Linkage relationships between beta- and delta-structural loci and African forms of beta thalassaemia

Five families are described in which there have been matings between individuals doubly heterozygous for beta thalassaemia and the delta-chain variant haemoglobin A2' to normal persons. In all there were 24 informative offspring. There were no crossovers between the beta-thalassaemia and delta-chain loci; in three of the families the genes were linked in cis and in two families the genes were found in trans.Together with previously reported families there have now been 58 opportunities for crossing over between the beta-thalassaemia and delta-chain loci and there have been two possible and one highly probable crossovers. Of the total of 9 families reported to date 4 have had the genes for beta thalassaemia and Hb A2' in cis and 5 in trans. These findings are contrasted with the findings in families where a beta-chain structural variant and Hb A2' have been observed together and these genes have always been found in trans and never in cis. The reasons for linkage disequilibrium of this type are discussed. It is concluded tentatively that the distance between the delta-structural and beta-thalassaemia loci is greater than that between the delta-structural and beta-structural loci. To date this conclusion can only be applied to the beta+ -thalassaemia and beta-thalassaemia genes as found in the African population, since this is the only population with a high incidence of delta-chain mutants which allow linkage analysis of this type to be carried out. (AU)

Haematological levels in Jamaican infants

A longitudinal study of 300 infants from birth to 1 year of age was carried out in Kingston, Jamaica. Haemoglobin levels were estimated 7 times during the year and serum iron and total iron binding capacity once. Hb electrophoresis was performed. In singleton children with Hb genotype AA, AS, or AC, and of birthweight 2.5kg or over, Hb levels were low after 3 months of age. These low levels were associated with iron deficiency, which was probably due to poor iron stores at birth followed by poor iron intake or absorption. It was not possible to determine whether folic acid deficiency or protein deficiency was also important. Hb levels varied with age, socioeconomic class, birthweight, sex, and rate of weight gain. The growth and health of 4 girls with homozygous sickle cell disease is mentioned.(AU)

Oxygen transport in sickle cell anemia

Oxygen transport and delivery in sickle cell anemia are discussed in terms of hemodynamics and blood oxygen affinity. The current concepts of the regulation of the hematocrit value by the oxygen pressure on the venous side of the renal capillary are reviewed, and the concept of 'anemia' redifined. The marked right shift in the oxygen dissociation curve of sickle cell anemia blood is analyzed in terms of the sickling process, the hemolytic anemia, and increase in 2.3 diphosphoglycerate. The clinical implications of this right shift in perpetuating sickling are discussed in the light of its possible correction by treatment with sodium cyanate (AU)

Erythrocyte Hb-S concentration: an important factor in the low oxygen affinity of blood in sickle cell anemia

The blood in sickle cell anemia has a very low oxygen affinity and, although 2,3-diphosphoglycerate (2,3-DPG) is increased, there is doubt as to whether this is the only factor responsible. In this study of 15 patients with sickle cell anemia (Hb SS) no correlation was found between oxygen affinity (P 50 at pH 7.13) and 2,3-DPG in fresh venous blood. Whole populations of Hb SS erythrocytes were therefore separated, by an ultracentrifuge technique, into fractions of varying density. The packed red cell column was divided into three fractions; a bottom fraction rich in deformed cells or irreversibly sickled cells (ISC), with a very high mean corpuscular hemoglobin concentration (MCHC); a middle fraction containing cells but free of deformed cells. Oxygen affinity was shifted to the right in all layers (mean P 50 (pH 7.13)ñ1SD: top 46.3ñ2.9 mm Hg; middle 49.8ñ4.9 mm Hg; bottom 61.0ñ5.8mm Hg) compared with normal blood (top 32.1ñ0.7 mm Hg; bottom 30.1ñ0.5 mm Hg). 2,3-DPG was increased in the top fraction, but was low or normal in the bottom fraction (top 21.8ñ3.4 æmol/g Hb; middle 17.7ñ2.2 æmol/g Hb; bottom 13.8ñ3.1 æmol/g Hb; normal whole blood 14.3ñ1.2 æmol/g Hb). The level of 2,3-DPG in top fractions could not account for the degree of right shift of P 50, and in the middle and bottom fractions the even greater right shifts were associated with lower levels of 2,3-DPG had a higher, but still abnormally low, oxygen affinity. A strong relationship was found between oxygen affinity and MCHc. The fractions with the greatest right shift in P 50 had the highest MCHC (top 32.4ñ2.0; middle 36.2ñ3.1; bottom 44.6ñ3.2 g/100 ml, respectively) and the plot of P 50 vs. MCHC showed a positive corelation (r=0.90,P<0.001). The red cell popualtion in sickle cell anemia is not homogeneous but contains cells of widely varying HB F content, 2,3-DPG, but they also have the highest concentration of Hb S. The dense, deformed cell called the ISC is but the end stage in a process of membrane loss and consequent increase in hemoglobin concentration. The P 50 of Hb SS blood is, to a large extent, determined by the presence of these cells (r=0.85, P<0.001). Increased concentration of Hb S in the cell favors deoxygenation and crystallization even at relatively high Poý. Lowered affinity for oxygen appears to be closely associated with Hb S concentration and not with 2,3-DPG content (AU)

Absorption of iron from maize (zea mays L.) and soya beans (Glycine hispida Max.) in Jamaican infants

The absorption of iron from 59Fe-labelled maize and soya-bean preparation was measured by whole-body counting in forty-two apparently healthy Jamaican infants and compared with the absorption of ferrous ascorbate. The mean absorption of Fe from maize was 4.3 percent and from soya bean baked at 300§, 9.4 percent, compared with 28.5 percent for ferrous ascorbate. In a group of children given boiled soya beans the mean absorption of Fe was 2.8 percent, and of ferrous ascorbate 16.7 percent. There was much variability between replicate tests made on the same child at intervals of 1-2 weeks. The absorption of food Fe was not increased in children who were considered to be anaemic (haemoglobin less than 100 g/l) or Fe-deficient (serum Fe less than 500 æg/l and saturation of total Fe-binding capacity less than 15 percent). The poor availability of Fe in maize meal, which is a staple food of children in Jamaica, is probably an important cause of the high prevalence of Fe-deficiency anaemia (AU)

Haemoglobin, iron, folate and vitamin B12 levels in pregnant and lactating women in Jamaica

An island-wide survey of 167 unselected pregnant or lactating Jamaican women revealed a 45 per cent incidence of iron deficiency anaemia during pregnancy and the first six months of lactation. A high incidence of eosinophilia, probably the result of intestinal parasitism, was noted. There was no evidence that folate deficiency contributed to the anaemia in these women although red cell folate levels fell throughout pregnancy and the first six months of lactation. Two women who had uncomplicated folate deficiency were not anaemic. Serum B12 levels were found to be considerably higher than those reported in European women during pregnancy and lactation and the lower levels were found in the second rather than the third trimester (AU)

Combination chemotherapy in the management of lymphoma - abstract

This preliminary report describes our experience with a modification of MOPP regime (nitrogen mustard, vincristine, prednisone and procarbazine) in 21 patients with advanced (Stage III and IV) malignant lymphoma. Six patients had Hodgkin's disease; 9 lymphosarcoma; and 4 reticulum cell sarcoma. The desease was unclassifiable in 2 cases. There were 6 fatalities, none of which could be attributed to therapy. Several side effects of therapy occurred but none of these were serious. Seven patients defaulted for a variety of reasons. Eight patients are still undergoing treatment and 3 of these are at present in remision. The number of patients is at present too small for any firm conclusions to be drawn, but it is probably worthwhile continuing with this form of therapy. However, careful selection of patients is essential, particularly because of the high rate of default (AU)

Haemoglobin H disease caused by alpha-thalassaemia and a new abnormal haemoglobin with an elongated alpha-chain (Hb constant spring) - abstract

Of the 120 or so variants of human haemoglobin polypeptide chains so far described, nearly all are the result of the substitution of a single amino acid residue for another, or a deletion of one or more residues in the chain, caused by a point mutation in the codens of the chromosomal DNA. Hb H disease is also a genetically determined haemolytic anaemia, common in Orientals, but is caused by a reduced rate of synthesis of the O-chain of normal haemoglobin, resulting in an excess of á-chains (Hb H). A study of a Chinese family in Jamaica has revealed a slow moving haemoglobin in three children who have clinical haemoglobin H disease and in their fathers and siblings who have no haematological abnormality. The mothers have classical O-thalassaemia trait, as do some of the other siblings. Detailed biochemical analysis of this variant has shown that the O-chain is abnormal and is elongated by the addition of 31 residues to the 141 of the normal OA-chain. The extra residues are continuous with the normal C-terminal (O-141 Arg.) Biosynthetic studies, incorporating H(to 3rd power) leucine have indicated a low rate of synthesis for this abnormal chain. Interest lies in the nature of the genetic defect which could produce this abnormalty. While considering several hypotheses, the authors favour the theory that the genetic codon for 'end of chain' is the site of a mutation. This hypothesis is strengthened by finding Glutamine to be the next residue after the C-terminal Arginine. This extra piece of chain bears no resemblance to any known human globin chain sequence, so that it is unlikely that it has resulted from an unequal crossing over in a similar way to the Lepore haemoglobins. It may be that the messenge RNA for the normal OA-chain is longer than is required to direct synthesis of the chain. Further studies are in progress to try and define the nature of this genetic defect (AU)

Normal pregnancy in a patient with multiple myeloma and sickle cell anaemia

A 39-year-old negro woman with sickle cell anemia, 32 weeks pregnant, was found to have multiple myeloma. The patient proceeded to full term normal delivery, and there was little deterioration in the following three years. The patient died 3 years and 8 months after delivery. The haematological and biochemical data are presented and problems of therapy in this case are discussed (AU)

Haemoglobin-H disease due to a unique haemoglobin variant with an elongated O-chain

The clinical and genetic properties of an unusual O-chain variant of human haemoglobin are described. It constitutes less than 1 percent of the total haemoglobin in heterozygotes and, when inherited together with an O-thalassaemia gene, produces the clinical picture of haemoglobin-H disease. Preliminary structural studies indicatge that, in addition to the 141 aminoacid residues which constitute the normal O-chain, this variant has about 31 extra residues attached to the C-terminal end.(SUMMARY)

Hemoglobin O Arab in four negro families and its interaction with hemoglobin S and hemoglobin C

Hemoglobin O Arab (O2á2 121 Glu leads to Lys) was found in 25 members of four apparently unrelated Negro families in the West Indian island of Jamaica. In each family the propositus had Hb SO disease. Two cases had been mistakenly diagnosed as Hb SC disease. Two persons heterozygous for both Hb C and Hb O Arab were found in these families, and Hb O Arab á thalassemia in one other relative. The clinical course and symptomatology of Hb SO disease is comparable to that in Hb SD(O2á2 121 Glu leads to GluNH2) disease and more severe than Hb SC disease. In vitro mixtures of Hb O Arab and Hb S change from a liquid to a gel phase at total hemoglobin concentrations weaker than those required to gel pure Hb S, whereas mixtures of Hb C require a stronger total hemoglobin concentration before gelling will occur. Oxygen dissociation studies on red cells containing Hb SO show a homozygous sickle-cell anemia and outside the range for subjects with sickle-cell Hb C disease.(AU)

Sickle cell Hb oarab disease - abstract

An infant presented with megaloblastic anaemia of folate deficiency complicating a haemolytic anaemia with hepatosplenomegaly. At first, the laboratory investigations indicated Hb SC disease but, as it is very unusual to see such severe clinical effects in this haemoglobinopathy, especially in infancy, further investigations were carried out which demonstrated a haemoglobin electrophoretically similar to Hb C but having certain distinguishing characteristics. This Hb was compared with Hb C and Hb E on various electrophoretic media. The tryptic peptide maps (prepared at the Institute for Anthropology, Leiden, Netherlands, by W. de Jong) showed an abnormality in beta Tp XIII and amino acid analysis further revealed that lysine had replaced the normal glutamic acid at the 121st residue in the beta chain. This substitution has been previously described for Hb O Arab. In the helical notation of Perutz this position, in the peptide chain, lies between the G and H helices, GH4. The glutamyl residue is invariant at this site in all human haemoglobin chains. Four mutations have been described at this site. One in the gamma chain, one in the alpha chain and two in the beta chain. The other one in the B chain is Hb D Punjab, and this also causes a more severe type of haemoglobinopathy when inherited together with Hb S. Another infant, presenting in a similar way, was found to have the same defect, Hb S with Hb O Arab. The mother of this second case has Hb O-Thalassaemia. A search was then carried out in patients who had previously been diagnosed as SC disease. Two further cases of Hb SO disease were found, making four families in all. The clinical features of Hb SO disease appear to be more like those of homozygous sickle cell desease than SC disease. There are more sickled cells in the blood, a lower haematocrit and haemoglobin level, a greater shift in oxygen dissociation curve and a shorter red cell survival. Hb O Arab is apparently not uncommon in Jamaica and all cases of suspected Hb SC disease who have a clinical course more like SS disease should be further investigated (AU)

Hemoglobin O Arab in four negro families and its interaction with Hemoglobin S and Hemoglobin C

Hemoglobin O Arab was found in 25 members of four apparently unrelated negro families in the West Indies of Jamaica. In each family the propositus had Hb SO disease. Two cases had been mistakenly diagnosed as Hb SC disease. Two persons heterozygous for both Hb C and Hb O Arab were found in these families, and Hb O Arab áthalassemia in one other relative. The clinical course and symptomatology of Hb SO disease is incomparable to that in Hb SD (O2á2121 Glu-> GluNH2) disease and more severe than Hb S2C2 disease. In vitro mixtures of Hb O Arab and Hb S change from a liquid to a gel phase at total hemoglobin concentrations weaker than those required to gel pure Hb S, whereas mixtures of Hb S with Hb A or Hb C require a stronger total hemoglobin concentration before gelling will occur. Oxygen dissociation studies on red cells containing Hb SO show a lowered oxygen affinity comparable to that found in homozygous sickle-cell anemia and outside the range for subjects with sickle-cell Hb C disease.(AU)

Beta-thalassaemia Hb E disease

B-thalassaemia Hb E disease occurring in a young Indian girl in Jamaica is described. Three years after splenectomy there is sustained clinical improvement and blood transfusions have not been necessary. The indications for splenectomy are discussed in relation to the pathology of the anaemia as revealed by radio-isotope studies of blood volume and red cell survival (AU)

A comparison between the characteristics of Jamaican adults with normal hemoglobin and those with sickle cell trait

In surveys of representative samples of Jamaicans aged 35-64 years living in rural and suburan communities, no significant differences in heights, weights, hematological indices, cardiothoracic ratios, blood pressures, glycosuria, proteinuria, parity or electrocardiographic abnormalaties were apparent between 167 subjects with the sickle cell trait, AS, and 1,282 subjects with normal hemoglobin, AA. Older women with the trait had a significantly higher prevalence of bacteriuria without other evidence of urinary tract pathalogy. The findings suggest that the trait is not appreciably associated with chronic disease. (AU)

Absorption of dietary iron and ferrous ascorbate by infants - abstract

There is no substantial evidence in adults that only a small proportion of the iron, chemically measured, in various foodstuffs is available for absorption. Hussain et al showed that only about 4.5 per cent of the iron present in wheat is absorbed by a normal adult whereas 12 per cent of the iron in ingested blood is absorbed. Even in the presence of iron deficiency the absorption of iron from carbohydrate foods is only marginally improved. In adults the iron absorbed from cooked soybean meal has been found to be better than that from any other vegetable source, and as the iron content of this food stuff is relatively high, it could be a useful source of iron for the infant. Absorption tests were carried out in 'normal' infants and treated malnourished infants, 9 months to 15 months old, using a whole body radioactivity counter and feeding corn or soybean meal which had radioactive iron (Fe59) incorporated into the plants during cultivation. The meals were arranged to contain 0.5 mg of iron and radioactivity remaining in the body at 7 days was used to calculate the percentage of iron absorbed. Test were repeated in the fasting subjects using ferrous sulphate and ascorbic acid mixture (ferrous ascorbate) at a dose level of 0.5 mg of iron per test. Only small amounts of radioactivity were administered, in the order of 0.1 æCi and the efficiency of the counter was such that at the 5 per cent absorption level, this could be measured with an accuracy of plus or minus 2.5 per cent of this figure. Cornmeal was given to 15 infants and an average absorption of 3 per cent of the iron was recorded compared to 24 per cent for ferrous ascorbate. In the first study in 10 infants given soybean meal, the mean absorption was 2.8 per cent but in this group the soybean meal was simply boiled and given as a porridge. In a further 9 infants the soybean porridge was baked at 300 degree F as a cake and then broken up and administered mixed with water. In this series the average absorption was 8 per cent which is more in keeping with the reported results in adults. In a further 6 infants the mean absorption of labelled haemoglobin iron was 14.4 per cent. During the course of the study it was noted that a pyrexia at the time of the absorption test was associated with a very low absorption of iron both from food and from ferrous ascorbate. Absorption measured in the same infant before or after the pyrexia was at expected levels for the iron status. Absorption was related to the haemoglobin P.C.V. and serum iron and tranferrin levels in all these infants. Iron absorption was usually but not always higher in those infants who were judged to be iron deficient(AU)

The irreversibly sickled cell: a determinant of haemolysis in sickle cell anaemia

Red cell survival was estimated in a group of adult sickle cell anaemia patients using the 51Cr technique. Counts of irreversibly sickled cells were performed on thin coverslip preparations of capillary blood. These counts are relatively constant within the same individual but show marked variations between individuals. A significant correlation has been demonstrated between the irreversibly sickled cell count and the red cell survival. This correlation does not apply to sickle cell anaemia patients with splenomegaly in whom the irreversibly sickled cell count is always low (AU)

Haemoglobin concentration, eosinophilia and intestinal helminths in children in rural Jamaica

Investigations on haemoglobin and haematocrit values, eosinophils and faecal helminth eggs in rural Jamaican infants and children are summarized. Haemoglobin levels rose from 10.6g percent at about the fifth month of life to 10.9g percent at one year and thereafter climbed slowly to 12.2g percent at 6 years and remained at this level to 15 years. Values for haematocrit and MCHC behaved similarly. The mean haemoglobin levels were about 1.0g percent below optimal values but about 2.0g percent above those reported from Gambia. Severe anaemia was rare but minor degrees of iron deficiency and, in the first year of life, of folic acid deficiency, may be common. 2 cases of sickle-cell anaemia and one of thalassaemia major were seen. Neither malaria, which has been eradicated nor hookworm is now an important cause of anaemia in Jamaica. Helminth eggs in stools were not common in the first and second years but were present in 60 percent of children in the third and fourth years. Ascaris lumbricoides was the most prevalent, giving rise to the heaviest concentration of eggs, followed by Trichuris trichiura. A few hookworm eggs were found in about 10 percent of children over 2 years. In one study involving 160 children aged about 3 years, no relationship was found between helminth eggs and haemoglobin levels, heiaghts, weights or symptoms which might be related to infection. Helminthiasis, although extermely common, does not appear to be a major cause of ill-health or of failure to thrive among Jamaican children. Eosinophils were numerous in the latter half of the second year of life and by 5 years, on average, comprised 13.5 percent of all white cells. Although an aetiology other than intestinal helminthiasis in not obvious, a correlation between eosinophils and faecal helminth eggs could not be demonstrated. Some children may have been infected with Toxocara canis (Summary)

Alpha thalassaemia phenotypes

The effects of deficient alpha chain synthesis at the clinical and subclinical level are illustrated by observations on 17 members of a family of mixed Chinese-Scottish-Negro origins. The presence of beta thalassaemia and its variants and the haemoglobin structural mutants have been excluded by presently available methods. The family includes 5 cases of Hb H disease, 3 cases of classical alpha thalassaemia trait and two adult subjects presumed to carry "silent" alpha thalassaemia gene. Clinical and laboratory aspects are presented (AU)