Invasive strains of staphylococcus and streptococcus contain a soluble factor which markedly increases tissue permeability and enhances the infections produced by these organisms, by other bacteria, and by vaccine virus as well. The non-invasive strains of the same species of staphylococci and streptococci do not contain this factor. The enhancing substance elaborated locally by organisms passes into the circulating blood and bringing about a general increase of tissue permeability may act to enhance local infections elsewhere. The factor is similar in the phenomena it elicits to the spreading factor extracted from many animal tissues, especially from testicle.

Brain and testicle tissue from immune rabbits brought in contact with the Levaditi or Noguchi strains of vaccine virus will fix or inactivate the virus. Extracts of normal testicles from susceptible animals enhance to an extraordinary degree the infectivity of both the neuro- and dermal strains of vaccine virus. The Noguchi virus is not affected by testicle extracts when injected into the skin, but kidney extract has a definite enhancing power on the strain when injected into either skin or testicle. The effect of tissue extracts seems to be on the cells of the host rather than on the virus. This is indicated by the fact that virus injected intravenously localizes most readily in an area of skin previously injected with testicle extract. Furthermore an enhanced lesion results if the virus is injected into an area as long as 3 days after the area has been injected with testicle extract. The augmenting substance of the tissue extracts is little affected by high dilutions, passes through a Berkefeld V candle and is carried down with the proteins precipitated by weak acids. Rabbits with enhanced lesions show general symptoms and about 25 per cent die with generalized vaccinia. Kidney, and probably skin, brain and liver extracts possess enhancing properties, but to a much less degree than the testicle. On the other hand, spleen, blood and probably lymph nodes and bone marrow not only fail to produce enhancement, but actually restrain or even suppress entirely the vaccinal skin infection.

Origin and distribution of the ground substance. It is generally accepted that, in adult life, the ground substance is a product of secretion of the C.T. cells (152, 257, 101, 11) and that through progressive transformations of this substance, argyrophilic fibers, collagen, and the matrices of all mesenchymal tissues are formed (101, 152). Its distribution has been studied by S. Bensley (11), who routinely used toluidine blue to detect it. She showed that in the guinea pig pancreas after duct ligation, and in the human uterine mucosa, there is a succession of phases: edema-* gelatinous ground substance-+ argyrophilic fibers-> collagen, the ground substance being considerably reduced at the last phase. The distribution of the ground substance was found to be the same in the umbilical cord, intima and media of blood vessels, C.T. of lower vertebrates, gastric mucous membranes, and in general in all reticular and embryonic tissues. Physical and chemical properties. Bensley's work has disclosed some general properties of the ground substance. By mounting fresh tissues in a medium of a different refractive index it is seen as a continuous, fairly granular, transparent substance in which fibers are imbedded. It is elastic and tends to retract when cut. As judged by the reactions of paramecia injected into the C.T., it is viscid and possibly acid. Its refractive index is between 1.33 and 1.34. It is extractable with 10% salt solution, and half-saturated lime water. It is digested by trypsin but not pepsin in contrast to collagen where the reverse is true. It combines with copper salts suggesting that it may contain a derivative of chondroitin sulphuric acid.

The experiments in this paper show that testicle extract causes India ink particles and those of Prussian blue to spread much more extensively through the intercellular spaces than similar suspensions made with Ringer's solution. Methylene blue inoculated intravenously localizes more extensively in areas previously injected with testicle extracts than in control areas receiving injections of tissue extracts without enhancing power. Kidney extracts have this property to a less degree, whereas spleen extracts and blood serum are devoid of it. The spreading power of extracts is destroyed by heating at 60°C. for 30 minutes, as is also the power to enhance infections. The precise mode of action of the Reynals factor is not known, but the results of the experiments here presented suggest that it may depend at least in part on the property whereby testicle extract increases the spread of injected material and alters the permeability of tissue cells. It is not inconceivable that changes in permeability facilitate the passage of vaccine virus through the endothelial cells of the blood and lymph vessels, and lead to the generalized vaccinia which is of frequent occurrence in the reported results (20). It has been shown that fluids and suspensions of inert particles are spread by the extract.B. tetanus and B. coli exotoxins and trypsin were not enhanced at all in their action despite the fact that they were spread through a more extensive area in the tissues. Viruses, on the other hand, are markedly influenced and in this respect resemble bacteria, not toxins and enzymes. It appears probable that a definite capacity for multiplication on the part of an injected substance is required if its pathogenic effects are to be enhanced. It may be concluded tentatively that the enhancing power of the testicle extract may depend on that property which not only spreads the injected material through a larger area but renders the tissue cells more easily penetrable by the agents.

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