ALBERT

Description: The cardiac and respiratory adjustments in chronic anemia and their clinical manifestations have been reviewed. When the oxygen carrying capacity of the blood is diminished, an adequate supply of oxygen to the tissues is maintained by an increased cardiac output, an increased velocity of blood flow, and a relatively more complete abstraction of the oxygen from the blood as it passes through the capillaries. With the increased blood flow, the average peripheral resistance is decreased but the state of the small blood vessels is not uniform everywhere; the blood flow in the hands and kidneys, for instance, may be reduced, while that of other parts of the body is increased. The total oxygen consumption of the body in anemia is not strikingly altered. The blood volume generally is slightly reduced but the plasma volume is normal. The deviations from the normal values vary from patient to patient, but generally are definite when the hemoglobin values are less than 50 per cent and are greatest at the lowest levels of hemoglobin concentration. The close interrelationship between the cardiovascular and respiratory systems is exemplified by the coincident changes in the respiratory system in anemia. The rate and depth of respiration often are increased together with a lowering in the vital capacity and its subdivisions, the reserve and complemental air volumes. The resid- ual air is somewhat increased. These deviations from the normal are similar to those observed in pulmonary congestion or edema and denote a loss of elasticity and expansibility favoring the occurrence of exertional dyspnea. The arterial blood saturation is usually normal at rest but, during exertion, a significant lowering becomes apparent. The importance of hemoglobin in the transport of carbon dioxide is reviewed; the decreased availability of hemoglobin as a buffer in carbon dioxide transport in anemia is compensated by the increased ventilation of the blood in the lungs, rendering the arterial blood somewhat alkalotic. The red cells also play an important role in regard to the respiratory enzyme, carbonic anhydrase. In the anemias due to blood loss, malnutrition, chronic infection, uremia, or leukemia, the blood carbonic anhydrase activity is parallel to the decrease in hemoglobin level leading to a deficiency not only of oxygen carrying capacity but also a decreased ability to absorb carbon dioxide from the tissues and to release it in the lungs. The following factors, many of which are closely interrelated, are operative in the production of dyspnea in anemic patients: the increased respiratory minute volume, the decreased vital capacity and its subdivisions, the abnormalities in carbon dioxide transport and dissociation, the reduced arterial oxygen capacity and the decreased blood oxygen saturation during effort, and the frequently observed elevated blood lactic acid values. The symptoms and signs exhibited by anemic patients, including palpitation and breathlessness on exertion, tachycardia, cardiac dilatation and hypertrophy, are described. In addition to an apical systolic murmur, other systolic and diastolic murmurs are occasionally heard. The arterial blood pressure is frequently lowered in anemia; the venous pressure is generally within the limits of normal. Electrocardiographic abnormalities occur in approximately one-quarter of anemic patients but are minor and not specific in character. The occurrence of angina pectoris, congestive failure, and intermittent claudication in some patients with the development of anemia, and disappearance of these conditions as the anemia is alleviated, is discussed with particular reference to the underlying physiologic mechanisms.

Description: Methyl folic acid,2 N-(4-(4-quinazoline) amino) benzoyl)-glutamic acid, the Mg salt of formyl pteroyl glutamic acid, the Mg salt of formyl pteroic acid, pteroyl aspartic acid, oxyfolic acid and oxypteroic acid have been studied as to their effect on blood regeneration in selected cases of Addisonian pernicious anemia, nutritional macrocytic anemia and tropical sprue. In the amounts administered, only the Mg salt of formyl pteroyl glutamic acid was effective in producing reticulocytosis and an increase in red blood cells, hemoglobin, white blood cells and platelets, and it was not as effective per unit of weight as was folic acid per se. Presumably this compound is slowly changed into folic acid in the body. It is of special interest that the Mg salt of formyl pteroic acid (Streptococcus lactis factor) was negative in producing hemopoiesis. These observations show the very great specificity of the folic acid molecule.

Description: A technic for repeated femoral bone marrow biopsy in the rat is detailed. Differential counts confirmed the distribution of the cellular elements as described by other authors.

Description: These findings show that the administration of vitamin B12 to patients with tropical sprue was followed by general clinical and hematologic improvement provided the dosage was adequate. A single dose of 4 micrograms administered in case 4 produced little or no change. The larger dosage of 10-25 micrograms administered in the other cases was accompanied by striking increase in strength and vigor and a decrease in the diarrhea; however, in no instance was a maximal dose given and these patients quickly tended to relapse clinically and hematologically. They could be relieved promptly again either by another injection of vitamin B12 or by a compound of folic acid. (The conjugated compounds of folic acid used in these cases were used for experimental purposes, and they produced the same hematologic response as that of folic acid per se.) Case 3, who had an excellent hematologic response after eating one serving of 400 grams of liver, is regarded as especially significant in that it suggests that, as powerful as vitamin B12 is as a therapeutic agent, it is more effective when given with liver. It is especially noteworthy that cases 1 and 2, who had three injections of vitamin B12, have had steady clinical and hematologic improvement. The reader should have in mind that a single injection of approximately 100 micrograms of vitamin B12 probably would be needed to produce a full hematologic response in persons so ill. This tentative appraisal would suggest that this therapeutic compound, per unit of weight, is more effective in treating human disease than any compound that yet has been used.

Description: Seven rhesus monkeys were subjected to one or more episodes of acute thiamin depletion. It is clear that significant metabolic inadequacies preceded demonstrable structural changes. Diminished food consumption and weight loss were manifest about two weeks after thiamin was removed from the diet. When the deficiency was prolonged the animals became apathetic, inactive and progressively weaker. This was followed by ataxia and at times ptosis and tremors. Even in such advanced states of depletion, administration of thiamin produced dramatic improvement in locomotion, appetite and reactivity. The blood thiamin content of normal monkeys ranged from 5.5 to 10γ per 100 ml. of whole blood, values which are comparable to those of healthy human beings. Following withdrawal of thiamin the blood concentration fell to values of 4γ or less. The tissue content of thiamin was correspondingly reduced in depleted animals. The minimum daily requirement for thiamin calculated on the basis of the time required to redeplete a deficient monkey following a small dose of thiamin was approximately 15γ per kilogram body weight. Characteristic degenerative changes in the heart muscle and severe retrogressive changes in the nuclear structures of the central nervous system previously reported were noted. Based on careful hematologic studies in 4 animals it is concluded that thiamin is essential for normal erythropoiesis. Acute or chronic depletion results in anemia due to suppression of red blood cell formation as indicated by severe depression or absence of reticulocytes in the blood.

Description: Para-aminobenzoic acid, administered in large doses as sodium para-aminobenzoate caused a striking lowering of the leukocyte counts in five patients with chronic myelogenous leukemia and in one patient with subacute myelogenous leukemia. NaPAB caused less definite decreases of the white cell count in two patients with chronic lymphatic leukemia, but the periods of administration may have been too short to obtain maximal effects. In every instance, there was a prompt rise in the number of leukocytes when the administration of NaPAB was stopped. Although there was decrease in spleen size in some of the patients, the objective clinical improvement was but slight and temporary. All patients receiving NaPAB in large doses had concomitant glycosuria, apparently on a renal basis. It is to be emphasized that NaPAB is not considered a practical adjunct to the therapy of leukemia at this time. Rather, it is hoped that studies of the cellular chemistry involved in the apparent inhibitory action of NaPAB may yield information concerning the disordered metabolism of leukemic cells.

Description: Generalizing, it can be said that the pathologic cells seen in smears of the bone marrow in multiple myeloma resemble the plasma cell and vary from the very anaplastic and immature cell to the well-differentiated and almost characteristic plasma cell. The feature which the "myeloma" cell shares with the plasma cell is the abundant, granular, basophilic cytoplasm which tends to be fragile and undergo the same degenerative changes in each; namely, the formation of Russell bodies and vacuolization. Fairly frequently a perinuclear clear area or Hof is present and the nucleus tends to be eccentrically placed. Cytoplasmic extensions or pseudopodia may also be seen in either case, but they occur more often and more dramatically in instances of multiple myeloma. Multinucleated cells are commonly seen. In addition, myeloma-plasma cells will often have a large clear nucleolus and a leptochromatic nucleus and will exhibit a tendency to the formation of isolated areas of condensed chromatin. Cytoplasmic extrusions, free cytoplasmic bodies, occasionally complete with Russell bodies and vacuoles are almost universally present. All cases were of the plasma cell type; there was no exception. In these cases, the myeloma-plasma cell constituted from 2.5 to 96 per cent of the leukocytic elements present. The opinion was expressed that all so-called types of multiple myeloma are merely variations in differentiation of this same cell. It was noted that anaplasia, hypernucleation and lack of plasma cell predominance in certain cases were diagnostic pitfalls. Additional evidence was adduced to confirm the reticulo-endothelial origin of the myeloma-plasma cell. It was further observed that certain prognostically valuable information could be gleaned from a careful review of the cytologic characteristics in these cases.

Description: The results are reported of testing 1073 English bloods with the Rh antibodies anti-C, anti-Cw, anti-c, anti-D, anti-E and anti-e. The results of another series of 927 bloods, already published, are here reproduced. The total of 2000 bloods has been used by Fisher to estimate, by his method of maximum likelihood, the Rh chromosome frequencies in England. The estimates are: CDe 40.75 per cent, cde 38.86 per cent, cDE 14.11 per cent, cDe 2.57 percent, CwDe 1.29 per cent, cdE 1.19 per cent, Cde 0.98 per cent, and CDE 0.24 per cent. A brief account is given of the three pairs of alternative antigens shown by Fisher to be the basis of the Rh blood groups. Fisher’s interpretation must now be considered as established beyond doubt. A possible genetic basis of these related antigens is discussed.