bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the Risk of Hepatitis B Reactivation Among Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors
Authors: Benjamini Ohad , Zlotnick Maya , Ribakovsky Elena , Kedmi Meirav , Duek Adrian , Merkel Drorit , Leiba Merav , Danylesko Ivetta , Shem-Tov Noga , Yerushalmi Ronit , Shimoni Avichai , Avigdor Abraham , Nagler Arnon , Volchek Yulia
Published: October 2019

Background: Immunosuppressive therapy is a known risk factor for hepatits B reactivation. The highest risk is reported in hematologic patients treated with anti-CD20 monoclonal antibodies, glucocorticoids and hematopoietic stem cell transplantation. Currently, treatment with tyrosine kinase inhibitors (TKIs) in the vast majority of chronic myeloid leukemia (CML) patients is life-long. Recently healthcare professionals were advised to test for hepatitis B infection before initializing therapy with TKIs and closely monitor HBV carriers. The risk is considered class effect with all TKIs and recommendations are based on case reports.

Aim: The aim of the current study was to evaluate the risk of hepatitis B reactivation in patients with CML treated with TKIs.

Methods: The records of patients with CML treated with TKIs from a single center were systematically reviewed for hepatitis B serology and serum biochemistry.

Results: One hundred eighty one patients diagnosed with CML between the years 1983 and 2016 were evaluated. The median age at diagnosis was 49.7 years (range 18-89), 117/181 (65%) males, with median duration of follow up with TKI therapy of 5.3 years (range 0.4 to 33 years). Over a total of 1195 years of therapy with TKIs no cases of HBV reactivation were identified. Among 114 patients with hepatitis serology, 11 patients (10%) had evidence of prior resolved HBV infection (HBsAg negative/anti-HBc positive). Two of them had anti-HBs positive serology, one had negative PCR for HBV DNA and other two patients received lamivudine prophylaxis. Only one patient had HBsAg positive serology. None of the patients with positive hepatitis serology had clinical or biochemistry evidence of hepatitis B reactivation. The 67 patients without available hepatitis serology had normal liver transaminases at 6 months of TKI therapy and at last day of follow up, confirming that no overt hepatitis B reactivation occurred.

Conclusions: We evaluated hepatitis B reactivation in a rather large cohort of CML patients, treated with TKIs. Although there were no cases of HBV reactivation during long term follow up, it should be emphasized that even a low incidence may exert a significant risk due to the long duration of treatment in a chronic disease with lifelong therapy. Our study infers that patients with serology of prior resolved HBV infection are at low risk for hepatitis B reactivation. Larger cohorts of patients with positive hepatitis B serology in a multicenter long term evaluation should be performed in order to address current recommendations for patients' safety and concerns.

Disclosures

No relevant conflicts of interest to declare.
Non-Transferrin-Mediated Iron Delivery
Authors: Knutson Mitchell
Published: October 2019

In iron overload conditions such as thalassemia major and hereditary hemochromatosis, the iron-carrying capacity of plasma transferrin is exceeded, giving rise to non-transferrin-bound iron (NTBI). NTBI is taken up preferentially by the liver, and to a lesser extent, the kidney, pancreas, and heart. How NTBI is taken up by various tissues has been elusive. We recently demonstrated that the plasma membrane metal-ion transporter SLC39A14 (ZIP14) mediates NTBI uptake and iron loading of the liver and pancreas, but not the kidney, heart or most other tissues¹ Given that the heart is particularly susceptible to iron-related toxicity, we are currently investigating the contribution of other iron transporters to iron loading of this organ. Possible alternative cardiac iron importers include L-type and T-type calcium channels, divalent metal transporter 1 (DMT1), and SLC39A8 (ZIP8). To examine the role of DMT1 and ZIP8 in cardiac iron metabolism, we generated mice with cardiomyocyte-specific disruption of DMT1 (Dmt1heart/heart) or ZIP8 (Zip8heart/heart). The mice were then crossed with hemojuvelin knockout (Hjv-/-) mice, a model of juvenile hemochromatosis characterized by high circulating levels of NTBI. Dmt1heart/heart mice were found to have cardiac non-heme iron concentrations that were 30% lower (P<0.01) than those of wild-type littermate controls at 6 weeks of age. Interestingly, however, double mutant Hjv-/-; Dmt1heart/heart mice accumulated more cardiac non-heme iron (3.9X control) than did single-mutant Hjv-/- mice (2.3X control) at 6 weeks of age. Cardiac-specific disruption of Zip8 did not affect cardiac non-heme iron concentrations under basal conditions or when mice were crossed with Hjv-/- mice. Collectively, these data indicate that DMT1 and ZIP8 are dispensable for iron loading of the heart in a mouse model of hemochromatosis. Our data additionally suggest that DMT1 may play a role in normal cardiac iron metabolism.

Reference:Jenkitkasemwong S, Wang C, Coffey R, et al. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis.Cell Metabolism.2015; 22(1):138-150.

Disclosures

No relevant conflicts of interest to declare.
Innate Immune Signaling in Regulation of Immunity
Authors: Trinchieri Giorgio
Published: October 2019

Innate resistance, as an integral part of inflammation, and adaptive immunity participate in oncogenesis and tumor surveillance. For a long time, innate resistance was considered a primitive nonspecific form of resistance to infections that was eclipsed by the potent and specific acquired immunity of higher organisms. More recently, it has been recognized that innate resistance is not only the first line of defense against infections but also sets the stage and is necessary for the development of adaptive immunity. Advances in cancer biology have revealed that the defensive mechanisms of innate resistance and inflammation are indeed manifestations of tissue homeostasis and control of cellular proliferation that have many pleiotropic effects on carcinogenesis and tumor progression and dissemination. The interaction of innate and adaptive immunity with carcinogenesis and tumor progression is complicated and results in effects that either favor or impede tumor progression. Innate immune receptors both sense and regulate the composition of the microbiota, the large number of commensal microorganisms that colonize the barrier surfaces of all multicellular organisms, including those of humans. The microbiota affects many functions of our body and the two together comprise one metaorganism. Microbial imbalance particularly in the gut plays a critical role in the development of multiple diseases, such as cancer, autoimmune conditions and increased susceptibility to infection. Alteration in innate immune signaling and immunity may change the composition of the microbiota affecting tumor initiation both at the barrier sites (e.g. in the gut) and systemically. The commensal microbes not only may affect the development and progression of cancer but they have also important effects on the response to cancer therapy. Mostly through their interaction with innate receptors, commensal microorganisms modulate the ability of the organism to respond to cancer immunotherapy and chemotherapy by affecting the threshold of response of tumor-associated myeloid cells and their ability to sustain anti-tumor immunity.

Disclosures

No relevant conflicts of interest to declare.
Megaloblastic Anemia Probably Caused by Defective Utilization of Folinic Acid
Authors: HAURANI FARID I. , WANG GEORGE , TOCANTINS L. M.
Published: October 2019

A 12 year old negro girl was studied who presented a picture of megaloblastic anemia refractory to physiologic doses of vitamin B-12 and to folic acid. However, remission could be induced and maintained by pharmacologic doses of vitamin B-12 (1000 µg. per week), by folinic acid or by a combination of vitamin C (or homocysteine) and folic acid. Folinic acid determinations and the clinical response to various metabolites indicated the existence of a metabolic defect in the utilization of folinic acid. The hereditary nature of this defect was suggested by the fact that two siblings might have had a similar condition.
The Role of the Kidney in the Production of the Erythropoietic Factor
Authors: NAETS JEAN-PIERRE
Published: October 2019

The role of the kidney in production of erythropoietin was investigated. Dogs were made anemic by phlebotomy and were then subjected to bilateral nephrectomy, ureter ligation or ureter section. Erythropoietic stimulating activity in the dog plasma was judged by measuring the incorporation of Fe59 into the red cells of starved rats. No erythropoietic activity could be found in the dog plasma 24 and 48 hours after nephrectomy, but erythropoietic activity was found after ligation of the ureters.
THE HEMATOLOGIC RESPONSE IN DOGS TO THE ADMINISTRATION OF ANTI SPLEEN SERUM
Authors: MIALE JOHN B.
Published: October 2019

1. Intravenous injection into dogs of rabbit anti-dog-spleen serum in doses of 0.04 cc./10 Kg. results in a significant increase in the mononuclear cells of the peripheral blood.

2. The rise in circulating mononuclears occurs promptly, with 24-48 hours, and is sustained, generally for 20 days.

3. A large dose of the same serum, 5.4 cc./10 Kg., exerted an opposite effect, poducing a significant decrease in circulating mononuclears.

4. The possible significance of these findings is discussed.
DEVELOPMENT OF INCLUSION BODIES CONTAINING RIBOSE NUCLEIC ACID IN MYELOMA CELLS AFTER INJECTIONS OF STILBAMIDINE. DETERMINATION OF STILBAMIDINE IN MYELOMA TISSUE
Authors: SNAPPER I. , MIRSKY A. E. , RIS H. , SCHNEID B. , ROSENTHAL M.
Published: October 2019

The cytoplasm of myeloma cells is rich in ribose nucleic acid. The basophilic inclusion bodies which develop in myeloma cells under the influence of stilbamidine contain ribose nucleic acid. The myeloma tissue of patients treated with stilbamidine contains appreciable amounts of stilbamidine.

There is reason to believe that the nucleoproteins of myeloma cells differ from the nucleoproteins of other cells. This could explain why stilbamidine reacts with the nucleoproteins of myeloma cells only, and not with the nucleoproteins of other cells.
THE ERYTHROPOIETIC ACTIVITY OF CHOLINE CHLORIDE IN MEGALOBLASTIC ANEMIAS
Authors: DAVIS L. J. , BROWN ALEXANDER
Published: October 2019

1. The effect of the administration of choline chloride has been observed in 10 cases of megaloblastic anemia of various types.

2. Choline was without effect in a case of untreated Addisonian pernicious anemia which subsequently responded to parenteral liver therapy.

3. Choline was also without effect in a case of nutritional megaloblastic anemia, in a case of megaloblastic anemia of pregnancy, and in two cases of megaloblastic anemia associated with the sprue syndrome. All these cases had proved refractory to injections of potent liver extract before the choline was given, and all responded to subsequent oral liver or folic acid therapy.

4. A significant erythropoietic response to choline occurred in two cases resembling Addisonian pernicious anemia which were refractory to parenteral liver extracts.

Secondary responses followed the administration of choline in two other cases of Addisonian pernicious anemia and in a case of megaloblastic anemia of pregnancy, all of which had already responded to injections of liver extract.

5. The significance of these observations is discussed. It is concluded that choline possesses no direct erythropoietic activity, but that under certain circumstances it may potentiate the effect of liver extracts.

It is suggested that refractory megaloblastic anemias may be divided into two groups. In one, represented by well known syndromes associated with defective absorption or pregnancy, the lack of response to parenteral liver extracts is not corrected by choline. In the other, represented by two cases simulating Addisonian pernicious anemia, choline is effective in overcoming, partially or completely, the refractoriness to parenteral liver therapy. Consideration is given to the view that the refractoriness of this group results from hepatic dysfunction.

6. The most satisfactory method of administering choline probably consists of intravenous injections in daily doses of 1 gram. Larger doses given intravenously are frequently accompanied by unpleasant side effects, while oral administration appears to be relatively less effective.

7. It seems unlikely that choline will be of practical value in the treatment of refractory megaloblastic anemias, for which oral liver preparations provide the most certain and effective treatment. It is possible, however, that choline may be of use in cases complicated by severe hepatic disease.
SUCCESSFUL TREATMENT OF LIVER-REFRACTORY ANEMIA WITH SYNTHETIC LACTOBACILLUS CASEI FACTOR
Authors: WALDENSTRÖM JAN
Published: October 2019

Four cases of liver-refractory macrocytic anemia are described. Three were treated with folic acid perorally and reacted well.

The first was an instance of nontropical sprue with atrophy of the spleen that was diagnosed clinically and confirmed at postmortem examination. The megaloblastic anemia also became completely refractory to crude liver extracts and liver digested with gastric juice.

The second case was successfully treated with liver extracts for twelve years. After that time she suddenly became refractory with severe leucopenia. Folic acid in large doses had an excellent effect and the patient has kept relatively normal blood values for about a year without further treatment of importance. It should be noted that the morbid condition of the tongue could not be influenced by folic acid.

The third case should probably be classified as idiopathic steatorrhea. Folic acid gave a full remission of the macrocytic anemia.

The fourth case resembled typical pernicious anemia more closely, as a histamine-fast achlorhydria was present. This patient had been refractory to liver treatment but reacted well to folic acid in ordinary doses.

The fifth case was a typical instance of idiopathic stcatorrhea with probable atrophy of the spleen. She had a moderate anemia that was refractory to liver extracts. Folic acid perorally and intramuscularly neither influenced the anemia nor the fecal fat.

In a series of cases of uncomplicated pernicious anemia, the immediate response to folic acid in doses of 20 to 30 mg. daily was good. Full remissions as regards hemoglobin and erythrocytes could be expected with a total dosage of 400 to 600 mg.

Certain cases of pernicious anemia refractory to liver extract may respond to folic acid. This indicates that the two substances probably have different mechanisms of action.
THE RELATION OF THERAPY IN PERNICIOUS ANEMIA TO CHANGES IN THE NERVOUS SYSTEM. EARLY AND LATE RESULTS IN A SERIES OF CASES OBSERVED FOR PERIODS OF NOT LESS THAN TEN YEARS, AND EARLY RESULTS OF TREATMENT WITH FOLIC ACID
Authors: BETHELL FRANK H. , STURGIS CYRUS C.
Published: October 2019

Seventy patients with pernicious anemia have been observed for periods of not less than ten years. The clinical course in these cases has been analyzed with particular reference to changes in the neurologic status.

Most of the patients, whether treated with oral preparations of stomach or liver, or parenteral crude or refined liver extracts, showed significant improvement of their neurologic manifestations. The period of improvement was limited, essentially, to the first year of therapy.

Thirty-six members of the series received treatment regularly and were maintained consistently in complete hematologic remission. Fifteen of the patients did not adhere to an optimal therapeutic regimen, and their blood values were frequently abnormal, although definite relapses did not occur. In the former group there were no instances of development or progression of neural lesions. In the latter such adverse changes as did occur were transient and reversible on resumption of adequate therapy. Nineteen patients in the series suffered clinical and hematologic relapses after their initial response to intensive therapy. The end results in this group were not so favorable, but nevertheless serious progression of spinal cord involvement was rarely observed. The apparent infrequent occurrence of pronounced changes is attributed to the short duration of the relapses and to the relatively mild degree of nervous system involvement present when the diagnosis of pernicious anemia was made. It may be assumed that patients with more extensive neural disease who suffered relapses, progressed to a fatal termination.

The observations reported in no way justify the conclusion that irregular or sub-optimal therapy is without serious risk. They are presented in order to indicate what the long-term clinical results may be in the case of patients with pernicious anemia, who frequently fail to adhere to an ideal therapeutic regimen.

The early results of treatment with synthetic folic acid, as observed in a series of 15 patients, indicate that both the hematologic and neurologic response to this form of therapy is much less predictable than is the case with stomach or liver preparations. It is suggested that disturbance of folic acid metabolism is not the sole cause of either the hematologic or the neurologic manifestations of pernicious anemia, but that inability to utilize folic acid effectively may play a part in the development of both myeloid and neural abnormalities.
THE DEVELOPMENT AND PROGRESSION OF SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD IN PATIENTS WITH PERNICIOUS ANEMIA TREATED WITH SYNTHETIC PTEROYLGLUTAMIC (FOLIC) ACID
Authors: Ross J. F. , BELDING H. , PAEGEL B. L.
Published: October 2019

1. Twenty-one patients with pernicious anemia were maintained on synthetic folic acid (pteroylglutamic acid) therapy alone for periods ranging from eight to seventeen months. Satisfactory blood levels were maintained in all cases receiving daily oral doses of 1.25 to 15.0 mg. Severe hematologic relapse occurred within six months in a case treated with monthly injections of 30 mg.

2. Synthetic folic acid in oral doses of 15 mg. daily induced satisfactory hematopoietic responses in 3 patients with pernicious anemia in severe relapse, but only slight hematopoietic response in a fourth patient with mild pernicious anemia but severe subacute combined degeneration of the spinal cord.

3. Ten patients showed a significant improvement in blood values for a few months after substitution of folic acid for liver extract. With one exception these subsided after six or more months to pre-folic acid levels comparable with those previously maintained with liver extract alone.

4. These observations suggest that a combination of orally administered folic acid and parenterally injected liver extract may maintain a better hematologic status than either substance alone.

5. A previously untreated patient with severe subacute combined degeneration of the spinal cord failed to show improvement in neural disease during twentyeight days of folic acid therapy.

6. Eleven patients developed, or showed progression of, subacute combined degeneration of the spinal cord during folic acid treatment. Neurologic disease developed in most of these patients when the peripheral blood was normal.

7. One patient showed an extremely explosive onset and rapid progression of neural disease. The progression of the disease was rapid in 3 other cases.

8. The institution of liver extract therapy in adddition to folic acid in 5 patients who developed subacute combined degeneration during folic acid maintenance therapy failed to prevent progression of the disease in 4 cases, and only partially arrested the disease in the fifth, in which improvement occurred more rapidly when folic acid was discontinued.

9. Subacute combined degeneration occurred with greater frequency in patients on large daily doses of folic acid than it did in patients with small or intermittent doses.

10. The possibility is discussed that folic acid in large daily doses may actually precipitate or aggravate neurologic disease.

11. It is suggested that folic acid may interfere with the metabolism of 1(+) glutamic acid in the central nervous system and possibly disturb the formation or function of acetylcholine.
THE ROLE OF ALLERGY IN THE PATHOGENESIS OF PURPURA AND THROMBOCYTOPENIA
Authors: MADISON FREDERICK W.
Published: October 2019

It has been suggested that, for purposes of etiologic investigation, thrombocytopenic purpura be separated into its two component parts, thrombocytopenia and purpura, and that they be regarded as two coexisting abnormalities rather than as a single disease. Historical review of the development of knowledge of the pathogenesis of purpura emphasizes the importance and soundness of this dual approach. Both thrombocytopenia and purpura have been shown to have a complex etiologic pattern with multiple potential etiologic factors. The curious similarity of these two groups of factors may at least partially explain the frequent coexistence of the two abnormalities in the clinical picture of thrombocytopenic purpura.

It has been shown that allergy has long been recognized as an etiologic factor of major importance in both purpura and thrombocytopenia. It is logical, therefore, that it should frequently be an important etiologic factor when the two conditions exist together, and it is suggested that when diagnostic methods are more adequate a considerable number of cases of "idiopathic" thrombocytopenic purpura will fall into that category and will yield therapeutically to a proper allergic approach.
HEMORRHAGIC DIATHESIS ASSOCIATED WITH THE PRESENCE OF AN ANTICOAGULANT IN CIRCULATING BLOOD. CASE REPORT AND LABORATORY STUDIES
Authors: SOULIER J. P. , BURSTEIN M.
Published: October 2019

A new observation of a hemorrhagic diathesis associated with the presence of an anticoagulant in the circulating blood is reported here. The patient was a 21 year old male, appearing by clinical evaluation to have hemophilia, but without a family history of hemophilia. The blood and plasma were strongly anticlotting and had a very long clotting time. The clotting time of recalcified citrated plasma was greatly delayed by removing the platelets. Freezing and thawing of platelet-rich plasma resulted in a marked shortening of the clotting time. Dilution of the plasma shortened the clotting time, while the addition of calcium and storage of the plasma had no effect.

The prolonged clotting time was not corrected by the addition of normal plasma or plasma fractions having antihemophilic activity. The prothrombin time was nearly normal. Small quantities of thromboplastin were very effective in shortening the clotting time. The anticoagulant had no antithrombin activity. The "progressive" antithrombin and antifibrinolysin of the patient’s plasma were normal.

The anticoagulant acts during the first phase of coagulation by inhibiting an (plasma) activator of prothrombin. It appears to be identical with the anticoagulant described in three previous publications from the United States.
A QUANTITATIVE METHOD FOR THE DETERMINATION AND CHARTING OF THE ERYTHROCYTE HYPOTONIC FRAGILITY
Authors: SUESS JOHN , LIMENTANI DAVIDE , DAMESHEK WILLIAM , DOLLOFF MIRIAM J.
Published: October 2019

A method is described for the determination and charting of the fragility of the red blood cells to hypotonic sodium chloride solution. For plotting the results obtained, a new method was used, employing the principle of "hemolytic increments," i.e., plotting the additional amount of hemolysis occurring in each successive tube of solutions of decreasing saline concentration.

By this method, curves are obtained somewhat similar to those of Price-Jones curves of red cell diameters. Such curves, when properly analyzed, afford an interpretation of the varying diameter thickness range of the red cell population and indirectly an insight into the types of red cells present, and of the possible hemolytic mechanisms present. Preliminary investigations indicate that they are particularly instructive in the hemolytic anemias and especially in the Mediterranean anemias.

A simplified shorter method was also devised for routine clinical use. This method, although not as useful for research purposes, has proved to be more accurate and yet less time consuming than most methods currently used.
THE EFFECT OF ENDOCRINOPATHIES ON THE BLOOD
Authors: DAUGHADAY WILLIAM H. , WILLIAMS ROBERT H. , DALAND GENEVA A.
Published: October 2019

Evidence has been presented that the gonads, thyroid, adrenal cortex and pituitary glands have a definite influence on blood formation. The normal sex difference in erythrocyte levels in animals, and probably in man, can be obliterated by castration and restored by appropriate replacement therapy. Hypothyroidism results in a moderately severe anemia in animals. In the uncomplicated form, the anemia is slightly macrocytic and associated with a hypoplastic bone marrow. In clinical experience the anemia may be complicated by the secondary effects of achylia gastrica leading either to iron deficiency or to a deficiency in the antipernicious anemia factor. Hyperthyroidism causes some alterations in the white blood cells, but has little effect on the red blood cell series. Hyperactive states of the adrenal cortex may be associated with a mild polycythemia. Adrenal steroids also have a marked lymphocytic effect, causing the release of beta and gamma globulins from lymphoid tissue. A mechanism involving the anterior pituitary and adrenal seems to exist, controlling the release of antibodies under certain conditions. It is suggested that other mechanisms also exist which control the number of circulating lymphocytes.

Deficiency of the anterior pituitary secretions results in anemia in animals and man. The anemia in animals is usually microcytic and hypochromic and may respond to several types of replacement therapy. In man anemia develops slowly and is rarely severe. Moderate reductions in the red blood cell count occur and the color index varies. There is hypoplasia of the bone marrow. The anemia in man does not respond uniformly well to the therapy now available, but improvement often occurs with the replacement of "end-organ" hormones.

The preponderance of evidence indicates that the regulation of blood formation is not primarily under hormonal control. The effects noted in various glandular disorders are due to alterations in metabolism produced in the bone marrow as well as all other body tissues.
STUDIES ON FREE ERYTHROCYTE PROTOPORPHYRIN, PLASMA IRON AND PLASMA COPPER IN NORMAL AND ANEMIC SUBJECTS
Authors: CARTWRIGHT G. E. , HUGULEY C. M. , ASHENBRUCKER HELEN , FAY JANE , WINTROBE M. M.
Published: October 2019

1. A total of 108 erythrocyte protoporphyrin determinations has been made in 66 normal individuals. The geometric mean ± standard error of the mean was 31 (26-38).

2. A total of 196 determinations of plasma iron in 92 normal individuals was made. The mean ± standard error of the mean was 104.7 ± 3.4 µg per cent.

3. In a total of 150 determinations of plasma copper in 105 normal individuals, the mean ± standard error of the mean was 118.6 ± 1.2. µg per cent.

4. No significant difference in plasma iron was noted between the sexes but in females the plasma copper was significantly higher and the erythrocyte protoporphyrin slightly higher than in males.

5. Erythrocyte protoporphyrin, plasma iron, and plasma copper determinations have been made in over 112 patients with a variety of clinical conditions associated with anemia. In general, it was found that in pernicious anemia in relapse the erythrocyte protoporphyrin values were normal, the plasma iron normal or high and the plasma copper usually normal. Anemia due to iron deficiency as well as the anemia of infection were accompanied by high values for erythrocyte protoporphyrin, hypoferremia and hypcrcupremia. In nephritis with anemia the erythrocyte protoporphyrin was generally increased, the plasma iron low or normal and the plasma copper increased. Anemia associated with lymph node disorders or leukemia was accompanied by a normal or high EP, a low or normal plasma iron and an increase in plasma copper. Thalassemia major was found to be accompanied by both hypercupremia and hyperferremia; in thalassemia minor the serum iron values were normal although hypercupremia was found. Hyperferremia was noted in aplastic anemia. In cases of plumbism the erythrocyte protoporphyrin was markedly increased. Hypocupremia was noted only twice, in one patient with severe nephritis and hypoalbuminemia and in one patient with hemochromatosis.
RELATION OF ADRENAL CORTICAL HORMONE TO LYMPHOID TISSUE AND LYMPHOCYTES
Authors: VALENTINE WILLIAM N. , CRADDOCK CHARLES G. , LAWRENCE JOHN S.
Published: October 2019

The hormonal control through the hypophyseo-adrenal cortical system of lymphoid tissue structure and function is an important concept. We cannot at the present time regard that the concept is established fact. Final judgment must await additional work and the clarification of some of the inconsistencies which appear to exist. It seems reasonable that lymphoid tissue is one of the end organs of adrenal cortical hormone and that it may perhaps play a role in the response of the organism to stress. It seems quite clear that the sugar hormone of the adrenal cortex is capable of producing structural alterations in lymphoid tissue. Change in thoracic duct lymphocyte numbers as a result of augmentation in the amount of available adrenal cortical hormone is at present controversial. Experiments in this laboratory have failed to demonstrate it. The production of lymphopenia, at least in some species and possibly in man, by increasing available sugar hormone is supported by some evidence. The exact mechanism of production of lymphopenia is open to question, its relationship to changes in lymphoid tissue structure being one of inference. The converse situation—absolute lympocytosis resulting from deprivation of adrenal cortical hormone—is the subject of controversial reports. At best, it must be admitted that relatively slight alterations from the accepted normal range of lymphocyte values occur in the adrenal insufficient organism. Changes in plasma gamma globulins and antibody titers associated with changes in the amount of available cortical hormone are reported. It should be clarified whether such changes have necessarily resulted from lymphocyte dissolution or are related to other of the variegated actions of adrenal cortical hormone.

The relationship of adrenal cortical hormone to lymphoid tissue and lymphocytes and the relationship of the latter to the response of the organism to stress must indeed be complex. It is reasonably well established that the life span of the lymphocyte is very short indeed1,58,22 and each lymphocyte presumably liberates its metabolically important contents within a few hours at the most. If stress continues for any period of time, as often it does, it is difficult to visualize the wisdom of interfering with the production of metabolically vital substances in order to secure the transient benefits of lymphoid tissue dissolution. It is also somewhat difficult to regard as proved that the various changes reported after hormone augmentation or deprivation necessarily represent the normal mechanism by which these factors are regulated and kept within physiologic limits. More investigations are required to answer such questions and to further elucidate the interrelationship of the adrenal cortex and lymphoid tissues.
CHANGES IN CIRCULATING LEUKOCYTES INDUCED BY THE ADMINISTRATION OF PITUITARY ADRENOCORTICOTROPHIC HORMONE (ACTH) IN MAN
Authors: HILLS A. GORMAN , FORSHAM PETER H. , FINCH CLEMENT A.
Published: October 2019

1. Pituitary adrenocorticotrophic hormone (ACTH), when administered in a single intramuscular dose of 25 mg. to human subjects with unimpaired adrenal function, results in a characteristic alteration of the leukocytic pattern. This consists of an increase of circulating neutrophils and a decrease of circulating lymphocytes and eosinophils.

2. The decrease in circulating lymphocytes and eosinophils is contingent upon the stimulation of a functionally competent adrenal cortex, and does not occur in its absence. The neutrophilic response is present but somewhat diminished in adrenal insufficiency.

3. The entire pattern of leukocytic alterations found in normal subjects after administration of ACTH can be induced in patients with Addison’s disease by 17-hydroxycorticosterone (20 mg.) but not with desoxycorticosterone glucoside (30 mg.).

4. Prolonged adrenal stimulation by ACTH, given over a four day period in a dose of 10 mg. every six hours, results in a sustained and striking elevation of neutrophils and depression of eosinophils; the lymphocytes, after an initial depression lasting not more than twenty-four hours, may increase above their initial levels in spite of the continued increased secretion of adrenal hormones.

5. The relation of the adrenal cortex to the characteristic nonspecific leukocyte pattern, observed as a response of the organism to any type of insult, is discussed.
THE BLOOD PICTURE IN ADDISON’S DISEASE
Authors: BÁEZ-VILLASEÑOR JOSÉ , RATH CHARLES E. , FINCH CLEMENT A.
Published: October 2019

The blood picture of 100 patients with Addison’s disease was analyzed. Under basal conditions, there was a tendency toward lymphocytosis and neutropenia. Under stress, the blood picture remained fixed. The impaired ability of those patients to show leucocytosis and lymphopenia is attributable to their impaired adrenal function. While large doses of desoxycorticosterone and maintenance doses of adrenal extract had no effect on the blood picture, 17-oxysteroids produce both neutrophilia and lymphopenia. The anemia present in Addison’s disease is normocytic and normochromic.
ACUTE THROMBOCYTOPENIA INDUCED IN DOGS BY ADMINISTRATION OF URETHANE (ETHYLCARBAMATE)
Authors: CRUZ W. O. , MOUSSATCHÉ H.
Published: October 2019

1. Dogs treated for one to two weeks with daily injections of urethane (ethyl carbamate) subcutaneously, in doses of 0.4 Gm. per Kg. of body weight, presented a typical picture of thrombocytopenic purpura.

2. The pathologic changes consisted in numerous purpuric lesions in the small intestine and a smaller number on the skin, heart, lung, cortical zone of the kidney, epiploon, and, rarely, on the stomach and large intestine.

3. The hematologic changes occurred in the following sequence: leukocytosis, leukopenia and thrombocytopenia, and finally acute anemia coinciding with severe intestinal hemorrhage. In the final phase, the coagulation time was normal and the bleeding time very much increased.
SEPARATION OF LEUKOCYTES FROM WHOLE BLOOD BY FLOTATION ON GUM ACACIA
Authors: SPEAR FRANCES
Published: October 2019

An inexpensive solution possessing the physiochemical properties necessary for separating leukocytes and erythrocytes on the basis of differences in specific gravity has been described.
ACUTE RENAL INSUFFICIENCY DUE TO INCOMPATIBLE TRANSFUSION AND OTHER CAUSES, WITH PARTICULAR EMPHASIS ON MANAGEMENT
Authors: MUIRHEAD E. E. , HALEY A. E. , HABERMAN SOL , HILL J. M.
Published: October 2019

1. Of 28,630 blood transfusions administered in Baylor Hospital over an eight year period there were 17 known hemolytic reactions (0.593 per 1000) of which 17.6 per cent were fatal.

2. Acute renal insufficiency occurred in 55.5 per cent of 18 cases of hemolytic reaction.

3. Factors other than hemolysis per se often occurred. The most common complication was hemorrhage with hypotension.

4. The mortality rate of the hemolytic cases with acute renal insufficiency need not be as high as one gathers from reports in the literature.

5. Good results may be obtained with a regime based on physiopathological principles and the main clinical abnormalities. The outstanding premise for the "three-phase" management is based on the consideration that damaged kidneys require time for regeneration and recovery.

6. Five main steps in the proposed method of management are: (a) adequate compatible blood for anemia and hypovolemia, (b) limitation of fluid intake during renal insufficiency to that immediately lost, (c) adequate dietary intake, (d) prevention of severe acidosis, (e) adequate water and salts replacement during diuresis.

7. Support was gained for this regime by successful application to other types of acute renal damage and insufficiency. Demonstrated complications were averted.

8. Common complications due to other types of management were: anemia and hypotension, fluid overload with cerebral and pulmonary signs, dehydration with shocklike state and at times convulsions during the recovery phase.

9. Peritoneal irrigation in its present form resulted in two major complications averted by the proposed method of management.
HEMOLYTIC Rh IMMUNE GLOBULINS: EVIDENCE FOR A POSSIBLE THIRD ORDER OF ANTIBODIES INCAPABLE OF AGGLUTINATION OR BLOCKING
Authors: HILL JOSEPH M. , HABERMAN SOL , JONES FRANCES
Published: October 2019

We believe that sufficient evidence exists to justify 3 classes of Rh antibodies based on their reactivity. These are the classical agglutinin, the blocking antibody, and the proposed "cryptagglutinoid." Sufficient distinction exists to retain the blocking antibody as determined by Wiener’s original blocking test. This antibody is further characterized by failure to act in Chown’s capillary technic. The identity of this antibody with its important role in reawakening investigation in this field of immunology should not be lost through inclusion in the broader group of those antibodies determined by the albumin test and similar methods. The proposed third order antibody or "cryptagglutinoid" which is usually, but not always, detected by these more inclusive tests, and the capillary technic, appears to be of great clinical importance because of the frequency with which it appears in significant titres. Detection of isoimmunization and closer correlation of antibody titre with clinical severity of disease should be possible through study of this "cryptagglutinoid" antibody.
PERIODIC (CYCLIC) NEUTROPENIA, AN ENTITY A COLLECTION OF SIXTEEN CASES
Authors: REIMANN HOBART A. , DEBERARDINIS C. THOMAS
Published: October 2019

Sixteen cases of an entity, periodic neutropenia, have been collected. They are characterized by remarkable clinical uniformity and regular recurrences of neutropenia at three week intervals. The entity may be a variant of a larger group of periodic conditions. The cause is unknown.
A NOTE ON THE EFFECTIVENESS OF VITAMIN B12 IN THE TREATMENT OF TROPICAL SPRUE IN RELAPSE
Authors: SUAREZ RAMON M. , SPIES TOM D. , HERNANDEZ-MORALES F. , PEREZ ENRIQUE , BENITEZ-GAUTIER MISS CLEMENCIA
Published: October 2019

Three cases of tropical sprue were treated with repeated injections of vitamin B12 and showed dramatic and sustained therapeutic responses.
FAMILIAL HYPOCHROMIC ANEMIA ASSOCIATED WITH POSTSPLENECTOMY ERYTHROCYTIC INCLUSION BODIES
Authors: MILLS HAROLD , LUCIA S. P.
Published: October 2019

A case is presented of familial, hypochromic, microcytic anemia, associated with the appearance of siderocytes in the peripheral blood following splenectomy. The medical literature of the recent past focuses attention on the clinical recognition of inclusion bodies, but their origin and significance have not been completely clarified. Rundles and Falls4 were the first to demonstrate them in hereditary hypochromic microcytic anemia, and in addition they have been shown to appear in acquired hemolytic anemia,2, 3 Banti’s syndrome,1 lead poisoning,3, 15 and in hemochromatosis, bacterial toxemias, industrial solvent poisoning, sickle cell anemia and acholuric jaundice.15

It is probable that the anemia in the case under discussion may have been due to some defect in iron metabolism. Neither the subject nor his maternal half-brother were demonstrated to have any objective evidence of hemolysis, and neither revealed reticulocytosis, despite intensive iron and liver therapy, a point in favor of poor utilization of iron. Furthermore, marked hemosiderosis was an outstanding feature of both cases signifying that at least one form of storage iron was available but not utilized.

The significance of inclusion bodies within erythrocytes is discussed and a classification of inclusion bodies is offered. A final statement regarding the nature of iron granules within red cells must await further research. When present within the erythrocytes of the peripheral blood or in the erythroid series of the bone marrow, they probably are the result of faulty iron metabolism either due to some inherent defect or secondary to the action of some noxious agent. Their prognostic significance is obscure, but this is probably related to the severity of the disease process of which they are an expression.
INFLUENCE OF FIBRINOGEN CONCENTRATION UPON PLASMA PROTHROMBIN TIME
Authors: WEINER MURRAY , SHAPIRO SHEPARD
Published: October 2019

The effect of the normal variations of fibrinogen concentration (180 mg. per cent to 650 mg. per cent) on the diluted (12.5 per cent) plasma prothrombin time in man, as observed in this study, is not significant.
Damaged DNA in lymphocytes of aplastic anemia
Authors: Hashimoto Y , Takaku F , Kosaka K
Published: October 2019

The size of single-stranded DNA in lymphocytes in GO stage from 22 patients with acquired primary and secondary aplastic anemia was estimated by alkaline sucrose gradient centrifugation. The average size was 9.3 (+/-0.3) times 10(7) daltons. The lymphocytes of patients contained significantly more single-strand breaks in DNA, compared to those of normal persons. The difference in size of single-stranded DNA which had been present in nontransformed lymphocytes could also be observed in transformed lymphocytes. Some characteristic differences could be observed in the sedimentation patterns of single-stranded DNA in the lymphocytes of patients with aplastic anemia and those of normal persons. The single-strand breaks in DNA suggested that the repair processes were disturbed in the DNA molecules of circulating lymphocytes from patients with acquired primary and secondary aplastic anemia.
A hitherto undescribed plasma factor acting at the contact phase of blood coagulation (Flaujeac factor): case report and coagulation studies
Authors: Lacombe MJ , Varet B , Levy JP
Published: October 2019

This paper reports an asymptomatic coagulation defect responsible for an abnormality at the contact phase of blood coagulation in vitro, distinct from Hageman factor and Fletcher factor deficiencies. Coagulation studies in a 50-yr-old French woman without bleeding tendency revealed the following results: whole-blood clotting time in glass tubes and activated partial thromboplastin time with kaolin and ellagic acid were greatly prolonged; one-stage prothrombin was normal; no circulating anticoagulant was detected, and the infusion of normal plasma corrected the coagulation defect with an estimated half-life of 6.5 days; the levels of factor VIII, IX, XI, and XII were normal; mutual correction was obtained with a Fletcher factor-deficient plasma; the level of whole complement was normal. Studies of the contact phase of blood coagulation and contact-induced fibrinolysis showed the same abnormalities as in Hageman factor- and Fletcher-deficient plasmas. These results indicate that the patient's plasma is deficient in a previously undescribed coagulation factor, which participates in the initial stage of the blood coagulation process in vitro. Family studies revealed consanguinity in the propositus' parents. The assay of this newly described factor in the propositus' children revealed a partial defect, compatible with a heterozygous state, in three of the four tested children. This indicates a recessive inheritance of this new blood coagulation defect.
The platelet function defect of cardiopulmonary bypass [see comments]
Authors: Kestin AS , Valeri CR , Khuri SF , Loscalzo J , Ellis PA , MacGregor H , Birjiniuk V , Ouimet H , Pasche B , Nelson MJ
Published: October 2019

The use of cardiopulmonary bypass (CPB) during cardiac surgery is associated with a hemostatic defect, the hallmark of which is a markedly prolonged bleeding time. However, the nature of the putative platelet function defect is controversial. In this study, blood was analyzed at 10 time points before, during, and after CPB. We used a whole-blood flow cytometric assay to study platelet surface glycoproteins in (1) peripheral blood, (2) peripheral blood activated in vitro by either phorbol myristate acetate, the thromboxane (TX)A2 analog U46619, or a combination of adenosine diphosphate and epinephrine, and (3) the blood emerging from a bleeding-time wound (shed blood). Activation-dependent changes were detected by monoclonal antibodies directed against the glycoprotein (GP)Ib-IX and GPIIb-IIIa complexes and P-selectin. In addition, we measured plasma glycocalicin (a proteolytic fragment of GPIb) and shed-blood TXB2 (a stable breakdown product of TXA2). In shed blood emerging from a bleeding-time wound, the usual time-dependent increase in platelet surface P-selectin was absent during CPB, but returned to normal within 2 hours. This abnormality paralleled both the CPB-induced prolongation of the bleeding time and a CPB-induced marked reduction in shed-blood TXB2 generation. In contrast, there was no loss of platelet reactivity to in vitro agonists during or after CPB. In peripheral blood, platelet surface P-selectin was negligible at every time point, demonstrating that CPB resulted in a minimal number of circulating degranulated platelets. CPB did not change the platelet surface expression of GPIb in peripheral blood, as determined by the platelet binding of a panel of monoclonal antibodies, ristocetin-induced binding of von Willebrand factor, and a lack of increase in plasma glycocalicin. CPB did not change the platelet surface expression of the GPIIb-IIIa complex in peripheral blood, as determined by the platelet binding of fibrinogen and a panel of monoclonal antibodies. In summary, CPB resulted in (1) markedly deficient platelet reactivity in response to an in vivo wound, (2) normal platelet reactivity in vitro, (3) no loss of the platelet surface GPIb-IX and GPIIb-IIIa complexes, and (4) a minimal number of circulating degranulated platelets. These data suggest that the “platelet function defect” of CPB is not a defect intrinsic to the platelet, but is an extrinsic defect such as an in vivo lack of availability of platelet agonists. The near universal use of heparin during CPB is likely to contribute substantially to this defect via its inhibition of thrombin, the preeminent platelet activator.
Diagnosis of t(2;5)(p23;q35)-associated Ki-1 lymphoma with immunohistochemistry
Authors: Shiota M , Fujimoto J , Takenaga M , Satoh H , Ichinohasama R , Abe M , Nakano M , Yamamoto T , Mori S
Published: October 2019

Some Ki-1 lymphomas carry a specific chromosomal translocation, t(2;5)(p23;q35). We have recently found a novel hyperphosphorylated 80- kD protein tyrosine kinase, p80, in a human Ki-1 lymphoma with this translocation. Subsequent cDNA cloning showed that p80 is a fusion protein of two different genes on chromosome 2p23 and 5q35, the novel tyrosine kinase gene and nucleophosmin gene, respectively. In this study, we intended to detect p80 on lymphoma tissues with immunologic methods. Thus, we developed rabbit polyclonal antibody using a synthetic peptide corresponding to a part of its kinase domain. The antibody (anti-p80) immunoprecipitated and immunoblotted p80 specifically from AMS3. Then, to examine whether t(2;5)(p23;q35) was present on biopsied lymphomas, reverse transcriptase-polymerase chain reaction (RT-PCR) covering the fusion junction of p80 mRNA was performed. Among 10 Ki-1 lymphomas and 10 additional lymphomas other than the Ki-1 lymphomas, expression of p80 mRNA was detected in three cases exclusively. When these 20 cases and additional 30 lymphomas were immunostained with anti-p80, positive staining was noted exclusively in the three cases found by PCR to have harbored the p80 mRNA. Thus, the present immunostaining, as well as PCR, was shown to be efficient for detecting lymphomas producing this chimeric protein/mRNA.