Glycosylated hemoglobins in a diabetic patient with sickle cell anemia

Results of analysis of blood samples from a diabetic sickle cell anemia (SS) patient and 4 nondiabetic SS patients for glycosylated hemoglobins by Bio-Rex 70 chromatography, high-pressure liquid chromatography, and affinity chromatography are presented. Glycosylated components of Hb S and Hb A2 and total glycosylated hemoglobins were quantitated in this manner. The levels of the various glycosylated hemoglobins were increased twofold in the diabetic patient compared to nondiabetic SS patients. The glycosylated hemoglobin levels in the diabetic SS patient and in the nondiabetic SS patients, however, were significantly lower than the levels normally seen in nonsickle diabetics and normal adults, respectively. In contrast to a previously reported diabetic SS patient, the present case appears to be not severely affected by sickle cell disease.     

Haptoglobin for the treatment of sickle cell disease

There are three haptoglobin phenotypes in humans designated: Hp1–1, Hp2–1, and Hp2–2. The Hp1–1 phenotype has been shown to be protective against certain diseases, and this has been suggested to be the result of better anti-inflammatory and antioxidative properties compared to haptoglobin polymers of the other phenotypes when clearing cell-free haemoglobin. We propose the use of haptoglobin for the treatment of sickle cell disease, where an oxidative state exists caused by a high level of cell-free haemoglobin. A significant number of sickle cell disease patients are severely affected and experience regular acute painful episodes resulting in hospitalisation.Therapeutic treatments for sickle cell disease are limited and therefore haptoglobin could represent a vital alternative therapy. A method has been developed as part of the commercial fractionation of plasma for preparing haptoglobin enriched for dimers. This is significant as it uses a mixture of plasma of all haptoglobin phenotypes, and allows annual production of hundreds of kilograms quantities of haptoglobin that may be required to allow treatment of thousands of sickle cell disease patients worldwide.     

Reduced water exchange in sickle cell anemia red cells: a membrane abnormality

We have measured the diffusional water permeability of sickle cell anemia red blood cells under isotonic conditions using pulsed nuclear magnetic resonance (NMR) techniques. We have found that the equilibrium diffusional permeability for sickle cells is about 1.61.10(-3) cm/s, or about 60% of the value measured for normal cells. This abnormality is not related to the heterogeneity generally found in cell populations in sickle red cells with different mean corpuscular hemoglobin concentrations. We speculate that the abnormality of water exchange under isotonic conditions in sickle cells reflects an alteration of membrane proteins responsible for water exchange, possibly caused by oxidation of Band 3 proteins.     

From a dry bone to a genetic portrait: a case study of sickle cell anemia

The potential and reliability of DNA analysis for the identification of human remains are demonstrated by the study of a recent bone sample, which represented a documented case of sickle cell anemia. beta-globin gene sequences obtained from the specimen revealed homozygosity for the sickle cell mutation, proving the authenticity of the retrieved residual DNA. Further investigation of mitochondrial and Y chromosome DNA polymorphic markers indicated that this sample came from a male of maternal West African (possibly Yoruban) and paternal Bantu lineages. The medical record, which became available after the DNA analyses had been completed, revealed that it belonged to a Jamaican black male. These findings are consistent with this individual being a descendent of Africans brought to Jamaica during the trans-Atlantic slave trade. This study exemplifies how a "reverse population genetics" approach can be applied to reconstruct a genetic profile from a bone specimen of an unknown individual.     

Mortality in sickle cell anemia in Africa: a prospective cohort study in Tanzania

Background

The World Health Organization has declared Sickle Cell Anemia (SCA) a public health priority. There are 300,000 births/year, over 75% in Africa, with estimates suggesting that 6 million Africans will be living with SCA if average survival reaches half the African norm. Countries such as United States of America and United Kingdom have reduced SCA mortality from 3 to 0.13 per 100 person years of observation (PYO), with interventions such as newborn screening, prevention of infections and comprehensive care, but implementation of interventions in African countries has been hindered by lack of locally appropriate information. The objective of this study was to determine the incidence and factors associated with death from SCA in Dar-es-Salaam.

Methods and Findings

A hospital-based cohort study was conducted, with prospective surveillance of 1,725 SCA patients recruited from 2004 to 2009, with 209 (12%) lost to follow up, while 86 died. The mortality rate was 1.9 (95%CI 1.5, 2.9) per 100 PYO, highest under 5-years old [7.3 (4.8–11.0)], adjusting for dates of birth and study enrollment. Independent risk factors, at enrollment to the cohort, predicting death were low hemoglobin (<5 g/dL) [3.8 (1.8–8.2); p = 0.001] and high total bilirubin (≥102 µmol/L) [1.7 (1.0–2.9); p = 0.044] as determined by logistic regression.

Conclusions

Mortality in SCA in Africa is high, with the most vulnerable period being under 5-years old. This is most likely an underestimate, as this was a hospital cohort and may not have captured SCA individuals with severe disease who died in early childhood, those with mild disease who are undiagnosed or do not utilize services at health facilities. Prompt and effective treatment for anemia in SCA is recommended as it is likely to improve survival. Further research is required to determine the etiology, pathophysiology and the most appropriate strategies for management of anemia in SCA.     

DNA-diagnosis of sickle cell anemia from chorionic villi: possible influence of maternal cell contamination

Summary The admixture of maternal tissue is a possible hazard of prenatal diagnosis from chorionic villi. Therefore the tolerable degree of maternal DNA contamination in prenatal diagnosis of sickle cell anemia was investigated by mixing various amounts of DNA from HbS carriers with DNA from normal individuals and sickle cell anemia patients. The results indicate that lower rate of admixed maternal DNA does not prevent an exact direct DNA-diagnosis of sickle cell anemia.The experimental part of this paper was performed at the Abteilung Humangenetik, Universität Ulm, D-7900 Ulm, Federal Republic of Germany     

Prevalence of diabetes mellitus in individuals heterozygous and homozygous for sickle cell anemia

Colorimetric determinations of glycosylated Hb were carried out in a sample (n = 97) of sickle cell anemia patients, and in an age- and sex-matched group of individuals (n = 45) heterozygous for sickle cell anemia, from the Eastern Province of Saudi Arabia. A statistically significant increase in the value of glycosylated Hb was found in sickle cell trait (HbAS) group, when compared with those of sickle cell anemia (HbSS) and normal (HbAA) groups. Since glycosylated Hb is considered a valid indicator of long-term blood glucose, and assuming normal red blood cell survival in HbAS carriers, the increased value of glycosylated Hb may suggest that there exists a higher incidence of undiagnosed diabetes mellitus in individuals with heterozygous inheritance for sickle cell hemoglobin than homozygous sickle cell patients and normal individuals. The mechanism underlying this observation remains to be defined.     

Rational bases for using oxygen-ozonetherapy as a biological response modifier in sickle cell anemia and beta-thalassemia: a therapeutic perspective

We are proposing to evaluate whether a complementary approach based on cycles of oxygen-ozone autohemotherapy (O3-AHT) already performed in millions of patients, can abate the chronic oxidative stress and improve the quality of life of serious hemoglobinopathic patients. Although a preliminary study has yielded encouraging results, it appears appropriate to perform a controlled, randomized and possibly multicentre clinical trial. The long use of this approach in other pathologies has proved to be very useful and it is hoped that scepticism will not prevail over scientific rationale. Ozone, as any other drug, has an intrinsic toxicity that, in the proposed application, is fully tamed by the blood antioxidant system.     

alpha-thalassemia in Bantu population from Congo-Brazzaville: its interaction with sickle cell anemia

Deletional alpha(+)-thalassemia (-alpha(3.7)) was investigated in four groups of unrelated individuals from the Bantu population (newborns, normal adults, sickle cells trait carriers, sickle cell anemia patients) of Brazzaville, Congo. The frequency of the (-alpha(3.7)) chromosome was similar between newborns (f = 0.40) and adult subjects (f = 0.36), and between sicklers and nonsickler subjects. The frequency of the (-alpha(3.7)) chromosome in sickle cell anemia patients (SS patients) did not change when age was stratified. The hematological characteristics of SS patients with (-alpha/alphaalpha, -alpha/-alpha) and without (alphaalpha/alphaalpha) alpha(+)-thalassemia were similar to those reported in Jamaican and US sickle cell anemia patients. alpha(+)-Thalassemia had an effect on the percentage of hemoglobin S in sickle cell trait carriers. Thus, the high frequency of alpha(+)-thalassemia in the Congolese population presumably results from this disorder having a selective advantage favoring survival. However, the frequency of alpha(+)-thalassemia was not affected by age. Although in this selective tropical environment, alpha(+)-thalassemia as elsewhere markedly affects the hematological characteristics of sickle cell anemia patients, however our data provide no evidence that alpha(+)-thalassemia increases survival of SS patients.     

Altered amount and activity of superoxide dismutase in sickle cell anemia

The amount and activity of superoxide dismutase (SOD) (EC 1.15.1.1) were measured in red cells collected from 50 white controls, 101 black controls, 50 patients with sickle hemoglobin (SS Hb), 12 with sickle trait, and 11 with other sickling hemoglobinopathies. Red cells from normal black subjects had more SOD amount and activity than normal whites (1.77 U/mg Hb and 2.96 micrograms/mg Hb vs. 1.47 U/mg Hb and 2.64 micrograms/mg Hb, respectively) or blacks with SS Hb or other sickling hemoglobinopathies. Patients with more severe manifestations of SS Hb had lower levels of SOD activity than those with milder symptoms but had the same amount of enzyme protein. Individuals with sickle trait had amounts and activities of SOD comparable to black controls. An alteration in defense to free radical oxygen may play a role in the severity of symptoms experienced by patients with homozygous sickle cell disease.     

Ultrastructural findings of congenital dyserythropoietic sickle cell beta thal-associated anemia.

The ultrastructural findings of erythroblasts and reticulocytes in one case of congenital dyserythropoiethic anemia (CDA) associated with a haemoglobinopathy, sickle cell beta thalassemia minor (Type V CDA), is described. The observations can be summarized as follows: 1) A lot of large breaks are present in the erythroblast nuclear envelope. 2) Nuclear membrane evaginations are filled with dense loose chromatin. 3) Electron-transparent areas (moth eaten chromatin) are evident in dense chromatin. 4) Electron-dense granular material, related to altered haemoglobin chain storage, is evident in the nucleus and in the cytoplasm. 5) Iron deposits are present in mitochondrial matrix. 6) Myelinic figures are present in reticulocyte cytoplasm. For the first time the ultrastructural findings in this type of associated CDA are described and related to the double origin of clinical symptoms.     

The first eukaryote cell: an unfinished history of contestation

The eukaryote cell is one of the most radical innovations in the history of life, and the circumstances of its emergence are still deeply contested. This paper will outline the recent history of attempts to reveal these origins, with special attention to the argumentative strategies used to support claims about the first eukaryote cell. I will focus on two general models of eukaryogenesis: the phagotrophy model and the syntrophy model. As their labels indicate, they are based on claims about metabolic relationships. The first foregrounds the ability to consume other organisms; the second the ability to enter into symbiotic metabolic arrangements. More importantly, however, the first model argues for the autogenous or self-generated origins of the eukaryote cell, and the second for its exogenous or externally generated origins. Framing cell evolution this way leads each model to assert different priorities in regard to cell-biological versus molecular evidence, cellular versus environmental influences, plausibility versus evolutionary probability, and irreducibility versus the continuity of cell types. My examination of these issues will conclude with broader reflections on the implications of eukaryogenesis studies for a philosophical understanding of scientific contestation.     

Responses of normal and sickle cell hemoglobin to S-nitroscysteine: implications for therapeutic applications of NO in treatment of sickle cell disease

Factors which govern transnitrosation reactions between hemoglobin (Hb) and low molecular weight thiols may define the extent to which S-nitrosated Hb (SNO-Hb) plays a role in NO in the control of blood pressure and other NO-dependent reactions. We show that exposure to S-nitrosylated cysteine (CysNO) produces equivalent levels of SNO-Hb for Hb A(0) and sickle cell Hb (Hb S), although these proteins differ significantly in the electron affinity of their heme groups as measured by their anaerobic redox potentials. Dolphin Hb, a cooperative Hb with a redox potential like that of Hb S, produces less SNO-Hb, indicating that steric considerations outweigh effects of altered electron affinity at the active-site heme groups in control of SNO-Hb formation. Examination of oxygen binding at 5-20 mM heme concentrations revealed increases due to S-nitrosation in the apparent oxygen affinity of both Hb A(0) and Hb S, similar to increases seen at lower heme concentrations. As observed at lower heme levels, deoxygenation is not sufficient to trigger release of NO from SNO-Hb. A sharp increase in apparent oxygen affinity occurs for unmodified Hb S at concentrations above 12.5 mM, its minimum gelling concentration. This affinity increase still occurs in 30 and 60% S-nitrosated samples, but at higher heme concentration. This oxygen binding behavior is accompanied by decreased gel formation of the deoxygenated protein. S-nitrosation is thus shown to have an effect similar to that reported for other SH-group modifications of Hb S, in which R-state stabilization opposes Hb S aggregation.     

Trace element distribution in the hair of some sickle cell anemia patients and controls

Hair samples of some young sickle cell anemia (SCA) and control patients in Nigeria were analyzed for 12 elements, viz, Se, Hg, Cr, Fe, Zn, Co, Cu, Br, As, Sb, Na, and Sc, using Instrumental Neutron Activation Analysis (INAA).

With the exception of Cu, which was found to be significantly higher in the hair of SCA patients (at the 0.05 level of the t-test), there were generally no significant differences in elemental concentrations within the two groups. A preliminary study of the elemental contents of the fingernails of the same subjects showed a higher abundance of most of the elements in nail than in hair. These preliminary results were compared with similar studies from some other parts of the world.

     

An explanation for the efficacy of procaine in the treatment of sickle cell anaemia

A study has been carried out into the effects of procaine on the activities (Na+,K+)- and (Ca2+,Mg2+)-ATPases of the human erythrocyte membrane. In general, procaine inhibited both types of ATPases activities but with characteristic inhibition profiles and varying degrees of efficacy. In addition, the effects of procaine on the transport of K+ and phosphate ions across the membrane of the human erythrocyte were monitored and compared. Procaine was found to stimulate K+ release and to inhibit phosphate uptake. At low concentrations, both processes were found to be concentration dependent. Stimulation of K+ release and inhibition of phosphate uptake reached plateaus at concentrations of 50 and 150 mM, respectively. The antisickling effect of procaine was explained mainly in the light of the changes it induces in the activities of membrane bound ATPases and the permeability properties of the erythrocyte membrane to cations and anions.