bluuebunny/crossref_metadata_2025 huggingface dataset:
The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor
Authors: Schlisio Susanne , Kenchappa Rajappa S. , Vredeveld Liesbeth C.W. , George Rani E. , Stewart Rodney , Greulich Heidi , Shahriari Kristina , Nguyen Nguyen V. , Pigny Pascal , Dahia Patricia L. , Pomeroy Scott L. , Maris John M. , Look A. Thomas , Meyerson Matthew , Peeper Daniel S. , Carter Bruce D. , Kaelin William G.
Published: March 2008

VHL, NF-1, c-Ret, and Succinate Dehydrogenase Subunits B and D act on a developmental apoptotic pathway that is activated when nerve growth factor (NGF) becomes limiting for neuronal progenitor cells and requires the EglN3 prolyl hydroxylase as a downstream effector. Germline mutations of these genes cause familial pheochromocytoma and other neural crest-derived tumors. Using an unbiased shRNA screen we found that the kinesin KIF1Bβ acts downstream from EglN3 and is both necessary and sufficient for neuronal apoptosis when NGF becomes limiting. KIF1Bβ maps to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors including neuroblastomas. We identified inherited loss-of-function KIF1Bβ missense mutations in neuroblastomas and pheochromocytomas and an acquired loss-of-function mutation in a medulloblastoma, arguing that KIF1Bβ is a pathogenic target of these deletions.
Erythrocytosis in Emphysema
Authors: FREEDMAN B. J. , PENINGTON D. G.
Published: March 2008

Marked erythrocytosis is frequently seen in hypoxia due to high altitudes and cyanotic congenital heart disease (Hurtado, Merino and Delgado, 1945) but is relatively uncommon in association with chronic respiratory failure (Baldwin, Cournand and Richards, 1949). This discrepancy has exercised a number of writers. Wilson, Borden and Ebert (1951) have proposed that bronchial infection may depress the erythropoietic response of the bone marrow in patients with chronic bronchitis and emphysema and Ratto, Briscoe, Morton and Comroe (1955) have postulated depression of erythropoiesis by carbon‐dioxide retention. Simpson (1957) found evidence of bleeding in a number of his emphysematous subjects and suggested that concealed haemorrhage may be of importance in modifying haematological changes in respiratory hypoxia.

More recently, Shaw and Simpson (1961) and Lertzman, Israels and Cherniack (1962) have proposed that expansion of plasma volume accompanying respiratory failure may account for the apparent infrequency of erythrocytosis in emphysema, but the view that the erythropoietic response to hypoxia is normal in emphysema is based on evidence which is not entirely satisfactory. Thus Shaw and Simpson compared the red‐cell mass in English subjects with emphysema with that of native Peruvian Indians living at high altitudes, a comparison which assumes similarity of nutrition and incidence of conditions such as intestinal infestation. Lertzman and associates compared the red‐cell mass in respiratory failure with that in patients with hypoxia due to other causes. In the majority of these latter patients, the hypoxia was due to obesity but the red‐cell mass was expressed per kilogram of body weight rather than as a function of height or lean‐body mass. In each of these studies the red‐cell mass in emphysema varied from within the normal range to more than double this figure in patients with hypoxia of comparable severity. The fact that many chronically cyanosed emphysematous patients show no significant increase in red‐cell mass remains unexplained and warrants further attention.

In the present investigation a small group of severely disabled patients was chosen for study. All suffered from chronic bronchitis and emphysema with persistent cyanosis during remission from acute pulmonary infection. Four exhibited the conventional haematological changes of secondary polycythaemia, whilst another four were similarly disabled but showed no such changes in the peripheral blood. The two groups were compared in an attempt to account for the apparent failure of erythropoietic response to hypoxia in the latter. The investigation was designed to ascertain whether the defect lay in the elaboration of erythropoietin, the humoral mediator of the hypoxic stimulus to the bone marrow, or in the response of the bone marrow to this humoral stimulus.
The Relation of Alkali‐Resistant Haemoglobin in Thalassaemia and Abnormal Haemoglobin Syndromes to Foetal Haemoglobin
Authors: Sturgeon P. , Schroeder W. A. , Jones R. T. , Bergren W. R.
Published: March 2008

Alkali‐resistant haemoglobin (haemoglobin F or foetal haemoglobin) normally constitutes the major haemoglobin component of the foetus; it is also present in gradually decreasing amounts through the first year of life. In the older individual, less than I per cent of the haemoglobin is of the foetal type; normally, most of the remaining haemoglobin is the adult variety—haemoglobin A.

Alkali‐resistant haemoglobin is found in greater than normal concentrations in several blood dyscrasias. In patients with thalassaemia major, it is invariably increased and frequently constitutes the major haemoglobin component (Fessas, 1959; Beaven, Ellis and White, 1961). On the other hand, in those who are homozygous for an abnormal haemoglobin, 20 per cent or less of the haemoglobin, as a rule, is alkali‐resistant and increased percentages are not invariably found (Beaven et al., 1961; Rucknagel and Neel, 1961). The abnormal haemoglobin syndromes are most characterized by the presence of electrophoretically abnormal haemoglobin(S), although alkali‐resistant haemoglobin may be present. Neither in thalassaemia major nor in thalassaemia minor, despite the frequently increased quantity of haemoglobin A2 (Fessas, 1959), have electrophoretically abnormal components been found. Both the thalassaemia and abnormal haemoglobin syndromes, have common clinical, haematological, biochemical, genetic and anthropological features. It has not seemed unlikely that thalassaemia is based on a genetically determined abnormality similar to that resulting in the abnormal haemoglobin syndromes; it is assumed, however, that a structurally modified haemoglobin is electrophoretically undetectable (Itano and Pauling, 1961).

Because an electrophoretically abnormal haemoglobin is absent in thalassaemia, one might consider that the alkali‐resistant haemoglobin is, in fact, the abnormal haemoglobin. This subject has been reviewed by Beaven and Gratzer (1959) who cite abundant biochemical and immunological evidence to the contrary. Nevertheless, recent publications report biochemical and immunological differences in the foetal haemoglobin of thalassaemia compared to that from the normal newborn (Derrien, 1959; Diacono and Castay, 1959). Studies on the structure of alkali resistant haemoglobin in thalassaemia and abnormal haemoglobin syndromes, however, have not been available.

Structurally, haemoglobin A is composed of a pair of α chains and a pair of β chains. In haemoglobin F, γ chains occur instead of β chains. From genetic evidence, the production of the three types of chain appears to be under the control of sets of allelic genes at separate loci; this subject has been reviewed recently (Rucknagel and Neel, 1961). The abnormal haemoglobins are products of mutant genes at the α and β chain loci. A single amino acid
The First Observation of an Abnormal Haemoglobin in a Jewish Family: Haemoglobin Beilinson
Authors: Vries A. de , Joshua H. , Lehmann H. , Hill R. L. , Fellows R. E.
Published: March 2008

Bothβ‐thalassaemia and α‐thalassaemia have been described in Oriental Jews (Matoth, Shamir and Freundlich, 1955; Ramot, Sheba, Fisher, Ager and Lehmann, 1959) and an abnormal methaemoglobin has been found by Mani, Kende and Ramot (1962) in a Polish Jewish family. No other abnormal adult haemoglobin has, however, yet been found in either Oriental or Western Jews. We should like to report a haemoglobin variant in an Ashkenazi (Western‐Jewish) family that came to Israel from Poland. In addition to its being an unusual observation in Jews, the variant itself has not been observed before. It resembles in its electrophoretic behaviour the haemoglobin L described in Indians by Ager and Lehmann (1957), but differs from L in its chromatographic properties and in the location of the mutational change within the globin moiety.
Platelet Clumping in vitro
Authors: Mitchell J. R. A. , Sharp A. A.
Published: March 2008

Osler (1874), Hayem (1878) and Eberth and Schimmelbusch (1886) showed that the process of blood clotting initiated platelet clumping in shed blood, and later workers (Roskam, 1922; Zucker and Borrelli, 1955; Bergsagel, 1956; Bounameaux, 1957) have shown that various coagulation factors released during the clotting process can produce this platelet clumping. There has, however, been a growing body of evidence to suggest that other mechanisms, not directly related to clotting, could also initiate platelet clumping (Sharp, 1958, 1961), and the existence of one such mechanism was confirmed by the observation that a protein‐free, heat‐stable, dialysable extract of human red cells could increase platelet adhesiveness (Hellem, 1960). Hellem called the active principle of his extract ‘Factor R’ fractionation of the extract showed that the active agent was adenosine diphosphate (ADP) and it was found that when this substance was added to platelet‐rich citrated plasma in concentrations as low as 0.02 μg./ml., platelet clumping was produced (Gaarder, Jonsen, Laland, Hellem and Owren, 1961).

We have studied this clumping phenomenon in vitro, tested other substances for clumping activity and searched for materials which would modify the process. This paper reports the results of these studies.
Haemophilia, Christmas Disease and the Xg Blood Groups
Authors: Harrison J. F.
Published: March 2008

In1954 the Medical Research Council and the Ministry of Health jointly asked various clinics and laboratories to act as reference centres for patients with hereditary bleeding diseases. In the following study, the register at one such centre has been used to trace families who might help determine the degree of linkage between haemophilia and Christmas disease and the X‐borne Xg blood groups. Information has also been obtained on the incidence of the two diseases.

Mann, Cahan, Gelb, Fisher, Hamper, Tippett, Sanger and Race (1962) reported the discovery of the Xg system. Two alleles, Xgaand Xg, are so far known; the antigen Xgais a dominant character and occurs in about 66 per cent of the male and 88 per cent of the female white population. Accounts have now appeared of attempts to measure linkage between Xg and colour blindness (Jackson, Symon and Mann, 1962), glucose‐6‐phosphate dehydrogenase (G6PD) deficiency (Adam, Sheba, Sanger, Race, Tippett, Hamper, Gavin and Finney, 1963), Duchenne muscular dystrophy (Clark, Puite, Marczynski and Mann, 1963), and haemophilia and Christmas disease (Davieset al., 1963). Lindsten, Fraccaro, Polani, Hamerton, Sanger and Race (1963) used the Xg blood groups to study 14 patients with an isochromosome for the long arm of the X, and suggested, with certain reservations, that the deutan colour blindness and Xg loci both lie on the short arm of the X chromosome.
The Marrow Reserve of Eosinophils
Authors: Hudson G.
Published: March 2008

The quantitative methods developed in this laboratory (Yoffey, 1960) have already been used to demonstrate the large ‘reserve’of mature and almost mature eosinophils in normal bone marrow and to study changes which it undergoes in the foreign protein response (Hudson, 1960, 1963). These studies indicated that large numbers of eosinophils are discharged from the marrow reserve during the first 24–30 hours following the re‐exposure of a sensitized guinea‐pig to foreign protein. Further experiments showed that the marked increase in the level of circulating eosinophils, which is usually observed in these circumstances, can be prevented by the administration of hydrocortisone, and the question arose of the mechanism by which cortical hormones could exert such an effect. Quantitative studies have been carried out in an attempt to throw light on this, and the results are the basis of the present communication.

It was noted that Samter, Erickson and Kofoed (1952) and Speirs (1958) had observed that ACTH and cortisone may depress or inhibit the peripheral eosinophilia in animals during the foreign protein response, and that Essellier and Wagner (1952) had reported no changes in the percentage of marrow eosinophils in patients in whom a high‐grade peripheral eosinophilia had been abolished by ACTH. There appeared, however, to have been no previous quantitative studies of the bone marrow in such circumstances.
Familial Pyridoxine‐Responsive Anaemia
Authors: Bourne M. S. , Elves M. W. , Israëls M. C. G.
Published: March 2008

Pyridoxine‐Responsive anaemia as a naturally occurring disease in man was first described by Harris, Whittington, Weisman and Horrigan in 1956. Since then 26 further cases have been described in the literature. Most reports concern single cases and suggest that pyridoxine‐responsive anaemia is not a single disease entity but rather a syndrome with variable aetiology. In only three instances could the disease have been inherited.

We report here details of a family in which six members suffered from pyridoxine‐responsive anaemia. We have investigated 83 members of the family and studied in detail the six affected members.
Studies on Desferrioxamine in Relation to the Absorption of Iron
Authors: Bannerman R. M. , Malpas J. S.
Published: March 2008

In Conditions of iron overload, and particularly primary haemochromatosis, any agent which would prevent or diminish the absorption of iron in the diet might play a useful part in therapy.

When desferrioxamine was first introduced it was suggested that this chelating agent, which has a very strong affinity for iron, might prevent the absorption of iron from the diet.

The present studies were designed to investigate the effect of desferrioxamine on the absorption of inorganic iron and haemoglobin iron labelled with 59Fe. In addition the fate of labelled ferrioxamine given by mouth was studied.
Red‐Cell Enzymes and Co‐Enzymes in Non‐Spherocytic Congenital Haemolytic Anaemias
Authors: Loder P. Bronwen , De Gruchy G. C.
Published: March 2008

The non‐spherocytic congenital haemolytic anaemias were classified on haematological grounds by Selwyn and Dacie (1954) into two main types—Type I and Type II. It now seems that Type I cases probably form a heterogeneous group while the Type II cases are probably a homogeneous group (de Gruchy, Santamaria, Parsons and Crawford, 1960). Robinson, Loder and de Gruchy (1961) presented evidence of impairment of cell metabolism in both Type I and Type II cases and suggested that in Type II cases there was an enzymatic defect in glycolysis beyond the stage of 2,3‐diphosphoglycerate (2,3‐DPG) synthesis. This was confirmed by the demonstration by Tanaka, Valentine and Miwa (1962) of a pyruvate kinase (PK) deficiency in Type II cases.

This paper reports observations in a number of patients with Type I or Type II non‐spherocytic haemolytic anaemia on (a) the activities of the enzymes of the Embden–Meyerhof glycolytic pathway, (b) the activities of the enzymes glucose‐6‐phosphate dehydrogenase and glutathione reductase, (c) the values of the co‐enzymes diphosphopyridine nucleotide (DPN) and reduced diphosphopyridine nucleotide (DPNH) and (d) the values of reduced glutathione. The significance of the findings is discussed together with their relevance to the classification of these anaemias.
Lymphography with Radioactive Contrast Medium in Lymphosarcoma and Reticulosarcoma
Authors: Chiappa S. , Galli G. , Palmia C. , Severini A.
Published: March 2008

Since 1961 we have been using a method of lymphography based on the intralymphatic injection of an oily contrast medium (Lipiodol Fluide) rendered radioactive by replacement of the inactive iodine by its isotope 131I (Chiappa, Galli, Barbaini and Ravasi, 1962; Ratti, 1962; Buraggi, D'Amico and Fava, 1963). The method has recently been taken up by other workers (Seitzman, Wright, Halaby and Freeman, 1963).

The method combines lymphadenographic investigation with elective radiotherapy of tumours located in the lymph nodes. The most promising results have been achieved in the treatment of systemic lymph node diseases, such as Hodgkin's disease, lymphosarcoma and reticulosarcoma (Chiappa et al., 1962; Chiappa, Galli, Guarino, Barbaini and Ravasi, 1963a; Chiappa and Galli, 1963). In a preliminary review of the case material treated at the Institute of Radiology (Chiappa, Galli and Severini, 1964), we reported the diagnostic and therapeutic results obtained in Hodgkin's disease.

The purpose of the present paper is to summarize our experience of lymphadenography with radioactive Lipiodol in lymphosarcoma and reticulosarcoma. We have treated 14 cases of lymphosarcoma, 18 cases of reticulosarcoma and three cases in which the histological diagnosis was lymphoreticulosarcoma. Five cases of lymphatic leukaemia, leukaemic and non‐leukaemic, have been included with the lymphosarcoma patients, because of the resemblance between the two in morbid anatomy, clinical course and lymphadenographic findings. The series thus totals 40 patients.

Although the various diseases are histologically and clinically different, they have certain lymphographic features in common: (a) the topographic distribution of the lymph node tumours within the area studied and, even more important, (b) the similarity of their response to irradiation with Lipiodol F131I.
Sideroblastic Anaemia in Man: Observations on Seventy Cases
Authors: MacGibbon Barbara H. , Mollin D. L.
Published: March 2008

During the past few years 70 cases of sideroblastic anaemia have been studied, many of whom were referred to us from other hospitals. Half of these patients have shown the primary, or idiopathic, form of this disorder, and half the secondary, in which another disease was associated with the sideroblastic anaemia. The main purpose of this paper is to describe the similarities and differences between these two forms of the anaemia, with particular reference to: (1) the clinical presentation and haematological features; (2) the evidence for pyridoxine deficiency and/or folic‐acid deficiency, and the haematological responses to therapy; and (3) the pathogenesis of such a deficiency state and its possible role in the production of the primary and secondary forms of sideroblastic anaemia.
Pyridoxine‐Responsive Anaemias
Authors: Gehrmann G.
Published: March 2008

Patients with sideroblastic anaemia do not respond to iron or other common haematinics. Since the first report by Harris, Whittington, Weisman and Horrigan (1956) on ‘Pyridoxine‐Responsive Anemia in the Human Adult’, 30 additional cases have been reported in the literature (Gehrmann, 1963).

The problem presented by these pyridoxine‐responsive anaemias is underlined by the fact that not all patients with sideroblastic anaemia respond to the administration of pyridoxine, and that in some patients with pyridoxine‐responsive anaemia the effect of treatment is incomplete whereas in others full regression of all abnormalities follows.

These different responses to the administration of pyridoxine and certain distinguishing clinical and laboratory features suggest that at least two miscellaneous groups of pyridoxine‐responsive anaemias exist. The available data suggest that some of these patients are actually deficient in pyridoxine and this allows us to distinguish between ‘pyridoxine‐deficiency anaemia’ and so‐called pyridoxine‐responsive anaemia. All the reported cases in the literature can be classified into these two groups. Furthermore, it seems justified to distinguish within the group of pyridoxine‐responsive anaemias cases of either hereditary (‘anaemia sideroblastica hereditaria’) or acquired (‘anaemia refractoria sideroblastica’) origin.

Features common to both pyridoxine‐deficiency and pyridoxine‐responsive anaemia are: (1) severe hypochromic anaemia with a dimorphic blood picture and a low reticulocyte count; (2) hyperferraemia and haemosiderosis; (3) maturation arrest of the erythroblasts with sideroblastosis (‘ring’ sideroblasts); (4) an increased iron disappearance rate but a decreased red‐cell uptake; (5) a slightly decreased or a normal red‐cell survival time; (6) absence of an abnormal haemoglobin, and (7) at least some correction of anaemia after the administration of pyridoxine.

Present knowledge of these two groups will be discussed in the present report and supplemented by personal observations. Patients with pyridoxine‐responsive anaemia which develops during the course of isoniazid treatment will be excluded, since this drug can induce true pyridoxine deficiency by forming a water‐soluble iso‐nicotinyl hydrazone complex (Williams and Abdulian, 1956).
Neutrophil (Leucocyte) Alkaline Phosphatase in Paroxysmal Nocturnal Haemoglobinuria
Authors: Lewis S. M. , Dacie J. V.
Published: March 2008

The alkaline phosphatase activity of the peripheral blood neutrophils has been studied extensively during the past 10 years, especially in leukaemia and allied disorders. A deficiency in paroxysmal nocturnal haemoglobinuria (PNH) was noted by Beck and Valentine (1951). This observation has been confirmed and it has been suggested that it is a characteristic feature of the disease (Hartmann and Auditore, 1959; Tanaka, Valentine and Fredricks, 1960; Lewis and Dacie, 1962).

In the present study neutrophil (leucocyte) alkaline phosphatase has been determined in a relatively large number of patients with PNH in order to assess the constancy of the defect and the relationship between the neutrophil alkaline phosphatase activity and the severity of the disease.

PNH is frequently associated with impaired marrow function, manifested by moderate pancytopenia. In a few cases severe, and possibly fatal, marrow failure may occur during the course of PNH. More commonly aplastic anaemia is the dominant feature at the onset while PNH becomes manifest only at a later stage (Dacie and Lewis, 1961). It is convenient to consider this ‘aplastic‐PNH’ syndrome separately from typical PNH, although during the PNH phase the disease is no different. Six patients with this syndrome have been studied and the neutrophil alkaline phosphatase results have been compared with those in typical PNH and in aplastic anaemia.
The Preservation of Leucocytes for Cytogenetic and Cytochemical Studies
Authors: Pegg P. J.
Published: March 2008

The development of cytochemical and cytogenetic techniques in clinical pathology has now reached the point where standardization is necessary if comparable results are to be obtained. There is, therefore, an urgent need for methods of storing cells of abnormal cytochemical constitution and karyotype for reference purposes. Techniques for the low temperature storage of bone marrow and peripheral blood leucocytes have been published by Ashwood‐Smith (1961, 1964) and other workers, and thus it was decided to study the possible application of these techniques to the storage of reference cells.
The Measurement of Iron Absorption by the Double Isotope Technique
Authors: Pitcher C. S. , Williams H. S. , Parsonson A. , Williams R.
Published: March 2008

Theprinciple of the double isotope technique for measuring iron absorption is to inject one isotope,59Fe, intravenously and give the other,55Fe, orally at the same time (Saylor and Finch, 1953). The59Fe is used to determine the percentage of plasma iron that is used for haemoglobin synthesis and it is assumed that the percentage utilization of the absorbed55Fe will be the same. From the relative amounts of the two isotopes present in the red cells at 10 days, it is possible to calculate the percentage of the oral55Fe absorbed. For the counting of the two isotopes in blood samples, the iron must be separated from the blood by digestion and precipitation followed by electroplating onto metal planchettes. The technique as originally described and as used by subsequent workers had a number of disadvantages. The various types of electroplating apparatus have proved unreliable in use or are complex in construction and the calculations have depended on the accurate recovery of known amounts of haemoglobin iron from blood samples (Hallberg and Brise, 1960; Brise and Hallberg, 1962). This is not easy to achieve in practice. The counting methods devised, including the use of gas flow counters and filters, have in our experience variable efficiencies.

The present report describes a relatively simple and reliable technique which has proved suitable for both single and serial measurements of iron absorption. The normal range of absorption by this method has been defined using a group of control subjects carefully screened to exclude mild unsuspected iron deficiency. Also reported is a comparison of the results obtained by this technique in a number of patients with widely differing absorption rates in whom iron absorption was also determined simultaneously by stool counting and by whole body counting.
A Study of the Coagulant Properties of Malayan Pit‐Viper Venom
Authors: Chan K. E. , Rizza C. R. , Henderson Marie P.
Published: March 2008

The commonest cause of snake‐bite in Northern Malaya is the Malayan pit‐viper (Ancistrodon rhodostoma), more than 300 cases being recorded each year. In a study carried out by Reid, Thean, Chan and Baharom (1963), 39 per cent of the victims suffered systemic poisoning, the outstanding feature of which was a prolonged defect of blood coagulation due to complete or partial disappearance of fibrinogen from the blood (Reid, Chan and Thean, 1963).

This paper describes in vitro experiments carried out to learn more about the action of the Malayan pit‐viper venom on the blood coagulation process and on the blood coagulation factors.
Heredity and Coagulation Studies in Ten Families with Factor XI (Plasma Thromboplastin Antecedent) Deficiency
Authors: Leiba H. , Ramot Bracha , Many Amira
Published: March 2008

Rosenthal, Dreskin and Rosenthal (1953) described a familial haemorrhagic disorder due to plasma thromboplastin antecedent (PTA) deficiency. Further studies have established the properties of this factor and its action in the early phase of thromboplastin generation (Rosenthal, 1954; Rosenthal, Dreskin and Rosenthal, 1955; Ramot, Angelopoulos and Singer, 1955; Campbell, Mednikoff and Dameshek, 1957; Cavins and Wall, 1960). The mode of hereditary transmission of this deficiency has been discussed by various authors (Cavins and Wall, 1960; Campbell et al., 1957; Rosenthal et al., 1955). Recently Rapaport, Proctor, Patch and Yettra (1961), using a quantitative assay of PTA, suggested that this deficiency is transmitted by an intermediate gene, which produces major PTA deficiency in the homozygote and minor PTA deficiency in the heterozygote. In the present communication, 10 families with PTA deficiency will be described and the mode of its inheritance will be discussed.
Fibrinolysis in Haemophilia: The Effect of ε‐Amino‐Caproic Acid
Authors: Mainwaring Dorothy , Keidan S. E.
Published: March 2008

In 1962 Abe, Sato, Kazama and Matsumura reported that two boys suffering from haemophilia had improved during treatment with ε‐amino‐caproic acid (ε‐A.C.A.) as shown by a diminished number of haemorrhages and decreased need for blood transfusions and that this improvement was associated with reduced fibrinolytic activity.

In order to assess the effect of ε‐A.C.A. in haemophilia, a trial has been conducted in six boys over a period of 6 months. They were all suffering from haemophilia A and their previous histories were available. During the trial they were seen at fortnightly intervals and on each visit a full record of all haemorrhagic episodes since the last visit was made, together with any subjective comments from the patient or his parents about pain, mobility, etc. At each visit a specimen of venous blood was taken for estimation of fibrinolytic activity, the patients attending at the same time of day in order to minimize physiological diurnal variation (Fearnley, 1960). Any changes in diet, activity or habits during the preceding 24 hours were also noted. Fibrinolytic activity was measured by the method of Lackner and Goosen (1959) (which is a modification of that originally described by Fearnley, Balmforth and Fearnley, 1957). During the first 3 months half of the patients were on treatment with ε‐A.C.A. and during the second 3 months the other half. The dosage was calculated by the percentage method (Catzel, 1962) based on the daily adult dose of 10 g. per day. No treatment was given during the control period.
Platelet Economy (Platelet Survival and Turnover)*
Authors: Mustard J. F. , Rowsell H. C. , Murphy E. A.
Published: March 2008

Investigators studying blood platelet survival and turnover have used the term ‘thrombo‐kinetics’ to describe the subject, by analogy with the usages of thermodynamics. Inasmuch as these phenomena reflect the interactions and hazards which the platelets encounter while discharging their function in the circulation, we prefer the term ‘platelet economy’ and we consider that the function and fate of the platelet cannot usefully be separated as objects of study.

A number of beliefs about platelet function and economy are widely held. First, the platelets play a leading role in haemostasis, a function which is discharged mainly when injury to the vessel wall occurs; their second main function is considered to be in coagulation, which they support or may even initiate. Beyond these, the platelets are thought to have little useful function. The platelet in vivo is commonly supposed to be a fragile structure, irreversibly damaged by aggregation. Some consider it to have a finite life span, determined by exhaustion of its inner reserves, while others consider its life span to be determined by the demands of the body without regard to the age of the individual platelet.

We shall present evidence suggesting that some of these views are gross over‐simplifications and some are erroneous.
A Notional Structure for the Rhesus Antigens
Authors: Knox E. G.
Published: March 2008

The increasing complexity of the Rhesus antigen–antibody reactions is testing the notation systems at present in use, but some of the difficulties are semantic. The Cc/Dd/Ee notation is applied both to genes and to antigens, and this may cause confusion if the two usages are not clearly recognized and distinguished. In particular, our concepts of antigen structure must not be restricted to the linear arrangement implicit in the gene notation. This paper is an attempt to infer a notional structure for the Rhesus antigens without this conceptual restriction.

The problem arises from a previous study (Murray, Knox and Walker, 1965) in which it was shown:

(a) that in a cde/cde (rr) mother, a foetus with the cDE/cde (R2r) genotype is a more potent D‐sensitizing stimulus than a CDe/cde (R1r) foetus, and
(b) that cDE/cde (R2r) infants with haemolytic disease of the newborn are more severely affected than CDe/cde (R1r) infants. As in the sensitizing mechanism, cDE/cde (R2r) seems to be a more powerful antigen than CDe/cde (R1r).

There is also evidence from serological studies that red cells of different genotypes have irregular antigenic strengths, even with respect to factors which genetically are in the same dose. Three main effects have been demonstrated.

(a) Dosage effects. A genotype homozygous for a particular factor produces more antigen than does the heterozygote. However, there are quantitative irregularities and the antigenic strengths in homozygotes and heterozygotes are seldom in a 2:1 or any other constant ratio.

(b) Cis‐ and trans‐effects. These effects are interactions between different pairs of factors. For example the presence of C‐antigen diminishes the amount of D‐antigen compared with that found when C is replaced by c. When the C and D genes are on the same chromosome this is known as a cis‐effect and when on opposite chromosomes a trans‐effect.

(c) Combined antigens. The most important are the anti‐Ce, ‐ce, series of antigen‐antibody reactions. Their special peculiarity is that they are found only when the two components are determined by the same chromosome and not when the genes are carried on opposite chromosomes.
In vivo Plasma Binding Capacity for Cyanocobalamin*
Authors: Schiffer L. M. , Cronkite E. P. , Meyer L. M. , Miller I. F.
Published: March 2008

Many investigators have alluded to or described the presence of multiple vitamin B12 binding proteins in human plasma (Mendelsohn, Watkin, Horbett and Fahey, 1958; Miller, 1958; Hall and Finkler, 1962; Rosenthal, Hill and Haessler, 1964; Heller, Epstein, Cunningham, Henderson and Yakulis, 1964). Recently, Hall and Finkler (1963, 1964) separated two cyanocobalamin plasma binders with distinctly different characteristics. One fraction (Transcobalamin II or TC II) is apparently a β‐globulin which is involved in the immediate carrier state, while the other (Transcobalamin I or TC I), an α‐globulin, is the endogenous B12 binding protein. Gabuzda, Worm‐Petersen and Lous (1965) confirmed these findings, demonstrating that cyanocobalamin is bound in vitro by a distinctly separate protein from that to which it is bound endogenously. Methods derived from a study of plasma binding by vitamin B12 analogues have been utilized to determine in vivo plasma binding capacity for cyanocobalamin (Meyer, Schiffer, White and Cronkite, 1965). It is proposed that this in vivo plasma binding capacity represents to a large extent the B12 carrying capacity of TC II.
A Histochemical Method for the Demonstration of Leucocyte Naphthylamidase Using Two Substrates: Alanyl‐ and Methionyl‐4‐Methoxy‐2‐Naphthylamide
Authors: Rutenburg A. M. , Rosales C. L.
Published: March 2008

Histochemical methods for the demonstration of naphthylamidase* in tissues were based on the coupling properties of 2‐naphthylamine (Burstone and Folk, 1956; Nachlas, Crawford and Seligman, 1957) after enzymatic release from amino acid naphthylamides. But significant diffusion of the amine and the lack of a suitable diazonium salt to achieve a sufficiently prompt capture reaction to form an insoluble dye as well as prolonged incubation prevented adequate histochemical localization. When the coupling rate of 2‐naphthylamine was found to be significantly enhanced by the presence of a methoxy group in the 4‐position (Nachlas, Goldstein, Rosenblatt, Kirsch and Seligman, 1959), l‐leucyl‐4‐methoxy‐2‐naphthylamide (Rosenblatt, Nachlas and Seligman, 1958) was synthesized and found to serve as a more satisfactory substrate for naphthylamidase demonstration (Nachlas, Morris, Rosenblatt and Seligman, 1960).

Replacement of the leucyl group in leucyl‐2‐naphthylamide by alanyl or methionyl groups resulted in a more rapid hydrolysis by naphthylamidase (Nachlas, Goldstein and Seligman, 1962; Smith, Kaufman and Rutenburg, 1965; Monis, Wasserkrug and Seligman, 1965). It therefore appeared likely that the substrates alanyl‐ and methionyl‐4‐methoxy‐2‐naphthylamides would yield further improvement of localization of enzymatic sites and would be potentially useful for the demonstration of naphthylamidase in tissues such as white cells which are known to have a low content of this enzyme.

In this report we present the data on the use of both substrates for the demonstration of naphthylamidase in human leucocytes.
The Effect of Acute Haemorrhage and Acute Haemolysis on the Intestinal Iron Absorption in the Rat
Authors: Chirasiri L. , Izak G.
Published: March 2008

As thetotal body pool of iron is extremely small, a very sensitive and accurate mechanism is required to preserve the balance between the amount of iron entering the body and that being excreted. Although much effort has been concentrated on clarifying the nature of this regulating mechanism, the conclusions arrived at by different investigators vary widely. It has been stated that the body iron pool is maintained by controlled absorption, while excretion plays only a minor role (Moore, 1955; Pirzio–Biroli, Bothwell and Finch, 1958; Pirzio–Biroli and Finch, 1960). It has been proposed by some investigators that the iron content, or the degree of saturation of iron–binding protein in the intestinal epithelium are responsible for the amount of iron absorbed from the gut (Hahn, Bale, Ross, Balfour and Whipple, 1943; Granick, 1946; Stewart, Yuile, Claiborne, Snowman and Whipple, 1950). Others have denied the importance of these mechanisms (Brown, Dubach and Moore, 1958) and have advocated, instead, the importance of erythropoietic activity in the regulation of iron absorption (Chapelle, Gabrio, Stevens and Finch, 1955; Bothwell, Pirzio–Biroli and Finch, 1958; Reynafarje, Lozano and Valdivieso, 1959). Still other workers have demonstrated that iron is lost from the body in desquamated intestinal epithelium in a selective manner so that needed iron is conserved and excess eliminated (Conrad and Crosby, 1963; Crosby, 1963).

In view of the many conflicting reports, it seemed of interest to explore the effect of anaemia due to blood loss and due to increased red‐cell destruction on the absorption of iron from isolated intestinal segments of the starving rat. The present communication deals with the results of these investigations.
Gastric Acidity and Iron Absorption
Authors: Jacobs A. , Rhodes J. , Peters D. K. , Campbell H. , Eakins J. D.
Published: March 2008

achlorhydria has been recognized as an associated feature of iron deficiency anaemia for many years (Faber, 1909; Witts, 1930). There has, however, been little agreement as to the part played by gastric acid in the absorption of iron from the intestinal tract. Early workers produced evidence that iron absorption was greater in the presence of normal gastric acidity than in cases of achlorhydria (Minot and Heath, 1932; Heilmeyer and Plotner, 1936; Barer and Fowler, 1937). Others found that this was not the case (Moore, Arrowsmith, Welch and Minnich, 1939; Grace, Doig and Wolff, 1954; Pirzio‐Biroli, Bothwell and Finch, 1958). More recently Goldberg, Lochhead and Dagg (1963) and Cook, Brown and Valberg (1964) have shown that in some circumstances iron is better absorbed by subjects with normal gastric acid than in those with a histamine fast achlorhydria.

In the present investigation quantitative studies of both iron absorption and of gastric acid production have been made in patients with iron deficiency anaemia and additional observations have been made in normal subjects. The relationship between iron absorption and gastric secretory capacity is examined.
Familial Thrombocytopenic Thrombocytopathy
Authors: Cullum Carol , Cooney D. P. , Schrier S. L.
Published: March 2008

A unique family with thrombocytopenic thrombocytopathy is described and the relevant literature is reviewed. Two of the more severely affected members who have clinical bleeding and thrombocytopenia were studied in detail. Their platelets are large, fail to adhere to wound surfaces, and are rapidly removed from the circulation. Their platelet thromboplastic activity is sharply reduced relative to their increased content of phospholipid and total lipid. It is postulated that the genetic defect is transmitted as an autosomal dominant.
Erythropoietic Cell Proliferation during Recovery from Acute Haemorrhage
Authors: Lord B. I.
Published: March 2008

Recovery of rats subjected to an acute haemorrhage by cardiac puncture has been followed during the subsequent 7 days. Cell proliferation in the spleen and bone marrow during this recovery process was studied by the autoradiographic technique.

By 7 days, the circulating red cell volume was normal as judged by daily measurement of the haematocrit. Both the spleen and the bone marrow made approximately equal contributions to the recovery process. In addition, the liver made a very small contribution. It is suggested that the process of recovery is by stimulation of the stem cell compartment to produce more cells going through the erythroid maturation sequence. The maximum number of erythroid cells in the spleen occurs between 2 and 4 days and at this time the cells are dividing with a mean cycle time of about 15 hours. In returning to normal, this mean cycle time then gradually increases making less divisions during the maturation sequence possible and, therefore, producing mature cells at an increasingly slower rate. The marrow probably behaves in a similar manner but because it is a considerably larger and more diffuse organ than the spleen, the experimentally observed changes are not so dramatic and, therefore, less easily analysed.
Platelets in the Carcinoid Syndrome: A Chemical and Ultrastructural Investigation
Authors: Crawford N. , Sutton Maureen , Horsfield G. I.
Published: March 2008

A combined chemical and electron microscopic study of normal platelets and platelets from patients with the carcinoid syndrome has revealed an association between their serotonin content and certain alterations in their cytoplasmic structure. In addition to a fibrillary structure of possible cytoskeletal significance, platelets also contain a system of microtubules and vesicles. When the platelet serotonin content is high this tubular structure is prominent and communicates with large vacuoles which may contain granular material. Normal platelets incubated with serotonin show similar alterations in structure. In addition, serial investigations of platelets from two carcinoid patients suggest that in addition to the normal active transport process for absorbing serotonin a diffusion process can operate when the cell is exposed to high environmental concentrations. The significance of these storage mechanisms in relation to normal and elevated platelet serotonin concentration is discussed.
Glandular Fever and Specific Viral Infections: Uptake of Tritiated Thymidine by Circulating Leucocytes
Authors: Besser G. M. , Davis Jane , Duncan Catherine , Kirk Barbara , Kuper S. W. A.
Published: March 2008

The circulating leucocyte nuclei in 20 out of 22 patients with glandular fever showed a raised level of uptake of tritiated thymidine in vitro. The uptake was confined to the glandular fever cells but in sonic cases it did not appear until the middle and late stages of the disease. In the few patients studied with the specific viral infection‐mumps, measles and rubella‐there was also increased thymidine labelling, but this was not seen in the two cases of chicken pox. This phenomenon in infections was similar to that seen in the reticuloses but was transient.
An Electron Microscope Study of Bone Marrow in Rheumatoid Disease
Authors: Wardle E. N. , Attan Jacqueline
Published: March 2008

The marrow of patients with various haematological complications of rheumatoid disease has been studied with the electron microscope. Although there is evidence that reticulum cells may be reluctant to turn over body iron, yet there is no evidence of iron excess in the reticulum cells of the marrow nor of a morphological defect of normoblast maturation.

Iron transfer is normal. Whereas in the early stages of red cell development iron can be seen to enter the normoblasts from the reticulum cells by the distinct process of ropheocytosis, in the late normoblast and reticulocyte aggregates of unused iron pass back to the reticulum cells. The reticulum cell is therefore important in regulating the distribution of iron within the marrow.

The reticulo‐endothelial system in rheumatoid disease shows evidence of response to antigenic stimulation. In particular a case of Felty's syndrome showed reticulum cell hyperplasia, lymphoblasts and material resembling rheumatoid factor in the granulocytes. Hyperplasia of the marrow reticulum may lead to a maturation arrest constituting ‘hypersplenism’.
Haemoglobin J‐Bangkok: A Clinical, Haematological and Genetical Study
Authors: Pootrakul S. , Wasi P. , Na‐Nakorn S.
Published: March 2008

A Thai family with haemoglobins A + J‐Bangkok in nine persons is described. This rare abnormal pigment had identical electrophoretic mobility to other haemoglobins J, but, as α2β256Asp, is not similar to any previously described haemoglobin. Carriers of this haemoglobin were clinically and haematologically normal except for the presence of 47.4–67.2 per cent Hb J. It was also possible to follow the increment of Hb J‐Bangkok from 16.15 per cent in the cord blood to 46 per cent at 2½ months and to 55.18 per cent at 1 year of age. One person is believed to harbour both an α‐thalassaemia and Hb J‐Bangkok genes without evidence of interaction.
The Fine Structure of Fibrin
Authors: Kay D. , Cuddigan B. J.
Published: March 2008

Using negatively staining techniques fibrin clots have been examined by electron microscopy, and finer detail of the clot structure has been observed than previously reported. From these observations a model of fibrinogen is proposed having different dimensions from those which are generally accepted and it is suggested that the fibrin clot is formed by end‐to‐end polymerization of the monomer with a one third molecular length overlap between laterally adjacent fibrils.
A Diffraction Method for Measuring the Average Volumes and Shapes of Red Blood Cells
Authors: Child J. A. , King J. , Newman T. H. , Waterfield R. L.
Published: March 2008

An instrument and technique are described for determining MCV, MCD and D/T from the visual measurement of the diffraction rings produced by red cells; MCV from the unfixed spherical cells and MCD from the fixed discoidal cells.

The method eliminates a serious error due to asymmetry in retinal sensitivity near the fovea.

The accuracy of the measurements is assessed from the repeatability of the observations of individual observers, and from the agreement between those of different observers.

The validity of the optical theory in the deduction of the cell dimensions from the diffraction measurements is confirmed in the case of spherical cells: (1) By the agreement found between the values of MCV obtained with the spherocytometer on the one hand, and with the electronic counter and centrifuge on the other. (2) By showing that the constants for the various diffraction rings produced by spherical cells have their theoretical values. However, the constants found for the rings produced by the fixed discoidal cells differ significantly from their theoretical values. Because of this, and because of the shrinkage of the fixed cells, the values for MCD and D/T are only relative. The same criticism applies to the standard method for determining these data from dried blood films; but in dried films the shrinkage is variable, whereas in the new method described the shrinkage is constant. Error arising from the intensity of light in a diffraction ring being proportional to the fourth power of the diameter of the cell was examined and found to be negligible in the case of D/T, and to reach a significant amount in MCV only when anisocytosis is extreme.

The possibility is considered that in abnormal cells variable shrinkage due to fixation may produce spurious variations in D/T. However, low values for D/T are found in spherocytosis, and high values in thalassaemia, in which the cells are flattened. Further, measurements of unfixed discoidal cells suspended in their own serum gave values of D/T closely parallel to those derived from the fixed discoidal cells.

Results may be misleading when a microcytic or macrocytic anaemia is responding to treatment, or following transfusion. The error can be recognized and, by centrifugation, the cells present before treatment can be separated from the newly formed cells and measured in the ordinary way.