Charles Cook

Effect of Cortisone on Healing of Corneal Wounds

THE evidence that cortisone inhibits wound healing in animals and man through its depressant action upon fibroblastic activity has already been reviewed (Duke-Elder and Ashton, 1951), but this conclusion might not apply equally to repair-processes in the non-vascularized tissue of the cornea, in which the metabolism is peculiar and the structure unique. The following experiments were therefore designed to determine the effect of cortisone upon the healing of perforating wounds of the rabbit cornea.

Mechanism of Corneal Vascularization

THE fundamental biological phenomenon of new vessel formation is one of enormous complexity, and has excited the interest of scientific workers for many years as shown by the extensive bibliography of the physiological and pathological aspects of the problem. The normal cornea, having the great advantages of avascularity, transparency, and ready accessibility to biomicroscopical examination, has been widely employed as an experimental tissue in these investigations. There are, however, several special features in the process of corneal vascularization which, as we shall subsequently show, prevent an exact analogy with vessel growth elsewhere, thus rendering the cornea, in fact, a somewhat unsuitable medium for the study of the general question of capillary growth, and necessitating a specific approach to the problem of corneal vascular invasion. This paper, although drawing upon the relevant findings in extra-ocular experimental work, is concerned in the main with the mechanism of vascularization as seen in corneal tissue.

Allergic Granulomatous Nodules of the Eyelid and Conjunctiva

Twenty-two cases of granulomas of the conjunctiva or eyelids were studied, and the clinical and pathologic features were tabled. All cases showed the histologic features of the Splendore-Hoeppli phenomenon, that is a giant cell and eosinophil granulomatous reaction to an antigen-antibody precipitate originally described in relation to parasites or fungi. Seven typical cases were selected for detailed description; in four of these cases, unidentified nematodes were the cause of the condition.

Effect of Cortisone on Vascularization and Opacification of the Cornea Induced by Alloxan

THERE are few reports in the literature of experimental work dealing with the effect of cortisone upon corneal vascularization, and the evidence so fair advanced is partly conflicting (Duke-Elder and Ashton, 1951), but there is already some indication from clinical observers that cortisone exerts a considerable inhibitory influence on the formation of ne\v vessels in the diseased cornea. The experimental vwork reported in this paper investigates this subject further by the use ot a recently evolved technique which has particular advantages for this study. Before proceeding to investigate the effect of cortisone upon corneal vascularization it is necessary to consider the possible stimuli which might initiate new vessel formation; although the causes are still quite unknown, many theories have been advanced, some of which have an especial bearing upon the experimental conditions. Thus assuming for the moment that new vessel formation arises in response to a chemical substance liberated in traumatized tissue, as suggested by Michaelson and Campbell (1949). any effect of cortisone may be due to a neutralizing mechanism, and the extent of its action Would then depend upon the, size of the lesion and the quantity of cortisone administered. Similarly, the severity of the lesion would be of importance were vascularization to result from alterations in the normal tissue tension, as suggested by Cogan (1949). In attempting, therefore, to assess the effect of a given dose of cortisone upon corneal vascularization, it is essential that the experimental lesion should be, as far as variation in individual animals will allow, both standardized, in order to permit comparison, and the minimal required to produce vascularization, to ensure adequate sensitivity. Although the work already published on this subject is of great importance in assessing the probable therapeutic value of cortisone, it cannot be held that caustic (Jones and Meyer, 1950; Leopold and others, 1951), or thermal burns (Lister and Greaves, 1951), are entirely satisfactory methods for investigating this problem, for the

Studies on Developing Retinal Vessels : I. Influence of Retinal Detachment

IN the early stages of the normal development of the human retina, the choroidal circulation is apparently responsible for maintaining retinal nutrition, but, as the metabolic requirements of the growing retina increase, this source of supply gradually becomes inadequate and new vessels bud into the retina from the hyaloid artery at the disc. The chorio-capillaris, however, continues throughout life to supply the outer retina to a depth of about 130 microns (Michaelson, 1951) and in health this zone is never invaded by retinal capillaries, which in a remarkably constant way, extend no deeper than the outer limits of the inner nuclear layer, despite the absence of any anatomical barrier. The sharp demarcation of this avascular area in the outer retina suggests that the chorio-capillaris is capable of supplying nutrition into the retina for only a limited distance; it would, therefore, be of interest to know what effect separation of the retina from the choroid might have upon the growth of retinal vessels. In this paper experiments are reported which show that detachment of the developing kitten retina, in which the normal pattern of vascular growth is in every way comparable to that in man, leads to a downgrowth of retinal vessels beyond the inner nuclear layer, frequently penetrating the retina completely and formning a network on its outer surface. Vessels may also extend into the vitreous to form glomerular tufts typical of such intravitreal vasoproliferation. In the adult cat, however, retinal detachment had no such influence on the retinal vasculature.

Corneal thickness in interstitial keratitis.

THE importance of the role played by changes in the thickness of the cornea in the induction of corneal vascularization has recently become increasingly recognized (Cogan, 1948; Ashton, Cook, and Langham, 1951; Langham, 1952, 1953; Ashton and Cook, 1953). However the relationship between the swelling and increase in opacity of the cornea to the rate and progress of vascularization of the cornea in humans has not hitherto been investigated. In the present study, an attempt has been made to bridge this gap in our knowledge by correlating alterations in corneal thickness with the clinical progress of a series of ten cases of specific and non-specific keratitis receiving cortisone therapy. Changes in the general macrosopical and slit-lamp appearances and in the degree of corneal opacity were noted in addition to the measurements of corneal thickness.

Studies on Developing Retinal Vessels: II. Influence of Retinal Detachment on Oxygen Vaso-Obliteration

BY direct observation, it was recently shown that the obliterative action of high concentrations of oxygen on the ingrowing vessels of the kitten retina may be prevented by retinal detachment (Ashton and Cook, 1954). The obliterated vessels re-open as soon as detachment begins, indicating that close apposition between retina and choroid is necessary for the obliterative phenomenon to operate. Since it is known that vaso-obliteration is also dependent upon the concentration of oxygen, it would appear that, once the retina detaches, effective levels of oxygen no longer reach this tissue. The maximum period, however, for which the vessels of the detached retina were observed in hyperoxia was 121 hours, and the question remained whether a longer period of exposure might not be required for oxygen to diffuse across the subretinal space and reach the retina in sufficient concentration. In this paper experiments are reported which show that retinal detachment prevents the vaso-obliterative effect of oxygen even when high concentrations are continuously maintained for 4 days. Survival in air after such detachment and exposure is followed by proliferative changes which are difficult to interpret in view of our findings on the effect of detachment alone (Ashton and Cook, 1955).

ROLE OF FAT EMBOLI IN DIABETIC RETINOPATHY

THE association between diabetes mellitus and disturbance of fat metabolism has long been recognized, and the lipoidal nature of the diabetic vascular changes has been emphasized by many workers particularly with reference to the retinal and renal changes. It is only in recent years, however, that fat emboli have been reported in association with diabetic vascular disease. Thus Wilens, Elster, and Baker (1951) demonstrated that the deposition of fat in the lesions of diabetic glomerulosclerosis is directly proportional to the severity of the renal involvement. Hartroft (1955) found that fat emboli in choline-deficient rats eventually gave rise to glomerular lesions resembling human diabetic glomerulosclerosis, and Kent (1955) showed that fat emboli indistinguishable from the traumatic variety were to be found much more frequently in diabetics than in non-diabetics. Retinal vascular lesions following traumatic fat embolism were reported by Czerny (1875), but the possibility that a similar process might play a part in the pathogenesis of diabetic retinopathy has attracted little attention, although it is noteworthy that Morgan (1949) reported that a case of traumatic fat embolism showed a fundus picture not unlike that occasionally seen in the diabetic, and that Urbanek (1933) remarked upon the similarity of the ophthalmoscopic picture seen after fat embolism to that in senile diabetics with arteriosclerosis. In view of these facts, the present investigation was undertaken to examine microscopically the retinal and renal lesions produced by experimental fat emboli in an attempt to evaluate their possible role in the pathogenesis of diabetic vascular disease.

Studies on developing retinal vessels. III. Role of sympathetic innervation in oxygen vaso-obliteration.

THE obliterative effect of high concentrations of oxygen on developing retinal vessels was first demonstrated in the eye of the kitten by Indian ink injection (Ashton and others, 1953) and was later observed directly by using a limbal window technique (Ashton and Cook, 1954); it has since been shown in eyes of puppies and new-born rats by ink injection methods (Patz, 1954) and in new-born mice by sections (Gyllensten and Hellstr6m, 1954). The mechanism whereby oxygen exerts this obliterative effect, however, is still entirely unknown, but the sum of experimental evidence so far obtained strongly suggests: (a) that the influence is exerted locally through the evolution or destruction of some factor or factors within the immature retina itself; (b) that the effect is confined to the immature retina by reason of its peculiar metabolism; (c) that the retina is vulnerable to hyperoxia through its structural and functional relationships to the choroid.