The polycythemia of high altitudes: iron metabolism and related aspects

Observations on the iron metabolism as related to the influence of a lowoxygen tension at high altitudes, and after the disappearance of this factorupon return to sea level, have been made in human subjects. They consistedmainly of studies of intestinal absorption and turnover rate of iron by meansof the radioactive isotope of this metal (Fe-⁵⁹). Additional observations weremade on blood volume, reticulocytosis, bone marrow cytology, life span ofthe red cells and hemoglobin breakdown pigments. The data obtained seemto justify the following conclusions:

1. There is an increase of intestinal iron absorption during the early periodof exposure to an altitude of 14,900 feet. After 48 hours of exposure, this wasestimated to be about 3 times higher than the absorption observed in subjectsat sea level and in native residents at the above-mentioned altitude.

2. There is an increase of plasma and red cell iron turnover rates after 2hours of arrival to 14,900 feet, indicating that the increase in the productionof red cells, to compensate for hypoxia, is a very early response.

3. The highest increase in plasma and red cell iron turnover rate takes place7 to 14 days after exposure to high altitude begins. After six months of exposure, there is still an elevated iron turnover rate. The native residents ofhigh altitudes (14,900 feet) have a red cell iron turnover rate of approximately30 per cent higher than healthy subjects at sea level.

4. A progressive decrease in the plasma and red cell iron turnover rate isobserved in native residents of high altitudes when brought down to sea level,the maximum of which is reached after two to five weeks, indicating a greatdegree of depression on red cell production. After that, a gradual return tonormal rate is observed in the weeks that follow.

5. The degree of reticulocytosis is in close relationship with changes in thered cell iron turnover rates.

6. Changes in the total blood volume, either during ascent or descent, takeplace only after several weeks. The red cell mass variations which occurduring the early periods of environmental change, are compensated by proportional changes in the plasma volume. The increase or decrease of the totalblood volume after this period is due exclusively to red cell mass modifications.

7. The bone marrow cytologic studies carried out in subjects temporarilyexposed or living permanently at high altitudes show a hyperplastic condition.The reverse, or an inhibition of red cell production, takes place when highaltitude polycythemic subjects are brought down to sea level. This constitutesthe cytologic counter-proof for the iron turnover studies.

8. The life span of the red blood cells, after descent from high altitudes tosea level, falls within normal patterns. However, by the method employed itis not possible to determine if there is an increased destruction of red cellsduring the first week. But if there is a greater destruction, this would be of asmall degree, affecting only the older elements. The increase in the hemoglobin breakdown pigments, which occurs under the influence of environmentalfactors, is also discussed.

9. In native residents of high altitudes the amount of free erythroprotoporphyrins is higher than in residents at sea level. The erythroprotoporphyrins innewcomers to high altitudes rise and reach a peak at the end of the secondmonth, followed by a gradual decline. On the other hand, when high altitudenatives are brought down to sea level, a marked decrease in erythroprotoporphyrins is noted. The rate of decrease is highest within the first months.

Submitted on June 11, 1958 Accepted on September 26, 1958     

Congenital Erythropoietic Porphyria. II. The Effects of Induced Polycythemia

Polycythemia and anemia were inducedin a patient with congenital erythropoietic porphyria as a possible means ofaltering erythropoiesis and its attendantporphyrin production. Maintenance ofhematocrits at 50 per cent and 60 percent for periods of 2 weeks decreasedboth erythropoiesis and porphyrin excretion to about one-half of their initiallevels. Conversely with a hematocrit of25, erythropoiesis and porphyrin production were increased to about twice thebasal level. Examination of the marrowshowed fluorescence in all late normoblasts and indicated that the patient hasonly one red cell population. During induced polycythemia, a shift in marrowerythroid population to relatively matureforms, apparently related to delayedenucleation, was accompanied by a retention of the reticulocyte pool andfluorescent cells within the marrow. During anemia, the occurrence of relativelymore immature erythroid cells was accompanied by a shift of the reticulocytepool and fluorescent cells into the circulating blood. During polycythemia, increases were observed in the relativenumber of nuclear vacuoles peculiar tothis disease, in the retention of radioironin the marrow and in the relative amountof stercobilin excretion. In anemia theseparameters decreased towards normal.

Submitted on June 30, 1969 Revised on March 16, 1970 Accepted on April 1, 1970     

Iron metabolism; utilization of intravenous radioactive iron

By determining the percentage utilization of intravenously administered radioiron for hemoglobin production over a period of two to three weeks, certainmeasurements of internal iron metabolism can be made.

With a normal rate of blood production, changes in per cent utilization reflectalteration in iron stores. Iron depletion is characterized by more rapid and morecomplete utilization of radioiron. States of iron excess in hemochromatosis can beidentified by their profound depression of radioiron utilization.

If, on the other hand, storage iron is not greatly altered, the percentage utilization is determined by the function of the erythropoietic tissue. In myelophthisicanemias, in uremia, and in infection, a similar depression of the curve is found.

The rate of erythropoiesis may further be estimated by the slope of the utilization curve, and evidence of abnormal red cell destruction is found in early andabrupt plateau of the utilization curve.

A correlation has been made in a variety of hematologic disorders between theradioiron utilization for hemoglobin production and the clinical factors whichmight be expected to affect iron metabolism in these patients.

     

Hookworm Anemia: Iron Metabolism and Erythrokinetics

Iron metabolism, balance of red cell production and destruction and ironabsorption from hemoglobin were determined in 11 patients with heavy hookworm infection and severe anemia.

The plasma iron, total iron binding capacity, bone marrow hemosiderinand plasma Fe⁵⁹ clearance are in agreement with the idea that the anemia associated with hookworm infection is of the iron deficiency type.

The rate of red cell production measured by the E/M ratio, absolute reticulocyte count and plasma iron turnover showed an increase to about twicenormal, while the rate of destruction estimated by the T erythrocytesurvival showed a destruction about 5 times normal. This unbalance betweenproduction and destruction could explain the severity of the anemia.

The increase of fecal urobilinogen output to twice normal was interpretedas due to the metabolism of the hemoglobin lost into the intestine rather than toan increase of hemolysis.

The estimation of fecal blood loss in the patients whose red cells weretagged with Cr⁵¹ and Fe⁵⁹, showed that the radioactivity counted with Fe⁵⁹was only about 63 per cent of the radioactivity counted with Cr⁵¹. This difference was interpreted as due to iron absorption from the hemoglobin lostinto the intestine.

The mean daily fecal excretion of iron reaches 4.7 mg. Since the ironmetabolism in these patients is in equilibrium, we have concluded that theiron loss is replaced by the iron from food; this is in addition to the 3 mg.hemoglobin iron which is reabsorbed from the blood lost into the gut.

Submitted on January 9, 1961 Accepted on April 2, 1961     

Increased Formation of Early-Labeled Bilirubin in Rats with Iron Deficiency Anemia: Evidence for Ineffective Erythropoiesis

The production of early-labeled bilirubin and erythrocyte hemoglobin hemewas measured in rats with iron deficiency anemia, using glycine-2-¹⁴C asprecursor. The erythropoietic component of the early pigment fraction wassignificantly augmented and the formation of labeled hemoglobin depressed inthe anemic animals, findings characteristic of ineffective erythropoiesis. Bycontrast, the hepatic component of early-labeled bilirubin was substantiallyenlarged during the acute response to iron therapy. These experiments illustrate that overproduction of bilirubin may originate from both erythropoieticand hepatic sources of the early-labeled fraction of bile pigment, as well asfrom hemolysis of circulating red blood cells.

Submitted on November 14, 1968 Accepted on January 21, 1969     

The anemia of the Di Guglielmo syndrome

The physiopathology of the anemia of the Di Guglielmo syndrome (erythremic myelosis) was studied in 11 patients with the acute and chronic varieties of the disease. Ferrokinetic studies were performed in three additionalpatients.

1. The anemia was normochromic and macrocytic; in contrast to the meancorpuscular volume, which was elevated, the mean corpuscular hemoglobinwas often normal. In several patients the mean corpuscular hemoglobin concentration was slightly lower than normal, suggesting slight hypochromia.

2. Reticulocytes were often increased but bore no relationship to the degree of the anemia nor to the shortening of the red cell life span. The reticulocyte count is an unreliable index of blood production in this disease.

3. The degree of erythroblastemia was highly variable. No direct correlation existed between the degree of erythroblastemia and the acuteness of thedisease, nor was there any relationship between the degree of erythroblastemiaand either the degree of anemia or the degree of erythrocytic destruction.

4. The bone marrow showed striking erythroblastic hyperplasia. This wasusually of the megaloblastic type. Primitive erythroblasts (erythrogones) wereconspicuous. The erythroblastic hyperplasia was out of proportion to the relatively minor reticulocytosis or the relatively slight diminution in red cellsurvival.

5. The nucleated red cells of the marrow showed variable numbers ofmegaloblasts and megaloblastoid forms, suggesting the presence of a vitaminB₁₂ deficiency (pernicious anemia). However, the vitamin B₁₂ concentrationof the serum was elevated, and there was no response to the administrationof vitamin B₁₂ or folic acid.

6. Varying numbers of erythroblasts in the bone marrow and in the peripheral blood showed periodic acid-Schiff (PAS)-positive granules in the cytoplasm. No chemical abnormalities of hemoglobin could be detected either bythe method of paper electrophoresis or by the alkali denaturation test.

7. Diminished red cell survival was present in most cases, but it was of arelatively slight degree. It was due to an "intracorpuscular" defect of the redcells.

8. The often great increase in fecal urobilinogen output as compared witha relatively minor rate of red cell destruction suggests "heme pigment diversion" or increased destruction of precursor red cells, as in pernicious anemia,where the same phenomenon has been observed.

9. The great increase in the number of erythroid cells in the bone marrowand the increased rate of iron turnover as compared with the relatively minorincrease in red cell destruction and iron utilization point to an "ineffective"type of erythropoiesis. The high degree of "ineffective erythropoiesis" seenin this disease may be characteristic of the neoplastic proliferation of the redcell series.

10. In conclusion, the anemia of the Di Guglielmo syndrome is due to acombined disturbance: (1) an "ineffective" type of erythropoiesis of markeddegree, perhaps due to an acquired (neoplastic) defect in the uptake or utilization of B₁₂ by the erythroblasts and (2) increased hemolysis resulting fromthe increased destruction of defective red cells.

Submitted on June 11, 1958 Accepted on August 13, 1958     

Erythrokinetics in pernicious anemia

Quantitative measurements of the erythropoietic activity of the marrow, ofcirculating red cell production and destruction have been made in patients withpernicious anemia in relapse and during response to vitamin B₁₂ therapy.

Total erythropoietic marrow activity as reflected by turnover of heme components proceeds at a rate of approximately 3 times normal. The delivery ofviable red cells to the circulating blood, however, does not increase above normal. This would indicate that the greater portion of marrow activity is ineffective in terms of blood production. This marrow dysfunction coupled with anincreased rate of cell destruction of approximately 3 times normal is responsiblefor the anemia. Total erythropoiesis is somewhat less, and effective erythropoiesisconsiderably less, than that which may be expected of the normal marrow underthe sustained stimulus of anemia.

The reticulocyte count is shown to be an unreliable index of blood productionin untreated pernicious anemia due to loss of reticulum from cytoplasma ofmany red cells before their delivery into circulation.

During the response to vitamin B₁₂ the ineffective erythropoiesis is convertedto effective erythropoiesis, whereas total erythropoiesis remains unchanged.The rate of blood production during recovery is 3 to 4 times normal.

Submitted on January 23, 1956 Accepted on May 3, 1956     

Studies on abnormal hemoglobins. III. The interrelationship of type S (sickle cell) hemoglobin and type F (alkali resistant) hemoglobin in sickle cell anemia

1. It could be demonstrated that of the three tested types of human hemoglobin—N (normal adult), S (sickle cell) and F (fetal)—only the reduced S compound shows tactoid and gel formation in sufficiently concentrated solutions.These physico-chemical phenomena may be used for the qualitative identificationof S hemoglobin.

2. The alkali resistant hemoglobin fraction, present in sickle cell anemiaerythrocytes (but not in trait red cells), was concentrated in purified form. Notactoid or gel formation could be elicited. Therefore, this alkali resistant pigment does not appear to be a variant of S hemoglobin. It seems probable thatsickle cell anemia erythrocytes contain two separate types of pathologic hemoglobin (S and F) which are not directly related to each other.

Submitted on June 21, 1951 Accepted on July 23, 1951     

Changes of hematocrit and hemoglobin concentration in the cold Himalayan environment in dependence on total body fluid

Introduction

The organism is exposed to a considerable hypoxic stress at high altitude, and the well-known polyglobulia is an effective strategy to sustain oxygen delivery to the tissue at reduced saturation of hemoglobin. In general, an increasing erythropoiesis is thought to be the reason, although this increase of red blood count can be observed after a short time of altitude exposure and the parameters are expressed as water-depending concentrations. Therefore, the influence of water distribution on hemoglobin (Hb) and hematocrit (Hct) values during a long-term exposure at high altitude was investigated.

Materials and methods

Measurements were performed in 12 mountaineers before, during, and either 7/8 or 11/12 days after a Himalaya expedition (26–29 days at 4,850 to 7,600 m altitude). Arriving at 4,850 m an initial increase of Hb and Hct was followed by a short decrease during the first week and a continuous increase during the further stay.

Results

In maximum, 131.3% (Hb) and 117.4% (Hct) of the starting point were reached during the fourth week at altitude after the attempt to reach the summit of Broad Peak (8,047 m). Parallel the dehydration in the beginning turned to a hyperhydration at the end of the stay (D₂O method).

Discussion

Erythropoietin rose only temporarily at altitude (max. +11 +1 mU/ml serum). Upon return, Hb and Hct normalized within a few days whereas hemoglobin mass (initially 881+ 44 g, CO-Hb method) was still increased by 13% (p?<?0.01).

Conclusion

In conclusion, a hemoconcentration effect (dehydration) is the reason of the initial peak of Hb and Hct. The further increase can only partially be explained by an absolute increase of Hb and Hct caused by stimulated erythropoiesis. A shift of intravasal fluid to the interstitial space is the other main reason of the observed changes in red blood count.     

Studies on the Erythropoiesis Inhibiting Factor in the Plasma of Animals with Transfusion Polycythemia

Further investigations of the action of polycythemic plasma filtrate were madeusing Fe⁵⁹ and with detailed examination of the blood and bone marrow. Thesestudies confirmed the appearance of an active thermostabile plasma factor(erythropoiesis inhibitor) which depressed erythropoiesis in normal rabbits orrats. The plasma obtained from bilaterally nephrectomized sheep subjectedto transfusion polycythemia also contained the erythropoiesis inhibitor. Blockade of the reticuloendothelial system using trypan blue, in sheep, inducedproduction of the active substance similar or identical with the erythropoiesisinhibitor produced after transfusion polycythemia.

Submitted on November 2, 1960 Accepted on October 10, 1961     

Hematologic observations of the course of erythroblastosis fetalis

Serial studies revealed characteristic changes in the peripheral blood ofinfants with erythroblastosis fetalis. In the presence of elevated nucleated redcells and reticulocytosis, replacement transfusion brought about a momentarydecline to normal levels followed by a second rise during the succeeding threedays before the values returned to low levels. Platelet counts diminished withina day after replacement and only gradually rose toward normal after approximately three days. Such a picture was not seen in the mildly affected babies whodid not receive replacement therapy, in whom the platelet values varied.

Within the first three months in both groups anemia developed in the presenceof little evidence of compensating marrow activity. After a decline of the hemoglobin to an average level of 7.6 Gm. per cent, erythropoiesis became adequatefor return to normal levels. This hypoplastic defect could not be correlated withany other parameter of the disease.

Abnormalities were noted in the osmotic and mechanical fragility of the redcells in this disease. The major population of cells was found to be more susceptible to osmotic stress while the limits of hemolysis were within the normalrange. The osmotic curves of the blood of those patients who were not transfused returned to normal within 4 weeks. Mechanical fragility of the red cellswas increased in a significant number, and this abnormality was observed untilthe time when minimal hemoglobin values were reached. There was no correlation of these variations in fragility with other laboratory or clinical manifestations of the disease.

Submitted on December 17, 1954 Accepted on February 20, 1955     

Idiopathic Dyserythropoietic Jaundice

1. The term "dyserythropoietic jaundice" is used to designate a peculiarabnormality characterized by marked overproduction of bilirubin and associated with unconjugated hyperbilirubinemia and great excesses of fecalurobilinogen. Labeling with N¹⁵ glycine revealed that these excesses weremainly unrelated to destruction of mature circulating red cells, which hadonly a slightly shortened life span.

2. The hyperplastic, normoblastic bone marrow exhibited considerablephagocytosis of red cells and normoblasts and marked hemosiderosis withmany iron-laden phagocytes. Siderocytes were relatively rare in the peripheralblood, which also exhibited consistent reticulocytosis, 3-10 per cent, butnormal erythrocyte porphyrin concentrations. There was increased plasmairon turnover but decreased appearance of Fe⁵⁹ in the circulating red cells.

3. The possibility is considered that there is a basic abnormality in hemoglobin synthesis in the normoblasts, with excessive production of hemoglobin or heme which is then converted to bilirubin either within thenormoblast or after excretion into the blood. The observed phagocytosis ofnormoblasts and erythrocytes may be a secondary rather than basic disturbance of the disease.

4. This case appears to represent a unique form of chronic jaundice dueto a remarkable overproduction of bilirubin without evidence of hemolysisin the ordinary sense. The extent to which this is related to intramedullarydestruction of young red cells or to a basic abnormality in hemoglobin synthesis in the normoblasts, as above, cannot be determined. It is consideredless likely that the overproduction is due to a true shunt—that is, bilirubinformation from porphyrin precursors. The marked dyserythropoiesis suggeststhat the overproduction of bilirubin was medullary rather than hepatic,although the latter is not excluded.

Submitted on December 26, 1963 Accepted on March 3, 1964     

The anemia of trauma

1. The anemia of civilian trauma (mainly limb injuries) has been studied in57 patients.

2. In 22 patients the red cell volume, after primary blood loss has probablyceased, has been compared with the follow-up "normal" red cell volume. Thered cell volume credit or deficit is taken as an index of the balance betweenprimary blood loss and blood transfused, and was found to be the major factorcontributing to the later polycythemia or anemia. The evidence suggests that ananemia of trauma due to unreplaced primary blood loss is still a common findingin civilian injuries today.

3. A further red cell volume estimate in 20 patients on the 4-14th day afterinjury showed on average a further fall of 11 per cent of the red cell volume.Evidence is presented for considering that there is a further disappearance ofred cells after primary blood loss has ceased in all patients—even in those whosered cell volume did not fall.

4. The evidence suggests that the anemia of trauma is largely preventable byadequate blood transfusion in the majority of civilian injuries.

Submitted on August 15, 1955 Accepted on October 15, 1955     

Studies of the production and life span of erythrocytes in myeloid metaplasia

1. Four patients with agnogenic myeloid metaplasia and one patient withpolycythemia vera and myeloid metaplasia were studied with Fe⁵⁹, Cr⁵¹ andglycine-2-C¹⁴.

2. Three of the patients with agnogenic myeloid metaplasia had activesplenic, hepatic or renal erythropoiesis. One had deficient erythropoiesis.

3. The red cell life span was short in all of the patients with agnogenicmyeloid metaplasia, definite splenic sequestration occurring in two patients.The red cell life span was normal in the patient with polycythemia vera andmyeloid metaplasia.

4. The possible indications for splenectomy were discussed.

Submitted on July 25, 1958 Accepted on October 12, 1958     

The effect of acute protein deprivation upon erythropoiesis in rats

1. Hemoglobin concentration, blood volume, and erythrocyte radioiron uptake were measured in rats subjected to acute protein deficiency.

2. Removal of protein from the diet was followed promptly by hemoconcentration, diminution in blood volume, and drastic reduction in erythropoiesis.These changes were reversible, after 35 days, upon addition of protein tothe diet.

3. Protein intake is more essential for maintenance of normal erythropoiesisthan is total caloric intake.

4. The data suggest that hemoglobin concentration within the vascularsystem is more important than red cell volume in regulating erythropoieticrate.

Submitted on June 27, 1957 Accepted on September 15, 1957     

Familial erythroid multinuclearity

1. Dysplastic erythropoiesis, erythrocyte gigantism and giant plurinucleatedred cell precursors in the bone marrows of a woman and all 3 of her children aredescribed. All 4 subjects have mild anemia without symptoms therefrom.

2. The changes described are apparently irreversible but do not representmalignant nor agonal change.

3. It is likely that these findings represent an inherited anomaly of erythropoiesis. The nature of the genetic transmission cannot be determined from thesestudies.

4. We propose the designation familial erythroid multinuclearity to describethis anomaly of red cell production.

Submitted on March 20, 1951 Accepted on August 28, 1951     

The effect of human plasma transfusion on the fecal urobilinogen excretion on sickle cell anemia

1. The results of transfusions of whole plasma and blood on the fecal urobilinogen excretion of 5 children with sickle cell anemia have been reported.

2. The phenomenon observed by Josephs—a reduction in urobilinogen outputfollowing plasma transfusions—has been confirmed.

3. It has been observed further that in certain patients the continued use ofplasma transfusions induces a reversal of this phenomenon, namely an increase inurobilinogen output after each transfusion.

4. The possible significance of these phenomena is discussed and attention iscalled to the limitations inherent in accepting urobilinogen excretion as a validindex of hemoglobin destruction in certain disorders in which a defect of hemoglobin metabolism may be present.

     

A method of measuring the severity of a series of cases of hemolytic disease of the newborn

1. The hemoglobin concentration in the cord blood of infants affected withhemolytic disease is very closely related to their chance of survival. If the hemoglobin concentration is plotted against the chance of survival, a sigmoid curve isobtained. Probit analysis can be applied and the results of treatment can then besummarized in terms of the severity of the cases treated. For example, in thepresent series the cord hemoglobin concentration corresponding to a 50 per centchance of survival was 8.09 Gm./100 ml.

2. Application of probit analysis makes it possible to compare results obtainedin different centers, for due allowance is made for any difference in severity in thecases included in the different series.

3. In the present series, despite uniform treatment (exchange transfusion),over-all mortality fell from 37 percent in 1947 and 1948 to 3 per cent in 1950. It isshown that this can be entirely explained by a decrease in the number of severelyaffected infants.

4. Predictions of survival based on the cord hemoglobin concentration and cordbilirubin concentration combined are not significantly better than predictionsbased on cord hemoglobin concentration alone.

5. Infants with positive direct Coombs tests whose cord hemoglobin concentrations exceed 15.5 Gm./100 ml. have some risk (approximately 1 in 12) of developing kernicterus, if untreated.

Submitted on March 29, 1951 Accepted on April 18, 1951     

Further Observations on Polycythemia in Hepatocellular Carcinoma

Direct measurement of the red cell mass has confirmed a previous reportof the occurrence of polycythemia in patients with hepatocellular carcinoma.Twenty patients (17 males and 3 females) have been investigated. The redcell mass was increased in 11, normal in 8 and reduced in one. Because ofhypervolemia, present in 15 of the 20 patients investigated and attributable tothe associated cirrhosis of the liver, the hematocrit might be normal in thepresence of an increased red cell mass. A venous hematocrit of 48 per cent andabove was found invariably to be associated with an increase in the red cellmass. Using this criterion, 17 of 145 patients with hepatocellular carcinoma werefound to be polycythemic, an incidence of 11.7 per cent.

Plasma erythropoietic stimulating factor determined by Fe⁵⁹ incorporationinto red cells of fasted rats was not increased in 4 patients with hepatocarcinomaand polycythemia.

These findings are briefly discussed.

Submitted on June 6, 1961 Accepted on August 12, 1961     

The Hemolytic Anemia of Human Bartonellosis

A study of the processes of formation and destruction of blood has beencarried out, in addition to other investigations of the physiopathology of theanemia of human bartonellosis. From the results obtained the following conclusions may be drawn:

1. The life-span of the red cells parasitized by Bartonella bacilliformis isgreatly shortened. However, not all the parasitized red cells are prematurelydestroyed.

2. Red cells from normal subjects are partially destroyed when they are injected into infected patients. More than 50 per cent of them survive normally.

3. The mechanical fragility of the red cells is increased in the majority ofthe cases.

4. The index of sequestration of red cells by the liver and spleen was increased in the three patients studied. Also, the products of catabolism of hemoglobin were increased in all the patients studied.

5. The increased production of red cells as a response to the great destructionwas prevented at first, but later it reached its peak, being in some cases fivetimes greater than normal.

6. The search for agglutinins and hemolysins was negative.

7. The amount of free protoporphyrins in the red cells was increased, indicating that there was some interference to the synthesis of hemoglobin thatwould also explain the hypochromia of the red cells.

8. The increase in the diameter of the red cells was independent of the actualamount of reticulocytes.

Submitted on November 23, 1960 Accepted on February 12, 1961