28 (2021): 67. http://dx.doi.org/10.1051/parasite/2021063.
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Background: Artemisinin-based treatment in malaria patients with abnormal hemoglobin may be ineffective because of their genetic particularity, which could lead to resistance. The main purpose of this study was to assess the effect of artemisinin derivatives on in vivo parasite clearance according to erythrocyte variants. In vivo response was investigated through retrospective data obtained over a 42-day artemether-lumefantrine/artesunate amodiaquine efficacy protocol conducted from 2012 to 2016. Results: A total of 770 patients in Côte d’Ivoire attending the hospitals of Anonkoua-koute (Abidjan), Petit Paris (Korhogo), Libreville (Man), Dar es salam (Bouaké), Ayamé and Yamoussoukro with acute uncomplicated falciparum malaria were selected for successful hemoglobin typing. HbAS, HbSS, HbAC, and HbSC genotypes were found. Parasite clearance time was obtained for 414 patients. In the population with abnormal hemoglobin, parasite densities on admission and parasite clearance rates were significantly lower in the HbSC group compared to HbAA (p = 0.02 and p = 0.007, respectively). After PCR correction on day 42, the acute treatment rate was 100% for each group. Parasite half-life and time for initial parasitaemia to decline by 50 and 99% were longer for the HbSC group (p < 0.05). The study also investigated the prevalence of K13-propeller polymorphisms across different hemoglobin genotype groups. A total of 185 and 63 samples were sequenced in the HbAA group and patients with abnormal Hb, respectively. Only two nonsynonymous mutations D559N and V510M were found in the HbAA group. Conclusion: Although this study proved good efficacy of artemether-lumefantrine and artesunate amodiaquine in the treatment of uncomplicated Plasmodium falciparum malaria in patients with abnormal hemoglobin, the increased delay of parasite clearance may represent a threat to health in these patients in relation with sickle cell crisis, which could support selection of parasites resistant to artemisinin.
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Sankaranarayanan, Ranjini, D. Ramesh Kumar, Janki Patel, and G. Jayarama Bhat. "Do Aspirin and Flavonoids Prevent Cancer through a Common Mechanism Involving Hydroxybenzoic Acids?—The Metabolite Hypothesis." Molecules 25, no. 9 (2020): 2243. http://dx.doi.org/10.3390/molecules25092243.
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Despite decades of research to elucidate the cancer preventive mechanisms of aspirin and flavonoids, a consensus has not been reached on their specific modes of action. This inability to accurately pinpoint the mechanism involved is due to the failure to differentiate the primary targets from its associated downstream responses. This review is written in the context of the recent findings on the potential pathways involved in the prevention of colorectal cancers (CRC) by aspirin and flavonoids. Recent reports have demonstrated that the aspirin metabolites 2,3-dihydroxybenzoic acid (2,3-DHBA), 2,5-dihydroxybenzoic acid (2,5-DHBA) and the flavonoid metabolites 2,4,6-trihydroxybenzoic acid (2,4,6-THBA), 3,4-dihydroxybenzoic acid (3,4-DHBA) and 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) were effective in inhibiting cancer cell growth in vitro. Limited in vivo studies also provide evidence that some of these hydroxybenzoic acids (HBAs) inhibit tumor growth in animal models. This raises the possibility that a common pathway involving HBAs may be responsible for the observed cancer preventive actions of aspirin and flavonoids. Since substantial amounts of aspirin and flavonoids are left unabsorbed in the intestinal lumen upon oral consumption, they may be subjected to degradation by the host and bacterial enzymes, generating simpler phenolic acids contributing to the prevention of CRC. Interestingly, these HBAs are also abundantly present in fruits and vegetables. Therefore, we suggest that the HBAs produced through microbial degradation of aspirin and flavonoids or those consumed through the diet may be common mediators of CRC prevention.
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Lagoo, Jyoti, and Arpita Lagoo. "The study of the incidence of pregnant women with sickle cell disease." International Journal of Reproduction, Contraception, Obstetrics and Gynecology 8, no. 10 (2019): 3950. http://dx.doi.org/10.18203/2320-1770.ijrcog20194360.
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Background: The sickle cell disease is major public health problem which causes high morbidity and mortality in India. It is observed that SCD is scourge in Chhattisgarh since long past. Sickle cell disease is a term for a group of genetically inherited disorders characterized by production of abnormal hemoglobin. “Hemoglobin-S” results from a point mutation in the beta globin gene. The main objective is to study the incidence of pregnant women with sickle cell disease.Methods: It is a hospital based prospective study. It was conducted at Obstetrics and Gynecology department of LTBRKM Govt. Medical College, Jagdalpur, Chhattisgarh. The study was carried out from August 2014 to October 2015. The study included screening of all patients attending antenatal clinic and in labour ward during emergency. 75 cases were found to be sickling positive. Permission from Institutional Ethics Committee was obtained.Results: The incidence of SCD in India is 44%, in Chhattisgarh is 17%.At our institute in pregnant women is 1.75%. The incidence of HbAs group was 70.66% and HbSS was 26.66%. In Hb AS group maximum 47% patients were in age group of 26-30 years. and also in same age group the incidence of HbSS group was 60%. In age group of 31-35 years. 22% of patients were of HbAS group, but only 10% of patients were of HbSS group. HbAS group and HbSS group the percentage of primi gravida were 49% and 60% respectively. It is noted that in HbAS group only 3% of patients had parity >4, but in HbSS group it was 10%.Conclusions: In conclusion, it has been shown that the clinical statuses of the most sickle cell diseases patience were not seriously affected by pregnancy if they are given appropriate prenatal care. All pregnant women should be screened for sickle sell hemoglobinopathy in endemic region, like in our state Chhattisgarh.
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Ezebuo, Fortunatus C., Sabinus Oscar O. Eze, Colin B. Lukong, and Ferdinand C. Chilaka. "Interaction of Normal and Sickle Hemoglobins for Sodium Dodecylsulphate and Hydrogen Peroxide at pH 5.0 and 7.2." ISRN Hematology 2013 (October 10, 2013): 1–5. http://dx.doi.org/10.1155/2013/629640.
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Clinical manifestations of malaria primarily result from proliferation of the parasite within the hosts’ erythrocytes. The malaria parasite digests hemoglobin within its digestive vacuole through a sequential metabolic process involving multiple proteases. The activities of these proteases could lead to the production of ROS which could lead to the death of the parasites due to the destruction of their membrane. The action of SDS on hemoglobins can be likened to the way malarial proteases destabilizes host hemoglobin. Hence, the study was designed to determine the binding parameters of SDS and H2O2 for normal, sickle trait carrier and sickle hemoglobins at pH 5.0 and 7.2 using UV-VIS Titration Spectrophotometry. Hb-SDS interactions were significantly different at pH 5.0 but were not at pH 7.2. Also, Hb-H2O2 interactions were statistically different at pH 5.0 and 7.2. The interactions suggest that HbA and HbS are easily destabilized than HbAS and that HbAS has more affinity for H2O2. These suggest a production of more ferryl intermediates or hydroxyl radicals. All these interactions may hinder the development of the malaria parasite at the intraerythrocytic stage and could likely account for a significant proportion of the mechanism that favours the resistance to malaria by individuals with HbAS.
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Ferreira, Junia Raquel Dutra, Caroline Conceição Guarda, Rayra Pereira Santiago, et al. "Cardiometabolic and Hemostatic Profiles of Women Carriers of Hemoglobin Variants Using Combined Oral Contraceptives." Blood 128, no. 22 (2016): 4851. http://dx.doi.org/10.1182/blood.v128.22.4851.4851.
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Abstract Introduction: Several studies reported combined contraceptives influence in hemostatic and lipid profile besides the concern about the thromboembolism and cardiovascular risks due to the steroids hormones use. As women with hemoglobin (Hb) variants have a pre-existing inflammatory condition and considering the high frequency of hemoglobin variant worldwide, this study aims to evaluate the association of hematological, lipid, glicemic, inflammatory and hemostatic profiles in women using combined oral contraceptives and carriers of hemoglobin variants. Methods: We performed a cross-sectional study including 591 women in reproductive-age. We investigated their hemoglobin profile and COCs use. Of them, we included 60 women with HbAA, 21 with HbAC, 25 with HbAS and 7 with HbSC profiles, all of them combined oral contraceptives users. Among those combined oral contraceptives nonusers, 9 were HbAC and 19 HbSC. We evaluated fasting serum glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), C-reactive protein (CRP), fibrinogen, D-dimer and hematological profile among the studied groups. This study was conducted in accordance and approved by the Research Ethics Committee of the Fundação Oswaldo Cruz - FIOCRUZ, Brazil; and also with the Helsinki Declaration of 1975, and its revisions. Mann-Whitney U tests were used to compare two groups of values within the same variable. Results: We observed significant differences in some hematological and cardiometabolic parameters in women carriers of different Hb variants and using COCs. We found relevant increases in CRP levels in HbSC and HbAC women that seem to be associated with different types of progestins present in combined oral contraceptives formulations. Also, combined oral contraceptives use seems to be associated with decreased HDL-c levels in HbAC women. Otherwise, D-dimer levels were increased in all women with Hb variants, independently of the contraceptive use. Conclusions: Although combined oral contraceptive remains an important method to prevent unintended pregnancy, our data suggest that contraception in women carriers of Hb variants, including those in heterozygosis, should be carefully evaluated, especially, considering the pre-existent inflammatory and pro-thrombotic conditions that together with combined oral contraceptive use may result in additional health problems, such as cardiovascular and thromboembolic diseases. Disclosures No relevant conflicts of interest to declare.
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Albiti, Anisa H., and Kwabena Nsiah. "Comparative haematological parameters of HbAA and HbAS genotype children infected withPlasmodium falciparummalaria in Yemen." Hematology 19, no. 3 (2013): 169–74. http://dx.doi.org/10.1179/1607845413y.0000000113.
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Jin, David K., Lauren M. Young, Loic Vincent, et al. "Multimodular Analysis of Angiogenic Biomarkers in the Primary Treatment of Multiple Myeloma: Correlative Studies of the BiRD Trial." Blood 106, no. 11 (2005): 3483. http://dx.doi.org/10.1182/blood.v106.11.3483.3483.
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Abstract Biomarkers that predict the angiogenic propensity of multiple myeloma and the impact of therapy on angiogenesis remain unknown. Nevertheless, many putative anti-angiogenic agents are currently being evaluated in clinical trials. We describe the results of a multimodular analysis of angiogenic biomarkers including a novel in vitro functional assay, the human umbilical vein endothelial cell (HUVEC)-based angiogenic scale (HBAS), to assess the overall angiogenic activity in the plasma of patients with multiple myeloma. Plasma fractionated from the peripheral blood of myeloma patients was added to primary HUVEC and cultured under serum-free conditions for 24 hours. Angiogenic morphology was then examined and scored using a six-point angiogenic scale. Analysis of a cohort of ten consecutive patients with multiple myeloma undergoing the BiRD protocol (Biaxin, Revlimid and dexamethasone) showed that the majority had higher HBAS scores at baseline than age-matched normal subjects. Plasma samples from stage IIIA disease consistently scored higher than those from stage II disease on the functional angiogenic scale (mean score of 2.8 versus 1.0, p&lt;0.005), suggesting a more pro-angiogenic state for further advanced disease. The HBAS also correlated with increased levels of plasma and platelet vascular endothelial growth factor-A (VEGF-A) as quantified by ELISA. Interestingly, VEGF-A levels in platelet lysate were significantly higher than those in plasma and more closely paralleled the functional HBAS scores. In addition, two-color flow cytometric analysis of cellular biomarkers demonstrated an angiogenic switch defined by increased mobilization of circulating CD133+VEGFR2+ endothelial progenitor cells in patients with active disease as compared to normal subjects (2.2-fold increase; p&lt;0.005). Treatment with BiRD effectively attenuated all tested angiogenic parameters and correlated with a positive clinical response. Collective assessment of angiogenic biomarkers may be a promising resource for predicting clinical outcomes and for validating the potential impact of anti-angiogenic therapy in multiple myeloma.
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Mannu, Alberto, Marco Blangetti, Salvatore Baldino, and Cristina Prandi. "Promising Technological and Industrial Applications of Deep Eutectic Systems." Materials 14, no. 10 (2021): 2494. http://dx.doi.org/10.3390/ma14102494.
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Deep Eutectic Systems (DESs) are obtained by combining Hydrogen Bond Acceptors (HBAs) and Hydrogen Bond Donors (HBDs) in specific molar ratios. Since their first appearance in the literature in 2003, they have shown a wide range of applications, ranging from the selective extraction of biomass or metals to medicine, as well as from pollution control systems to catalytic active solvents and co-solvents. The very peculiar physical properties of DESs, such as the elevated density and viscosity, reduced conductivity, improved solvent ability and a peculiar optical behavior, can be exploited for engineering modular systems which cannot be obtained with other non-eutectic mixtures. In the present review, selected DESs research fields, as their use in materials synthesis, as solvents for volatile organic compounds, as ingredients in pharmaceutical formulations and as active solvents and cosolvents in organic synthesis, are reported and discussed in terms of application and future perspectives.
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Gong, Lauren, Catherine Maiteki-Sebuguzi, Philip J. Rosenthal, et al. "Evidence for both innate and acquired mechanisms of protection from Plasmodium falciparum in children with sickle cell trait." Blood 119, no. 16 (2012): 3808–14. http://dx.doi.org/10.1182/blood-2011-08-371062.
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AbstractSickle cell trait (HbAS) is known to be protective against Plasmodium falciparum malaria, but it is unclear when during the course of infection this protection occurs and whether protection is innate or acquired. To address these questions, a cohort of 601 children 1-10 years of age were enrolled in Kampala, Uganda, and followed for 18 months for symptomatic malaria and asymptomatic parasitemia. Genotyping was used to detect and follow individual parasite clones longitudinally within subjects. Children with HbAS were protected against the establishment of parasitemia, as assessed by the molecular force of infection at older but not younger ages (at 2 years of age: incidence rate ratio [IRR] = 1.16; 95% confidence interval [95% CI], 0.62-2.19; P = .6; at 9 years of age: IRR = 0.50; 95% CI, 0.28-0.87; P = .01), suggesting an acquired mechanism of protection. Once parasitemic, children with HbAS were less likely to progress to symptomatic malaria, with protection again being the most pronounced at older ages (at 2 years of age: relative risk [RR] = 0.92; 95% CI, 0.77-1.10; P = .3; at 9 years of age: RR = 0.68; 95% CI, 0.51-0.91; P = .008). Conversely, the youngest children were best protected against high parasite density (at 2 years of age: relative density = 0.24; 95% CI, 0.10-0.54; P = .001; at 9 years of age: relative density = 0.59; 95% CI, 0.30-1.19; P = .14), suggesting an innate mechanism of protection against this end point.
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Tetteh, Mary, Otchere Addai-Mensah, Zakaria Siedu, et al. "Acute Phase Responses Vary Between Children of HbAS and HbAA Genotypes During Plasmodium falciparum Infection." Journal of Inflammation Research Volume 14 (April 2021): 1415–26. http://dx.doi.org/10.2147/jir.s301465.
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Wang, Yan, Shuhang Ren, Yucui Hou, and Weize Wu. "Capture of Acidic Gases from Flue Gas by Deep Eutectic Solvents." Processes 9, no. 8 (2021): 1268. http://dx.doi.org/10.3390/pr9081268.
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Up to now, many kinds of deep eutectic solvents (DESs) were investigated for the capture of acidic gases from flue gases. In this review, non-functionalized and functionalized DESs, including binary and ternary DESs, for SO2, CO2 and NO capture, are summarized based on the mechanism of absorption, physical interaction or chemical reaction. New strategies for improving the absorption capacity are introduced in this review. For example, a third component can be introduced to form a ternary DES to suppress the increase in viscosity and improve the CO2 absorption capacity. DESs, synthesized with halogen salt hydrogen bond acceptors (HBAs) and functionalized hydrogen bond donors (HBDs), can be used for the absorption of SO2 and NO with high absorption capacities and low viscosities after absorption, due to physicochemical interaction between gases and DESs. Emphasis is given to introducing the absorption capacities of acidic gases in these DESs, the mechanism of the absorption, and the ways to enhance the absorption capacity.
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Orimadegun, Adebola Emmanuel, and Olugbemiro Sodeinde. "Glucose-6-phosphate dehydrogenase status and severity of malarial anaemia in Nigerian children." Journal of Infection in Developing Countries 5, no. 11 (2011): 792–98. http://dx.doi.org/10.3855/jidc.1837.
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Introduction: Glucose-6-phosphate dehydrogenase (G6PD) deficiency (Gd-) contributes to morbidity and mortality in sub-Saharan Africa but recent data on the interaction between Gd- and malaria among children is scarce. We hypothesised that, being a haemolytic factor, Gd- makes severe malarial anaemia (SMA) more common and even more severe. Methodology: We selected 930 children aged 0.5-12 years attending a reference hospital with microscopically proven falciparum malaria. G6PD and haemoglobin were typed by the fluorescent spot test and electrophoresis, respectively. Molecular typing by PCR and restriction enzyme digestion was also performed on 15% of randomly selected samples. Haematocrit (PCV) values, haemoglobin type, blood group, presence of sickle cell trait (HbAS), and parasite counts were compared between G6PD-normal and deficient children. Results: Prevalence of Gd- was 16.4% and 8.1% among boys and girls with malaria, respectively. Mean PCV was 22.8% in deficient children compared with 21.0% in normal children (p=0.041). In boys, 2.7% of Gd- had PCV ≤10%, as compared to 13.6% in Gd+ (p = 0.005). Similarly, 21.3% of Gd- had PCV ≤15% compared with 39.4% in Gd+ (p=0.003). No such difference was found among girls. Overall, HbAS was typed in 7.6% and was more common in Gd- (13.0%) than in Gd+ (6.8%), but the difference was not statistically significant (p=0.058). The mean parasite counts were significantly lower in Gd- (15477.5/μl) than in Gd+ (19784.4/μl; p=0.013), and it was independent from HbAS. Conclusion: Gd- males but not females were significantly less likely to develop severe malarial anaemia.
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Randle, H. "Equine behavioural science: perspectives on problems." BSAP Occasional Publication 35 (2006): 109–27. http://dx.doi.org/10.1017/s0263967x00042622.
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It is crucial to emphasise the importance of a sound scientific underpinning in the tackling of equine problems and regulation of those who treat equines. It is becoming increasingly common for two types of ‘practitioner’ to be consulted by owners of horses experiencing some kind of behavioural problem, namely Horse Whisperers (HWs) and Horse Behaviour Advisors (HBAs).Throughout this paper HWs are considered to be those who can ‘communicate with an equine, in a para–normal, gifted manner’, whilst HBAs are considered to be those who ‘advise on horse behaviour, especially problem behaviour’. The commonly used term ‘Horse Behaviourist’ has deliberately not been used as it is technically incorrect. Anyone with a rudimentary knowledge of psychology and learning theory will know that behaviourists are proponents of ‘behaviourism’ – a particular way of explaining learning. It is not a generic term referring to the study of animal behaviour – that is ‘ethology’. Worryingly today the term ‘ethology’ is being employed as a marketing tool.
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Kalinowska, Monika, Ewelina Gołębiewska, Grzegorz Świderski, et al. "Plant-Derived and Dietary Hydroxybenzoic Acids—A Comprehensive Study of Structural, Anti-/Pro-Oxidant, Lipophilic, Antimicrobial, and Cytotoxic Activity in MDA-MB-231 and MCF-7 Cell Lines." Nutrients 13, no. 9 (2021): 3107. http://dx.doi.org/10.3390/nu13093107.
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Seven derivatives of plant-derived hydroxybenzoic acid (HBA)—including 2,3-dihydroxybenzoic (2,3-DHB, pyrocatechuic), 2,4-dihydroxybenzoic (2,4-DHB, β-resorcylic), 2,5-dihydroxybenzoic (2,5-DHB, gentisic), 2,6-dihydroxybenzoic (2,6-DHB, γ-resorcylic acid), 3,4-dihydroxybenzoic (3,4-DHB, protocatechuic), 3,5-dihydroxybenzoic (3,5-DHB, α-resorcylic), and 3,4,5-trihydroxybenzoic (3,4,5-THB, gallic) acids—were studied for their structural and biological properties. Anti-/pro-oxidant properties were evaluated by using DPPH• (2,2-diphenyl-1-picrylhydrazyl), ABTS•+ (2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), FRAP (ferric-reducing antioxidant power), CUPRAC (cupric-reducing antioxidant power), and Trolox oxidation assays. Lipophilicity was estimated by means of experimental (HPLC) and theoretical methods. The antimicrobial activity against Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Bacillus subtilis (B. subtilis), Salmonella enteritidis (S. enteritidis), and Candida albicans (C. albicans) was studied. The cytotoxicity of HBAs in MCF-7 and MDA-MB-231 cell lines was estimated. Moreover, the structure of HBAs was studied by means of experimental (FTIR, 1H, and 13C NMR) and quantum chemical DFT methods (the NBO and CHelpG charges, electrostatic potential maps, and electronic parameters based on the energy of HOMO and LUMO orbitals). The aromaticity of HBA was studied based on the calculated geometric and magnetic aromaticity indices (HOMA, Aj, BAC, I6, NICS). The biological activity of hydroxybenzoic acids was discussed in relation to their geometry, the electronic charge distribution in their molecules, their lipophilicity, and their acidity. Principal component analysis (PCA) was used in the statistical analysis of the obtained data and the discussion of the dependency between the structure and activity (SAR: structure–activity relationship) of HBAs. This work provides valuable information on the potential application of hydroxybenzoic acids as bioactive components in dietary supplements, functional foods, or even drugs.
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Barbosa, Ana Maria Rodrigues, José Felipe Pinheiro do Nascimento Vieira, Eliane Cristina De Sá de Sousa, and Mayara Ladeira Coêlho. "PREVALÊNCIA DE HEMOGLOBINOPATIAS EM GESTANTES ASSISTIDAS POR UM LABORATÓRIO DE SAÚDE PÚBLICA NO PIAUÍ." Jornal de Ciências da Saúde do Hospital Universitário da Universidade Federal do Piauí 1, no. 2 (2018): 73. http://dx.doi.org/10.26694/2595-0290.20181273-847140.
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OBJETIVOS. O objetivo geral deste estudo é determinar a prevalência de hemoglobinas variantes HbS, HbC, HbD, bem como das pacientes diagnosticados com a doença falciforme. METODOLOGIA. Trata-se de em estudo descritivo, retrospectivo e transversal com abordagem quantitativa, com base no banco de dados Net Lab do Laboratório de Saúde Pública do Piauí, coletados no período de março a setembro de 2016, dos resultados obtidos de janeiro de 2013 a dezembro de 2015. RESULTADOS. Foram analisados 219 relatórios de pacientes gestantes, verificou-se uma maior prevalência de gestantes portadoras com o traço falciforme (HbAS e HbAC) correspondendo a AS 81,46% das pacientes e com genótipo AC 12,20%. Enquanto que para as pacientes com a doença (SC e SS), correspondeu a SC 5,37% e SS uma percentagem mais baixa (0,98%). CONCLUSÃO. Este estudo mostrou a alta prevalência do traço falciforme encontrado na população de gestantes estudadas de acordo com sua origem racial, constatando a hipótese da prevalência do traço na população negra do estado do Piauí, visto que sua herança genética está presente em todas as regiões do estado.
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Mukherjee, Malay B., Roshan B. Colah, Pallavi R. Mehta, et al. "Multicenter Evaluation of HemoTypeSC as a Point-of-Care Sickle Cell Disease Rapid Diagnostic Test for Newborns and Adults Across India." American Journal of Clinical Pathology 153, no. 1 (2019): 82–87. http://dx.doi.org/10.1093/ajcp/aqz108.
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Abstract Objectives Sickle cell anemia is the commonest genetic disorder in India, and the frequency of the sickle cell gene is very high in the remote tribal areas where facilities are generally limited. Therefore, a rapid and affordable point-of-care test for sickle cell disease is needed. Methods The diagnostic accuracy of HemoTypeSC was evaluated against automated high-performance liquid chromatography (HPLC) as the gold standard for its efficacy in a newborn screening program. Results A total of 1,559 individuals (980 newborns and 579 adults) from four participating centers were analyzed by both methods. HemoTypeSC correctly identified 209 of 211 total hemoglobin (Hb) SS cases, for a 99.1%/99.9% total HbSS sensitivity/specificity. Overall, HemoTypeSC exhibited sensitivity and specificity of 98.1% and 99.1% for all possible phenotypes (HbAA, HbAS, and HbSS) detected. HPLC is relatively expensive and not available in most laboratories in remote tribal areas. Conclusions We conclude that the rapid, point-of-care testing device HemoTypeSC test is suitable for population and newborn screening for the HbS phenotype.
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Sambuughin, Nyamkhishig, Mingqiang Ren, John F. Capacchione, et al. "Multifactorial Origin of Exertional Rhabdomyolysis, Recurrent Hematuria, and Episodic Pain in a Service Member with Sickle Cell Trait." Case Reports in Genetics 2018 (November 7, 2018): 1–6. http://dx.doi.org/10.1155/2018/6898546.
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Individuals with Sickle Cell Trait (SCT), generally considered a benign carrier state of hemoglobin S (HbAS), are thought to be at risk for exertional rhabdomyolysis and hematuria, conditions that can also be caused by various other acquired and inherited factors. We report an SCT positive service member with an exertional rhabdomyolysis event, recurrent hematuria with transient proteinuria, and episodic burning pain in the lower extremities. Clinical and genetic studies revealed the multifactorial nature of his complex phenotype. The service member was taking prescription medications known to be associated with exertional rhabdomyolysis. He carried a pathogenic mutation,NPHS2p.V260E, reported in nephropathy and a new variant p.R838Q inSCN11A, a gene involved in familial episodic pain syndrome. Results suggest that drug-to-drug interactions coupled with the stress of exercise, coinheritance of HbAS andNPHS2p.V260E, and p. R838Q inSCN11Acontributed to exertional rhabdomyolysis, recurrent hematuria with proteinuria, and episodic pain, respectively. This case underscores the importance of comprehensive clinical and genetic evaluations to identify underlying causes of health complications reported in SCT individuals.
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Hassan, D. A., C. Marques, G. M. Santos-Gomes, et al. "Differential expression of cytokine genes among sickle-cell-trait (HbAS) and normal (HbAA) children infected withPlasmodium falciparum." Annals of Tropical Medicine & Parasitology 103, no. 4 (2009): 283–95. http://dx.doi.org/10.1179/136485909x435049.
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Delobel, Julien, Kristina Keitel, Katia Balmas-Bourloud, Tarsis Mlaganile, Valerie D'Acremont, and Raffaele Renella. "Harnessing the Power of Global Health Studies for Sickle Cell Disease: Validation of a Rapid, Open-Source, Paper-Based Screening Assay in a Cohort of 1103 Tanzanian Children." Blood 132, Supplement 1 (2018): 510. http://dx.doi.org/10.1182/blood-2018-99-109726.
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Abstract Introduction: Global health research is hampered by the lack of inexpensive and reliable assays to annotate clinical study cohorts for geographically localized endemic genetic disorders. The most prevalent modifier in Africa is sickle cell disease (SCD, HbSS). In SCD, sickling of erythrocytes by polymerization of hemoglobin S (HbS) causes vaso-occlusion and hemolysis, leading to significant morbidity/mortality and constituting a major healthcare and economic burden. The inhomogeneity bias introduced into the clinical data of patient cohorts by the changes associated to undiagnosed SCD is a significant challenge. Thus, our aims were to: a) optimize a paper-based screening test for SCD for its application in suboptimal and resource-limited conditions, b) demonstrate the feasibility of retrospective SCD annotation of a large cohort of children enrolled in a global health research study, and c) extract novel evidence on potential differences in clinical presentation between febrile children with and without SCD enrolled in this cohort. Materials & Methods: First, we adapted and simplified a paper-based SCD assay (Piety et al. 2017) for suboptimal sample conditions (frozen EDTA-whole blood) and limited-resource settings. Five microlitres of thawed EDTA-whole blood was solubilized (high phosphate buffer with saponin/sodium hydrosulfite), and blotted on standard blotting paper. Dots formed by capillarity, and their aspect depended on HbS%. A high-resolution scanner and two smartphone brands were compared for image capture. An algorithm for visual calling of the presence an HbS allele was developed, and the freeware ImageJ determined peripheral/central pixel intensities. An HbS dosimetric curve was determined after identification of optimal parameter correlations by scatter plot matrix. Second, blood samples from 1103 children aged 9 to 35 months enrolled in a randomized open prospective non-inferiority pediatric cohort study on algorithm-based management of febrile illnesses in Tanzania (ePOCT Trial, 2014-6, NCT02225769, Swiss/Tanzanian IRB approval, Keitel et al.2017) were assayed with the optimized paper test. In parallel, confirmation by gold-standard alkaline Hb electrophoresis (Helena Biosciences, UK) was performed. Third, clinical data from the newly SCD-annotated ePOCT database was analyzed (STATA software suite) to identify clinical features associated with febrile illnesses in the HbAA/AS/SS groups. Results: All EDTA-blood samples frozen onsite in Tanzania (shipped and then stored for >1 year) could be assayed. The test was rapid (5'), inexpensive (0.05 USD/test) and accessible (widely available reagents, no requirement for costly equipment, open-source freeware). Determination of HbS status (homozygous HbSS/AA or heterozygous HbSA) was effective both visually and by informatic means. Smartphone cameras yielded identical results (R2=0.96 & 0.97) when compared to a high-definition scanner. Local prevalence was at 1.6% and 13.6% for HbSS and HbAS respectively, in line with previously published data. By visual sorting of blood dots, the assay was 100% sensitive and 75.8% specific for the determination of HbSS-SCD and 97.6% sensitive and 87.5% specific for the identification of an HbS allele (in an hetero- or homozygous state). After analysis of the annotated ePOCT multiparametric clinical dataset, we observed that cough as the main complaint was more prevalent in children with HbSS (OR 3.1, 95% CI: 1.1-8.3). HbSS children were more severely malnourished (MUAC/age average z-scores -0.7 vs 0.0, p=0.01) and slightly more anemic (Hb 9.1 vs 9.8 g/dL, p=0.06) when compared to HbAA counterparts. Interestingly, children with HbAS had a better nutrition status than those with HbAA (MUAC/age average z-score 0.14, p<0.01). Also, education of mothers of HbSS children was significantly lower (primary education OR 0.3 (95% CI: 0.1-0.8). Conclusions: We demonstrated that the retrospective annotation of clinical cohorts for SCD with an optimized paper-based assay is feasible, straightforward and inexpensive. Our approach has the potential to eliminate the interpretation bias associated with SCD, and thus facilitate the downstream analysis of valuable datasets in other studies. As a proof of principle, we examined a properly annotated dataset highlighting novel features of febrile illness in children with SCD and HbAS carriers in Africa. Disclosures No relevant conflicts of interest to declare.
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D'Surney, S. J., and R. A. Popp. "Oxygen association-dissociation and stability analysis on mouse hemoglobins with mutant alpha- and beta-globins." Genetics 132, no. 2 (1992): 545–51. http://dx.doi.org/10.1093/genetics/132.2.545.
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Abstract Oxygen association-dissociation and hemoglobin stability analysis were performed on mouse hemoglobins with amino acid substitutions in an alpha-globin (alpha 89, His to Leu) and a beta-globin (beta 59, Lys to Ile). The variant alpha-globin, designated chain 5m in the Hbag2 haplotype, had an high oxygen affinity and was stable. The variant beta-globin, (beta s2) of the Hbbs2 haplotype, also had an elevated oxygen affinity and in addition was moderately unstable in 19% isopropanol. Hemoglobins from the expected nine (Hbag2/Hbag2;Hbbs/Hbbs x Hbaa/Hbaa;Hbbs2/Hbbs2) F2 genotypes can be grouped into five classes of P50 values characterized by strict additivity and dependency on mutant globin gene dosage; physiologically, both globin variants gave indistinguishable effects on oxygen affinity. The hemoglobin of normal mice (Hbaa/Hbaa;Hbbs/Hbbs) had a P50 = 40 mm Hg and the hemoglobin of Hbag2/Hbag2;Hbbs2/Hbbs2 F2 mice had a P50 = 25 mm Hg (human P50 = 26 mm Hg). Peripheral blood from Hbag2/Hbag2;Hbbs/Hbbs, Hbaa/Hbaa;Hbbs2/Hbbs2 and Hbag2/Hbag2;Hbbs2/Hbbs2 mice exhibited normal hematological values except for a slightly higher hematocrit for Hbag2/Hbag2;Hbbs/Hbbs and Hbag2/Hbag2;Hbbs2/Hbbs2 mice, slightly elevated red cell counts for mice of the three mutant genotypes, and significantly lower values for the mean corpuscular volume and mean corpuscular hemoglobin for Hbag2/Hbag2;Hbbs2/Hbbs2 mice.