XI. PATHOLOGY 497 



also CF, has no such direct effect. Girdwood''^ has found that the tissues 

 of a patient dying with untreated pernicious anemia contain PGA or its 

 conjugates, but he was unable to demonstrate the presence of B12. The 

 writer and his associates also have evidence that the marrow of pernicious 

 anemia patients is not completely devoid of PGA or related compounds. 

 It ma3', therefore, be inferred that B12 instilled directly into marrow pro- 

 motes, in a manner not understood, but possibly through removal of an 

 inhibitor eff'ec-t, the metabolic function of PGA. 



The therapeutic efficacj'' of PGA when given orally or parenterally in 

 relatively large doses may be due to a mass action effect, as suggested by 

 Miter and associates.^^ In this important article the authors present theo- 

 retical considerations based on clinical evidence of the metabolic inter- 

 relationships of PGA, B12, and other materials which participate, either as 

 constituents or as enz3TTies, in the synthesis of nucleic acids, and they at- 

 tempt to integrate earlier work on microbiological synthesis of imcleic acids 

 with clinical observations on the therapeutic effects of PGA, Bi2, thymine, 

 and such precursor substances as uracil, methionine, and choline. In their 

 view, megaloblastic erythropoiesis is the result of disturbed metabolism of 

 nucleoprotein which normally depends upon a chain reaction involving the 

 presence of methyl group donors, transmethylating agents, such as PGA 

 and related compounds, and possibly unknown substances, such as the 

 Will's factor. These agents enable purines and pyriraddines to be formed 

 from precursor materials. B12 functions later in the chain reaction and is 

 concerned with the synthesis of nucleosides, including thymidine. Supply 

 of increased amounts of methyl donor compounds, namely methionine and 

 choline, may, in certain circumstances, partially overcome a deficiency of 

 PGA and produce hemopoietic response. Administration of PGA or CF 

 will usually, if not always, cause at least temporary improvement, even in 

 the presence of B12 deficiency, probabl}'- through a mass action effect in 

 the presence of small quantities of B12. The subsequent hematologic relapse 

 and the frequent development or exacerbation of nervous system disease 

 observed in pernicious anemia patients treated with PGA may be explained 

 by depiction of remaining stores of B12. It is of interest that the converse 

 of this phenomenon has not been observed; that is, the administration of 

 B12 to patients with primary PGA deficiency, such as in megaloblastic 

 anemia of pregnancy, fails to produce even transient improvement and 

 may actually serve to aggravate the clinical and hematologic manifesta- 

 tions due to lack of PGA. It must be supposed that in these situations 



=" R. H. Girdwood, Edinburgh Med. J. 58, 309 (1951). 



39 K. W. Vilter, D. Horrigan, J. F. Mueller, T. Jarrold, C. F. Vilter, V. Hawkins, 

 and .\. Seaman, Blood 5, 695 (1950). 



