One aspect of Garrod’s theory that much exercised the minds of his contemporaries was that for him _uric acid_ was the alpha and omega of the disease, and as Ewart remarks, “If we are not over-anxious as to the stability of this mid-air foundation, everything is evolved smoothly from it on the lines of the theory.” Fortunately, however, for the progress of the art of medicine, men _were_ over-anxious as to the why and wherefore of that accumulation of uric acid in the blood which Garrod held to be a necessary antecedent of gout. He himself, as we know, attributed it to a _functional renal defect_ which may be inherited or acquired. To others, however, this assumption of renal inadequacy was not wholly satisfying, hence the origin of the many widely differing hypotheses from time to time advanced as to the pathogeny of the disorder. Broadly speaking, the various conceptions proffered as to the causation of gout fall into one or other of the following categories. The primary alteration in gout is variously assumed to be:— (1) In the blood or tissues, the so-called histogenous theories. (2) In the bodily structures, either inborn or induced. (3) In hepatic inadequacy. (4) In hyperpyræmia. (5) In the nervous system. HISTOGENOUS THEORIES In his classic work, “On Urine” (1860), Parkes expressed his scepticism as to the valency of Garrod’s assumption of a _primary renal inadequacy_. In shrewd forecast of latter day views he was of opinion that both uric and phosphoric acids existed in some untoward combination in the _blood_ or _organs_, and that this same impeded its excretion. As he says, “If this be the case, the deficient elimination is, as it were, only a consequence of more important antecedent aberrations in metamorphosis of which impeded excretion is a natural sequence. What these are, however, is quite unknown; but an unnatural formation of uric acid, either from food or tissues, may possibly be part of them.” In 1866 Barclay lodged another objection to Garrod’s hypothesis, viz., that the baneful influence of uric acid was _exercised passively and physically_. Not only did he regard it as “far too mechanical,” but he also strongly dissented from his axiom that gouty inflammation was invariably attended by _uratic deposits_. Thus he asks, “Must we of necessity find urate of soda in the stomach and the bronchi before we can admit gouty gastritis, or gouty bronchitis?” Seemingly he believed in the existence of these two clinical entities, and inasmuch as urate of soda had not been detected _in situ_ in these disorders, he felt justified in denying that “true gouty inflammation is always associated with, or caused by, the deposit.” Moreover, this conclusion, he considered, derived colour from the fact that, “though the deposit and the inflammation were associated together in the joints, the urate of soda was seen in other parts without any evidence of its exciting inflammation there.”