James A. Stockman

Occlusion of Large Cerebral Vessels in Sickle-Cell Anemia

Abstract Seven patients with sickle-cell anemia and neurologic deficits secondary to Central-nervous-system dysfunction were studied with cerebral angiography after careful preparation. Preparation of the patient reduced the level of S hemoglobin to less than 20 per cent before study, and all studies were performed without sequelae. Six of the seven patients were found to have partial or complete occlusion of large cerebral vessels. The internal carotid artery was involved in all six patients. Disease in the anterior and middle cerebral arteries as well as the vertebral artery was also observed. Two patients had repeat studies. The disease appeared to be progressive. These findings, rarely reported, indicate that the common clinical assumption that the Central-nervous-system manifestations of sickle-cell anemia are a consequence of exclusively small-cerebral-vessel obstruction may in fact be erroneous.

Iron Absorption in the Thalassemia Syndromes and Its Inhibition by Tea

To determine the hemoglobin concentration at which iron absorption is minimal, five subjects with thalassemia major and one with thalassemia intermedia underwent a series of iron-absorption studies. The effect of tea as an inhibitor of non-heme iron absorption was also tested. Iron absorption increased as the hemoglobin concentration decreased, although iron absorption was much higher at any given hemoglobin level in the subject with thalassemia intermedia. In the subjects with thalassemia major, iron absorption averaged 10 per cent at hemoglobin concentrations between 9 and 10 and 2.7 per cent between 11 and 13 g per deciliter. The percentage of iron absorbed could be accurately predicted from the nucleated red-cell count (r = 0.91, P less than 0.001). Tea produced a 41 to 95 per cent inhibition of iron absorption. Since patients with thalassemia intermedia may absorb a large percentage of dietary iron, inhibitors of iron absorption, such as tea, may be useful in their management.

Iron Deficiency Anemia and Increased Urinary Norepinephrine Excretion.

Chronic iron deficiency in rats resulted in decreased MAO activity both in vitro and in vivo. Since MAO is an important enzyme in inactivation of catecholamines, urinary excretion of DA, NE, E, MN-NMN, and VMA was measured in 24-hour samples from 11 iron-deficient children before and after treatment with intramuscular iron. Pretreatment NE excretion was abnormally high and returned to normal (P=0.001) within one week of therapy. VMA excretion also was higher before than after treatment (P greater than 0.05), but most values were within the normal range for healthy children of comparable size. There was no significant difference between DA, E, and MN-NMN excretion before and after iron therapy. Anemic, non-iron-deficient children had normal urinary NE, E, and VMA excretion before and after transfusion. These findings suggest that the irritability, lack of attentiveness, and low performance scores of iron-deficient children may be related to alterations in catecholamine metabolic pathways secondary to dependence of MAO on adequate iron stores.

A prospective randomized study to determine the efficacy of steroids in treatment of croup.

We evaluated the use of dexamethasone in the management of acute laryngotracheobronchitis (croup). Thirty patients, ranging in age from eight to 60 months, were evaluated in a prospective, double-blind study. Patients received dexamethasone, 0.3 mg/kg at the time of admission and a similar dose 2 hours later, and were compared with a placebo group receiving saline. Sixteen patients received dexamethasone and 14 patients received the placebo. Severity of each group was scored by a standardized system. Patients receiving dexamethasone had a mean admission score of 8.46 points; patients receiving placebo, 8.14. Twenty-four hours after admission the patients in the treatment group had a mean score of 1.19 as contrasted with a score of 5.58 for the placebo group (P less than 0.01). We concluded that dexamethasone when administered in adequate dosage by an intramuscular route hastens the recovery of infants and children with acute uncomplicated croup.

Effects of intravascular, intrauterine transfusion on prenatal and postnatal hemolysis and erythropoiesis in severe fetal isoimmunization

In an investigation of the effects of intrauterine, intravascular transfusions (IUT) on fetal and neonatal hemolysis and erythropoiesis, 12 fetuses who received IUT for treatment of severe isoimmunization had serial measurements of hemoglobin concentration, Kleihauer-Betke stains to detect fetal hemoglobin-containing erythrocytes, and determination of plasma erythropoietin (EPO) concentration before each IUT, at birth, and postnatally. Reticulocyte counts and sensitizing antibody titers were measured in five fetuses. Mean values before the first IUT, before the final IUT, and at birth were as follows: hemoglobin level, 6.1, 9.1, and 11.3 gm/dl; reticulocyte count, 22.7%, 0.5%, and 0.9%; fetal hemoglobin-containing erythrocytes, 100%, 1.6%, and 1.5%; and EPO level, 12, 56, and 756 mU/ml, respectively. Only one neonate required exchange transfusion. In the first month postnatally, all infants had a profound anemia. All but one infant required simple blood transfusions postnatally. Before the first postnatal transfusion, mean hemoglobin concentration was 6.2 gm/dl, mean reticulocyte count was 0.8%, mean erythropoietin concentration was 23 mU/ml, and the sensitizing antibody titer remained markedly elevated. Except for the surge of EPO at birth, EPO levels did not rise prenatally or postnatally unless marked anemia (hemoglobin level less than 5 gm/dl) occurred. These observations suggest that the intrauterine and postnatal anemia in fetuses who receive IUTs may be explained both by hemolysis of newly formed erythrocytes by circulating antibody, which typically persisted for more than a month after birth, and by suppressed erythropoiesis.

Abnormalities of platelet aggregation in the vaso-occlusive crisis of sickle-cell anemia.

An impairment in the rate and per cent of first phase platelet aggregation with ADP was present in 10 patients with sickle-cell anemia during vaso-occlusive crises, when compared to their own base-line values and those of 20 normal control subjects. ADP released from erythrocytes or platelets could have been the mediator of this platelet “refractory state” since a concomitant decrease in platelet adhesiveness during the vaso-occlusive crises was also demonstrable. The effect of the platelet on the production or maintenance of the vaso-occlusive crisis of sickle-cell anemia requires further elucidation.

Oversimplifying Primary Care Supply and Shortages

RECENT REPORTS HAVE WARNED OF A CRISIS RELATED to a shortage of primary care physicians. However, much of the current concern seems to have stemmed from articles in the medical literature specifically reporting that fewer internal medicine residents are choosing to pursue primary care and that fewer medical students are choosing family medicine residencies. Hauer et al found, among a national sample of fourth-year medical students, that only 22% planned careers in internal medicine and just 2% intended to practice general internal medicine. Ebell hypothesized that fewer medical students are choosing primary care specialties as a result of lower salaries relative to other specialties. It is important to note that the results of his trend-line analysis showed this was true only for family physicians. There has not been an appreciable change in the proportion of pediatric residents who choose primary care pediatrics. Thus, the concerns expressed regarding primary care should really only focus on the care of adults. While this is a large and important patient population, adults are not the only group served by primary care physicians. Historically, primary care has encompassed internal medicine, pediatrics, and family medicine; in some instances, obstetrics/gynecology is included. These groups are similar with respect to their primary care roles, but they are markedly different in many other ways, including workforce projections. For these reasons, it is disappointing that national discussions about the “crisis in primary care” have moved beyond the valid concerns regarding a shortage of physicians providing primary care to adults and have somehow come to imply a shortage of all primary care physicians. Multiple government reports also fail to distinguish among the primary care specialties when reporting on the crisis in primary care. For example, in its February 2008 report to Congress, the Government Accounting Office reported findings predicting a shortage of primary care physicians in 2018, without reference to specific specialties. Assessments by those tasked with determining sufficiency of training the physician workforce are no more specific. A 2005 report by the Council on Graduate Medical Education did not distinguish among the primary care specialties when assessing the future training needs of the country in this important area. The need to understand primary care workforce issues in a specialty-specific manner is critical, because any policy changes or economic incentives that affect the proportion of physicians pursuing primary care will likely have a differential effect across the primary care specialties. For example, it might be viewed as positive if the number of internal medicine residents who pursue primary care were to double. Indeed, a November 2008 American Medical Association news release reported a new policy aimed at “increasing the ranks of primary care physicians” without any reference to specific primary care specialties. However, the most recent published data regarding pediatric residents completing training in 2008 demonstrated that 40% were planning to pursue a career in primary care, with 10% still undecided. Similar findings were seen among senior residents scheduled to complete their training in 2009 (G.L.F. and J.A.S., unpublished data, 2008). Thus in pediatrics, a doubling or substantial increase of the proportion entering primary care could result in a possible oversupply of primary care pediatricians, likely at the expense of needed pediatric subspecialists. Markedly increasing the number of primary care pediatricians in the pipeline could create more such physicians than jobs available, resulting in the opposite effect of any intended legislation or other policy solution aimed at primary care. In contrast, the idea that there is a shortage of primary care pediatricians—or that, relative to the past, there are fewer primary care pediatricians to care for the current population of children—is contrary to published workforce and population data. While the absolute number of children in the United States has remained relatively stable, the number of pediatricians has increased substantially (FIGURE). This has resulted in an increase in the number of primary care pediatricians, from 32 to 78 per 100 000 children in the period 1975 to 2005. Similarly, there has been an increase in

Unilateral optic neuropathy following vincristine chemotherapy.

Two subjects with acute lymphatic leukemia have been observed to have unilateral optic neuropathy five to seven days following administration of Vincristine (2.0 mg/sq m) during maintenance chemotherapy. Both subjects were in mission at the time their ocular problems developed. After discontinuance of Vincristine therapy, marked vision improvement in the affected eye occurred over the ensuing months. It is presumed that Vincristine therapy was the cause of toxic optic neuropathy in these patients.

Erythropoietin in cyanotic heart disease

We hypothesized that children with cyanotic congenital heart disease and moderate hypoxemia, as a result of erythrocytosis, and adequate iron stores would have low serum erythropoietin titers, low tissue oxygen delivery, and normal red cell 2,3-diphosphoglycerate (DPG) concentrations. We assessed hemoglobin levels, aortic oxygen saturation, iron stores, red cell 2,3-DPG, oxygen consumption, and systemic O2 transport in 19 hypoxemic patients, aged 3 months to 8 years. Low erythropoietin titers (less than 30 mU/dl) were found in 14 patients. Patients with high erythropoietin titers had lower Pao2 (36 +/- 7 vs 49 +/- 7 mm Hg, p less than 0.01), lower aortic saturation (68 +/- 12 vs 81 +/- 9%, p less than 0.01), and higher red cell 2,3-DPG (2.47 +/- 0.34 vs 3.23 +/- 0.73 mumol/ml, p less than 0.01). Aortic oxygen saturation higher than 80% was associated with a low erythropoietin titer and a hemoglobin level below that associated with hyperviscosity. The relationship between aortic oxygen saturation and hemoglobin concentration was strong (r = 0.77). These data suggest that for children less than 8 years of age, adequate compensation for moderate hypoxemia can occur with moderate increases in hemoglobin levels.

Preleukemic states in children with acute lymphoblastic leukemia

Two cases are reported of childhood acute lymphoblastic leukemia presenting with preleukemic states and 13 other cases in the literature are reviewed. Hypoplastic anemias, which transiently resolved spontaneously or with steroid therapy, were seen most commonly. Acquired hypoplastic anemias, even when associated with spontaneous resolution, may at times represent a preleukemic state.