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Studies on serum tocopherol levels, hematopoietic responses, and erythrocyte phospholipid fractions were carried out in agroup of low-birth-weight (mean, 1,530 gm) premature infants whose diets were supplemented with either water-soluble (TPGS) or fat-soluble (TA) forms of d-alpha tocopheryl (25 IU/day). Significantly higher serum tocopherol levels and early maintenance of higher hemoglobin values were observed in the infants who received the water-soluble tocopheryl preparation. Comparable but less marked differences in these values were identified in similarly paired groups fed lower concentrations of the tocopheryls in combination with iron. The lowest hemoglobin levels were recorded in the infants fed formulas containing TA and iron. Among a selected group of vitamin E-deficient infants, evidence of lipid instability in the erythrocyte membrane was manifested by decreased values of phosphatidyl ethanolamine.

Increased in vitro erythrocyte sensitivity to the hemolytic effects of hydrogen peroxide (H2O2) in the H2O2 fragility test has been widely associated with vitamin E deficiency. In the present study, H2O2 red cell fragility was abnormally elevated in many types of acquired and congenital anemias in children who were tocopherol sufficient. In addition to abnormal red cell H2O2 sensitivity known to occur in vitro in conditions involving defects in cellular devices for disposal of peroxides, it is likely that a wide variety of erythrocyte dysfunctions result in increased in vitro H2O2 hemolysis even in situations where the usually adequate mechanisms for peroxide detoxification are present.

With the aid of electron microscopy two different red cell lines have been identified in erythropoietic porphyria. A normal red cell series has been found in association with hemoglobin containing normoblastic nuclei and ferritin laden reticulocytes. The abnormal line presumably represents the porphyrin containing cells. A possible explanation to account for the abnormality in heme synthesis has been proposed.

Central nervous system infiltration was studied in a group of 47 children with acute leukemia. CNS involvement was found to occur more frequently and appear more rapidly in patients who presented with elevated peripheral WBC counts. CNS infiltration not suspected clinically was identified by spinal fluid examination in a significant minority of children at the time of the initial diagnosis of leukemia, indicating that lumbar puncture should be a routine part of the initial evaluation of patients with acute leukemia. Intrathecal amethopterin administered "prophylactically" at the time of initial diagnosis of leukemia did not prevent or decrease the frequency of occurrence of CNS infiltration. However, it did delay the onset of CNS involvement in patients with elevated WBC counts. Intrathecal amethopterin administered before the onset of CNS infiltration appears to be useful in delaying morbidity resulting from CNS involvement in children who present with elevated peripheral WBC counts.

The hematologic and serologic data of 87 cystic fibrosis patients, between the ages of 5 and 16 years, showed the following characteristics as compared with a group of age-matched normal control children: The cystic fibrosis patients were shorter, weighed less, and had lower pO 2 values than the control group. Although moderately polycythemic, they had lower MCHC's lowe serum-bound iron values, and higher iron-binding capacities. However, both BI and TIBC values were low in the group with the klowest pO 2 values. The blood vlumes, based upon height, were normal. Iron absorption, particularly in thosse with low iron values, was increased. Whereas the level of serum-bound iron was the major factor in regulation iron absorptioin, the red cell mass was, directly related to the degree of hypoxia. Pancreatic extract impeded absorption of iron, but to a lesser extent than it did in the control group.

Serum folate levels were serially determined in 57 premature infants from birth to 7 months of age. Twenty-four normal children and 21 normal adults served as controls. The mean value of folate activity was significantly lowest between 1 and 3 months of age. The values at 3 to 5 months of age approximated the normal controls and were coincident with the administration of adequate dietary folic acid. Twenty-eight per cent of the total number of premature infants and 68 per cent of those infants who weighed less than 1,700 grams at birth had low folate levels. Of interest is the fact that the premature infants with SFA deficiency failed to exhibit any significant hematologic responses to folinic acid. The unequivocal use of folic acid supplementation should be held in abeyance until absorption studies are completed.

An unusual case of erythropoietic porphyria with a severe hemolytic component and thrombocytopenia has been presented. The relationship between the porphyria and the thrombocytopenia, although unclear, showed definite evidence of persistent megakaryocytic hypoplasia. Additional information emphasizing the severity and chronicity of the anemic process included elevated F and A2 hemoglobins, hyperferremia and extramedullary hematopoiesis. The nature of the hemolytic process appeared to be intracorpuscular and not correctible by normal plasma, glucose or ATP. The abnormal in vitro hemolysis, coupled with the appearance of the abnormal nucleated and mature red cells, are suggestive of the defect in heme synthesis seen in some of the hypochromic hypersideremic anemias. A description of therapeutic attempts as well as the appearance of a folate deficiency are included in the report.

Disseminated intravascular coagulation in 4 full-term infants and one 4-year-old child was successfully treated with exchange transfusions of stored, 12- to 72 hour old, citrated whole blood. Heparin was not used. The causative, or related, disorders included the respiratory distress syndrome, ABO incompatibility, and streptococcal sepsis. In all patients, except one, an infant with galactosemia and streptococcemia, the clotting factors promptly returned to normal. In the galactosemic infant with streptococcal sepsis, a rebound delay occurred with return to normal of the secondary clotting disorder following correction of the metabolic defect. The mechanism of action is, in part, related to a “clearing” process by the exchange transfusion, which, because of ready availability, should receive priority as the treatment of choice for disseminated intravascular coagulation in the newborn infant and probably in older patients as well.

To our knowledge, this is the first reported case of Aspergillus endocarditis with widespread dissemination in infancy. The possible entry of the organism through the umbilical vein at birth during exchange transfusions, and the relatively silent clinical course in view of the spectacular postmortem findings, are noteworthy.

This paper reports on a long-term psychiatric study of 35 hemophilic children andtheir 22 families. Its purpose was to evaluate the adjustment of the young hemophilic patient to his illness and to his life situation, and the possible relationship between parental attitudes toward hemophilia and the child's personality development and clinical course. The majority of patients and their parents showed a good adaptation to the illness. The mothers, in particular, played an essential role in promoting a healthy personality development. Bleeding episodes without known trauma, often in relation to anticipated events, were observed in many prepubertal boys. Several adolescents showed an improved clinical state following a reversal of behavior from a passive dependent state to an aggressive, at times daring, independence. The study emphasizes the need for continuous, reassuring support given by the pediatrician. The encouragement of healthful interpersonal activity and of reasonably aggressive pursuits is especially important in promoting a good adaptation of the hemophilic child.

Description of a hemolytic anemia associated with vitamin E deficiency in premature infants prompted study of the relationships of medicinal iron, vitamin E, and hematologic parameters during the early life of such infants. A total of 186 patients categorized according to birth weight and gestational age were placed in study groups: (1) no iron or vitamin E supplement, (2) oral vitamin E supplement, (3) oral iron supplement, and (4) iron and vitamin E supplements. Significantly lower mean hemoglobin and serum vitamin E concentrations, with higher reticulocyte count and hydrogen peroxide fragility, were found during the second month of life in infants with a gestational age less than 36 weeks who were not receiving vitamin E. Hemoglobin values were lowest and reticulocyte counts highest in vitamin E-deficient infants of low gestational age who received supplemental iron. These observations suggest that therapeutic doses of iron increase red cell hemolysis during a period of vitamin E deficiency.

A study of 144 infants from a homogeneous, low-income group was undertaken in order to determine the effects of various protein and iron contents of prepared cow's milk formulas on hematologic values. Altogether, 4 formulas were used in the study: relatively lower protein (15 Gm. per liter) with trace or supplemental amounts of iron, and higher protein (24 Gm. per liter) with trace or supplemental amounts of iron. Complete hematologic data, including bound iron and iron-binding capacities, were obtained from birth through 18 months. Similar pre- and postpartum data were obtained on the mothers. All of the infants received iron-free cereals and consistent dietary regimens. Those infants who were fed the higher protein, trace-iron formulas had the lowest mean hemoglobin and serum iron levels. Conversely, the highest hemoglobin and iron values were observed among the infants fed the lower protein formulas, irrespective of the iron content.

The case records of 11 infants with prolonged hyperbilirubinemia have been presented. The elevation of indirect reacting bilirubin in these infants may be due to interference with the normal conjugating mechanism by a substance present in breast milk. Introduction of cow's milk formulas should be carried out as part of any extensive investigation of prolonged hyperbilirubinemia of the indirect type in otherwise well infants who have been wholly breast fed from birth.

I~ National Center for Health Statistics, Seasonal Variation of Births United States 19331963, Series 21, No. 9, p. 24. 2. U. S. Department of Public Health, Education, and Welfare, United States Public Health Service National Office of Vital Statistic, Vital Statistics of the United States vol. 1, 1958-1963. 3. Feggetter, S.: A review of 1,018 cases of congenital pyloric stenosis treated by Ramstedt operations, J. Internat. Coll. Surgeons 30: 696, 1958. 4. Carter, C.: The incidence of congenital hypertrophic pyloric stenosis, Brit. M. Bull. 17: 251, 1961. 5. Longino, L., Hendren, W., and Owing, R.: Congenital hypertrophic pyloric stenosis, Am. J. Surg. 10l: 605, 1961. 6. Ravitch, M. M.: Story of pyloric stenosis, Surgery 48: t l t 7 , 1962. 7. Donovan, E., and Stanley-Brown, E.: Congenital hypertrophic pyloric stenosis, Surg., Gynec. & Obst. 115: 403, 1962. 8. Singleton, A., and Fish, J.: Obstruction of the stomach and duodenum in infancy and childhood, Am. J. Surg. 106: 596, 1963. 9. tIanell, D.: Congenital hypertrophic pyloric stenosis, J. Abdom. Surg. 5: 51, 1963. 10. Beson, G., and Lloyd, J.: Infantile pyloric stenosis, Am. J. Surg. 107: 429, 1964. 11. Gharib, R.: The incidence of infantile hypertrophic pyloric stenosis, J. PEDIAT. 65: 622, 1964.

In summary, it appears that thrombocytosis frequently accompanies the less severe anemia of iron deficiency and may be related to platelet stimulation in a manner analogous to the erythropoietin increase seen in many of the anemic states. In some of the severely anemic individuals, thrombopenia has been observed related suggestively to several factors, including severe depletion of iron as iron enzymes, a folate deficiency or a transient thrombopoietin deficit. In order to determine with any degree of certainty the etiology of the thrombocytopenia, one would have to evaluate the platelet response in a similarly afflicted group of infants treated with folic acid or simply thrombopoietin rich plasma prior to iron therapy. In regard to the intriguing difference in the platelet response to oral and parenteral iron, subsequent studies, using either extremely small amounts of parenteral iron or large amounts of oral iron, regardless of the initial platelet and hemoglobin values, might cast light on the etiology of this occurrence.

DIABETES insipidus complicating acute leukemia has been reported but rarely. In a comprehensive review Rosensweig and Kendall 1 found 12 such cases, only one of which was in a child. The patient was recorded to have had acute granulocytic leukemia. 2 Of the remaining 11 adult patients, only one had acute lymphocytic leukemia. 3 This report presents the first well-documented case of diabetes insipidus complicating acute lymphocytic leukemia in a child. Report of a Case A 10-year-old Negro girl with acute lymphocytic leukemia was admitted to the Children's Clinical Research Center of University Hospitals of Cleveland in August 1967 following one month of polyuria and polydipsia. She had first presented ten months earlier with fever, dyspnea, and chest pain at which time a left pleural effusion was noted radiographically. Thoracentesis followed by biopsy and examination of scalene and anterior mediastinal lymph nodes established a diagnosis of lymphocytic lymphoma. Other abnormal

The association of vitamin E deficiency and hemolytic anemia in small premature infants prompted study of intestinal absorption of vitamin E in infants of various gestational and chronologic ages. A direct relationship was found between the gestational age of the premature infant and his ability to maintain vitamin E sufficiency during the first 3 months of life; infants of lowest gestational age were least able to achieve vitamin E sufficiency, even when receiving a vitamin E supplement. In infants whose gestational age was less than 32 weeks, progressive improvement in the intestinal absorption of the vitamin was seen as the chronologic equivalent of a full-term gestational age was approached. Oral administration of iron is implicated as interfering with the intestinal absorption of vitamin E. Since maintenance of vitamin E sufficiency appears to be nutritionally important in the premature infant, the efficacy of other routes of administration of the vitamin should be explored.

The article1 in the October 1968 issue on "Platelets in Prematures" deserves more than a few remarks in the commentary relative to the incidence and hazards of thrombocytopenia. The article is good in that it serves as a guideline relative to the range in platelet levels among premature infants, but the reader should not accept this simply as the normal range. For example, there is no discussion on the remarkably large number of infants with platelet counts above 400,000/mm3.

Serial IgG determinations were carried out on 29 children with acute leukemia. With the exception of the pretreatment assays, all determinations were performed during the course of specific antileukemic therapy. Following the initial introduction to cytotoxic agents, a significant, although temporary, reduction in IgG level occurred. The continuous use of antileukemic agents did not alter the IgG levels. Relapses, responsive to changes in therapy, were usually associated with moderate reductions in the IgG levels. Greater reductions in IgG levels occurred following the institution of changes in therapy. In both instances the declines were followed by a return in IgG to the normal range. Declines of significantly greater magnitude and rate occurred in those patients no longer capable of responding to therapy changes. In such patients, levels below 3.8 to 3.5 mg./ml. signified impending death, a lack of response to infection and inability to evoke an IgG response. An example of the interrelationships between clinical and immunologic responsiveness is shown by the patient in complete relapse with a normal IgG assay, who went into remission and had an impressive IgG response following a rubeola infection. Shortly thereafter, her disease process entered an irreversible relapse stage with an IgG level of 2.9 mg./ml., and death occurred within 30 days following a bacterial septicemia. The relationship between hematologic and immunologic responsiveness raises the provocative question of paradoxically maintaining an immunologically responsive state as a means of prolonging the survival time in the face of persistent immunosuppressive therapy.

Studies of red cell hydrogen peroxide hemolysis and intestinal absorption of vitamin E were conducted in 21 infants whose major presenting symptom was jaundice, in order to evaluate the efficacy of these simple laboratory techniques in differentiation of their disease conditions. The peroxide hemolysis test is based upon the assumptions that the intestinal absorption of fat-soluble vitamin E requires adequate amounts of bile salts and that vitamin E deficiency is reflected by abnormal sensitivity of the red cell membrane to hydrogen peroxide. Ultimate diagnoses in the infants studied, 14 of whom underwent open liver biopsy and operative cholangiogram, included biliary atresia, neonatal hepatitis, and primary congenital hemolytic processes. Although a single red cell hydrogen peroxide hemolysis test did not clearly differentiate between the various conditions studied, peroxide hemolysis used in combination with vitamin E absorption curves showed distinctly different patterns for each group of diseases. The information gained thus enabled prediction of the jaundice with accuracy and indicates that these laboratory techniques can be of great value in guiding the decisions regarding the necessity and timing of surgical exploration in jaundiced infants.

Normal white blood cells were cultured in plasma obtained from leukemic subjects during active disease and during remission. No mitotic activity was discernible with “remission” plasma, whereas normal cells cultured in “active” plasma showed considerable mitotic activity. Conversely, leukemic cells cultured in normal plasma showed no mitotic activity. It is proposed that there is present in leukemic plasma, during the active stages of the disease, a factor(s) capable of inducing mitoses in normal white cells.

The mean platelet count in 102 children with congenital cyanotic heart disease was found to be 235,000/mm3 ± 1 S.D. of 85,000/mm3 as compared to 260,000 ± 70,000 in an age-matched group of normal children. In the cyanotic children, whose mean oxygen saturation was >80%, the mean platelet level was 315,000/mm3 as compared to 185,000/mm3 in the 80% oxygen saturation group was 13.2 gm/100 ml as compared to 17.2 in the

VARIOUS epidemiological studies of childhood leukemia have been carried out in an attempt to determine whether certain host and environmental factors play a role in the pathogenesis of leukemia. 1-4 The relationship between incidence and socioeconomic background, peak incidence, age at onset, and seasonal variations have been examined, and the results of these studies have shown certain suggestive patterns. The relationship of certain genetic factors has been investigated, and in this regard it is known that the prevalence of leukemia among children with Down's syndrome is many times that expected; but whether other genetic factors play a role is much less obvious. Time and space relationships have also been examined, but statistical interpretations because of arbitrary designations have been inconclusive. 3,5 Most of the studies have focused on one or several of these points but were not part of a more comprehensive survey. In this study an attempt has been

Blood volume studies with the use of IHSA 131I were done on 25 normal children and 25 children with sickle cell anemia. Values which appeared to be significantly different when related to weight were no longer different when related to height. The best correlation was obtained when log blood volume was related to log height. Study of this relationship indicated that there was no significant volume difference between the anemic and normal children. Since volume relates best to lean body mass or to body water, the use of body weight alone as the basis for its determination will be inaccurate in individuals whose weights deviate from normal, if this deviation is clue essentially to fat. Thus, previous studies of high volume values in anemic children were probably related to the use of weight as the reference parameter. The following formula is recommended to calculate blood volume based on height: log B.V. = 0.247 + 2.14 log Ht.

The controversy surrounding the report of the Committee on Nutrition of the American Academy of Pediatrics regarding iron fortified formulas1 has stimulated us to submit the following further observations. It is evident that iron fortified formulas are efficient sources of iron. Equally well known is the fact that the incidence of nutritional iron deficiency is greatest in infants of lower socioeconomic groups. Providing these infants with iron supplemented formulas will effectively combat iron deficiency. However, despite an occasional comment to the contrary, it is our experience that the incidence of nutritional iron deficiency among infants in upper socioeconomic groups is exceedingly low.

The cardiac status of 36 children with sickle cell anemia, aged two to 17 years, was evaluated, by means of physical examination, phonocardiogram, chest roentgenogram, electrocardiogram, and Frank vectorcardiogram. Their hemoglobins were from 3.6 to 10.8 gm per cent. Pertinent physical and phonocardiographic findings were: (a) suprasternal notch thrill in 15 children, (b) abnormally loud third sound in 19, (c) prominent systolic ejection murmurs in all, with one having an apical holosystolic murmur, and (4) apical mid-diastolic rumble in 11. Chest roentgenograms revealed cardiac enlargement in 32 children, of which, ten showed marked cardiomegaly. The aortic arch was unduly prominent in 17 children. Of the 15 with suprasternal notch thrills, 11 had a prominent aortic arch. The electrocardiograms were normal in four children, showed LVH in 22, and CVH in two. Of the 30 vectorcardiograms, five were normal, 14 had LVH, three had RVH, and eight had CVH. The explanation for the inability of the electrocardiogram to detect right ventricular hypertrophy was usually the masking of a large terminal rightward force by a large posterior vector. There were certain significant differences in the magnitude of vector projections and of the timed, maximum and one-half area QRS vectors, as well as the T vectors between the children with sickle cell anemia and the normal. The hemoglobins of the children with cardiovascular abnormalities were significantly lower than those without these abnormalities.

We would like to offer several comments about the article by Wishingrad and Elegant concerning replacement transfusions (Pediatrics, 28:331, 1961). The authors consider a positive Coombs test sufficient indication for an exchange transfusion in an erythroblastotic infant born into a family in which previously affected siblings have required exchange transfusions. A positive Coombs test does not of itself serve as adequate indication for an exchange transfusion. There must exist the same criteria for an exchange transfusion in any affected patient, particularly when one considers the fact that this procedure is not totally benign.

Quantitaticn of peripheral blood lymphocyte immunoglobulin biosynthesis was evaluated as a method for detection of humoral immunodeficiency. Lymphocytes isolated from 3-15 cc of heparinized blood, using Ficoll-Hypaque gradients, were incubated in leucine free medium (1×106 cells/cc) with tritiated leucine for 48 and 72 hrs. Newly synthesized secreted IgG and total immunoalobulins were measured using specific anti-immunoglobulin antibodies coupled to insoluble bromacetylcellulose. Synthesis was readily detected in newborn infants as young as 28 wks gestation. The normal range (6 individuals) for total immunoglobulin synthesis and IgG synthesis was 1.3-5.5%, and 0.3-1.6%, respectively, of total secreted proteins. The lymphocytes of a patient with X-linked agammaglobulinemia synthesized no immunoglobulins. In a patient with non-X-linked agammaglobulinemia (with B-cells), total immunoglobulin and IgG synthesis was 0.20% and 0.13%, respectively. A patient with common variable hypogammaglobulinemia (normal IgM, low IgG, absent IgA) also showed depressed synthesis (total immunoglobulins 0.70%, IgG 0.40%). Quantitation of lymphocyte immunoglobulin biosynthesis appears to be a useful technique for the early diagnosis of humoral immunodeficiency and may be of potential value for the detection of immunodeficiency disease carriers.

In 1953, Weiner et al1published the first well documented case of a specific auto-immune hemolytic anemia, an adult from whose serum and red cell eluate antibodies with anti-e specificity were isolated. Subsequently, additional reports of specific auto-antibodies appeared in the literature and with rare exception were shown to be part of the Rh system.2-4Reference to the majority of these cases has been cited by Dacie,5who noted that the incidence of specific auto-antibodies approximated 30%, with anti-e being the most common. However, prior to 1961, no reports of specificity had been described among the 30 carefully reviewed cases in infants under 1½ years of age.6-8Shortly thereafter, the first such examples were reported by Laski and co-workers,9who described a 5½-month-old infant with anti-E and anti-f and a 2½-month-old infant with anti-D antibodies. The present report is a description of anti-D specificity in