Temporal Evolution of Step-Edge Fluctuations Under Electromigration Conditions

The temporal evolution of step-edge fluctuations under electromigration conditions is analysed using a continuum Langevin model. If the electromigration driving force acts in the step up/down direction, and step-edge diffusion is the dominant mass-transport mechanism, we find that significant deviations from the usual $t^{1/4}$ scaling of the terrace-width correlation function occurs for a critical time $\tau$ which is dependent upon the three energy scales in the problem: $k_{B}T$, the step stiffness, $\gamma$, and the bias associated with adatom hopping under the influence of an electromigration force, $\pm \Delta U$. For ($t < \tau$), the correlation function evolves as a superposition of $t^{1/4}$ and $t^{3/4}$ power laws. For $t \ge \tau$ a closed form expression can be derived. This behavior is confirmed by a Monte-Carlo simulation using a discrete model of the step dynamics. It is proposed that the magnitude of the electromigration force acting upon an atom at a step-edge can by estimated by a careful analysis of the statistical properties of step-edge fluctuations on the appropriate time-scale.Comment: 7 pages, 5 figure

THE RELATIVE REACTION WITHIN LIVING MAMMALIAN TISSUES : VII. THE INFLUENCE OF CHANGES IN THE REACTION OF THE BLOOD UPON THE REACTION OF THE TISSUES.

The introduction into the blood stream of dilute hydrochloric acid or sodium carbonate in quantities not too great to be compatible with life results in marked alterations in the color of certain of the matrix tissues stainable in vivo with phthalein indicators. Connective tissue in its various forms, and tendon and cartilage all become relatively more acid or alkaline than the normal. The hue of the kidney cortex also changes, as might be expected from its functions. The pancreas and lymph nodes, on the other hand, appear unaffected even when the injection is pushed to the extreme; and the slight to negligible alterations in the hue of the liver may be due to changes in the color of the associated secretion. The matrix tissues just mentioned behave as if unable to maintain a reaction of their own; whereas the elements of the parenchymal organs would seem to make their own conditions even when so much acid or alkali has been injected as will lead to death of the animal. Injections of lactic acid are well tolerated and it is difficult to bring about alterations in the color of the phthalein-stained matrix tissues by means of them. Salt solution, and sugar in large amount cause no changes in color such as would indicate changes in reaction. The results with the various phthalein indicators are in close accord, attesting that the information these give under vital conditions is reliable

THE FATE OF VACCINIA VIRUS ON CULTIVATION IN VITRO WITH KUPFFER CELLS (RETICULO-ENDOTHELIAL CELLS)

The pathogenic activity of vaccinia virus is in large part suppressed when it is mixed with living Kupffer cells or clasmatocytes in the test-tube and injected intradermally. Vaccinia increases in quantity when introduced into cultures of Kupffer cells in vitro, and survives in immediate association with these elements. No antiviral principle is elaborated by them under such conditions

THE INFLUENCE OF ETHER ANESTHESIA, OF HEMORRHAGE, AND OF PLETHORA FROM TRANSFUSION ON THE PRESSOR EFFECT OF MINUTE QUANTITIES OF EPINEPHRINE

Ether anesthesia has a marked influence in diminishing the pressor response to minute amounts of epinephrine injected directly into the circulation. Hemorrhage also acts to lessen or abolish the response, and to a degree directly proportional to the lowering of the blood pressure it causes. In the exsanguinated animal an amount of epinephrine three or four times that sufficient to produce a pressure rise of 10 to 15 mm. of mercury under normal conditions, may be entirely without effect. The response to large doses, on the other hand, is uninfluenced by ether or hemorrhage. The facts stated have a practical bearing not only on the employment of epinephrine to tide over collapse but on its possible utilization in the future to raise a low blood pressure to the normal height and maintain it during a considerable period. For the amount of epinephrine which under normal conditions will suffice to bring up the blood pressure may have little or no effect on an etherized individual or on one who has lost blood. The same difficulty will doubtless be encountered under other conditions. In animals rendered plethoric by transfusion the response to small doses of epinephrine lessens in proportion as the blood pressure is increased by the plethora

A VIRUS-INDUCED MAMMALIAN GROWTH WITH THE CHARACTERS OF A TUMOR (THE SHOPE RABBIT PAPILLOMA) : III. FURTHER CHARACTERS OF THE GROWTH: GENERAL DISCUSSION

Experimental study of the rabbit papilloma of Shope, a growth caused by a virus, has shown that it possesses the immediate characters whereby tumors are recognized. Often it looks and acts like a malignant neoplasm. It differs from the tumors as a group, however, in its incidence which is that of an infectious process, and from other mammalian tumors in that its cause has been demonstrated. The possible bearing of the findings upon the problem of tumor causation is discussed. The morphology and behavior of the generality of tumors can no longer be taken to exclude the possibility that these are produced by extraneous, living entities. The incidence of some of the tumors at least, and the failure to demonstrate their cause can both be explained on the assumption that they are due to such entities, widely distributed in or upon the animal population but effective only under special circumstances. Present knowledge makes this assumption reasonable as a basis for further work

THE CHARACTERS OF KUPFFER CELLS LIVING IN VITRO

The Kupffer cells procured from the liver of the rabbit and dog for culture in vitro have the typical characters of clasmatocytes. They are readily discriminated from the monocytes washed from the liver with them; and they have certain peculiar features which suffice to differentiate them from some at least of the clasmatocytes of other organs. Their surface is extraordinarily sticky,—far more so than that of blood leukocytes or of the clasmatocytes found in peritoneal exudates; and in consequence they are exceedingly difficult to handle in vitro. They put forth enormous, pellucid, circular membranes resembling those of exudate clasmatocytes but larger. Splenic clasmatocytes, on the other hand, put forth rather small, one-sided ground-glass membranes like broad tongues. On comparing them with Kupffer cells and exudate clasmatocytes one perceives that they are not wholly identical in their characters, but have secondary peculiarities. However, there exist good morphological reasons for grouping them together and terming them all reticulo-endothelial. Kupffer cells are notably sensitive to injury, surviving in Tyrode solution for a much shorter time than blood leukocytes. However, they can be readily cultured on lens paper in serum. Under such circumstances they scatter on the fibres and live separately, presenting the same general aspect as when in the liver; but in the course of proliferation they soon lose some of their pronounced characters, retaining such as are common to clasmatocytes in general. A considerable population of ordinary leukocytes exists in the hepatic sinuses over and above those circulating in the blood. During infection, their number may greatly increase. Several cubic centimeters of packed white cells have been obtained from the liver of a sick dog. The fact has been realized that leukocytes may stop a while in the liver, yet the extent of the accumulation which sometimes takes place seems deserving of stress

A VIRUS-INDUCED MAMMALIAN GROWTH WITH THE CHARACTERS OF A TUMOR (THE SHOPE RABBIT PAPILLOMA) : II. EXPERIMENTAL ALTERATIONS OF THE GROWTH ON THE SKIN: MORPHOLOGICAL CONSIDERATIONS: THE PHENOMENA OF RETROGRESSION

The injection of Scharlach R into the skin about rabbit papillomas resulting from virus inoculation causes them to invade the underlying tissue and form large, fleshy masses beneath the surface. Histologically these appear malignant, and they frequently invade the blood vessels. Covering young papillomas with a layer of collodion causes them to burrow downwards with result in discoid masses which enlarge progressively, both by expansive growth beneath the epidermis and by invasion. Such masses, like the nodules resulting from implantation, have the papillae turned toward their interior, the apparent reverse of the condition of affairs when the growth is situated on the skin surface. The reasons for this are analyzed. The peculiarities of the host influence skin papillomas not a little, as is plain from the forms they assume; but the epithelial changes induced by the virus take a single direction, and no significant variations from type have been encountered. Local or generalized retrogression of the experimentally induced papilloma is not uncommon. The histological alterations that take place are identical with those attending retrogression of the epidermoid tumors, and the reactive changes taking place in the surrounding tissue are also like those about such tumors. The slowing and cessation of growth that occur secondarily in the case of virus-induced skin papillomas are associated with the formation under them of a dense layer of connective tissue, and to this their behavior is attributable. Similar findings have been often recorded for tumors, notably for the epidermoid cancers produced in rabbits by tarring

A VIRUS-INDUCED MAMMALIAN GROWTH WITH THE CHARACTERS OF A TUMOR (THE SHOPE RABBIT PAPILLOMA) : I. THE GROWTH ON IMPLANTATION WITHIN FAVORABLE HOSTS

Rabbit papillomas developing on the skin as the result of virus inoculation can be readily transferred to the inner organs of favorable hosts by implanting bits of the living tissue. The growths thus produced proliferate actively as a rule and frequently cause death. Often they are markedly invasive and destructive; and they tend to recur after excision. Bacterial infection may greatly enhance their malignancy. Accidental dissemination may occur during operation, and distribution to the peritoneal surface has been repeatedly noted. There may be no cellular reaction whatever about the invading epithelium of interior growths, but usually some new formation of connective tissue takes place, its amount varying inversely with the rate of epithelial proliferation. An immediate reason exists for the inflammatory changes and scarring found beneath long-established skin papillomas, in the trauma and secondary infection to which the projecting, necrotizing masses have been subjected. In animals dying of progressively enlarging interior growths the skin papilloma may long have been stationary in size. The growths appearing after the transfer of papillomatous tissue to the inner organs are due to the survival and multiplication of transplanted cells. However, the virus can be readily recovered from them, in the case of wild rabbits. No distinctive changes in the blood of the host have been found. The virus itself is highly specific for the epithelium of the skin, failing to act not only upon that of the other organs thus far tested but even upon embryonic skin. The papilloma frequently penetrates into the blood and lymph vessels, especially at the edge of implantation growths. The intravascular injection of fragments of it sometimes results in pulmonary nodules of characteristic morphology. These are due to survival and proliferation of the injected cells. Secondary nodules have been encountered at autopsy in a lymph gland and in the lungs, but under conditions more suggestive of operative dissemination of the growth than of true metastasis. Implantation growths of the papilloma in favorable hosts have the morphology of epidermoid tumors of greater or less malignancy. They behave as these do and elicit similar changes in the surrounding tissue. The attributes and potentialities of the papilloma will be further considered in Papers II and III

THE PROGRESSION TO CARCINOMA OF VIRUS-INDUCED RABBIT PAPILLOMAS (SHOPE)

The papillomas induced in domestic rabbits with virus procured from cottontails undergo progressive changes in the direction of malignancy when they grow vigorously. From the beginning they exhibit the traits whereby tumors are characterized, and they have malignant potentialities. In seven animals of a group of ten carrying papillomas for more than 200 days, cancer has developed, and in an eighth a tumor of problematic malignancy has arisen. One of the remaining two rabbits died early in the cancer period, and the papillomas of the other eventually retrogressed. Ten cottontails with induced growths of much longer duration have not developed cancer. The malignant tumors have all been acanthomatous in type, and have arisen directly from the papillomas by graded, continuous alterations. These have often gone further after malignancy has been attained, and have eventuated in great anaplasia. Metastasis has been frequent, and transplantation to another host has proved successful. Individual growths have occurred expressive of each stage of the transformation to cancer, as if through a stabilization at this stage; yet despite the variety thus afforded, the tumors must all be looked upon as the consequence of alterations in cells of a single sort, namely epidermal cells affected by the virus, and the alterations themselves have taken a single direction. In the morphology of many of the cancers the influence of the virus is still manifest. The better the papilloma grew, the more likely was cancer to occur, and the greater was the tendency to multiple tumors. In the most favorable rabbits malignant changes took place at numerous locations in the papillomatous tissue, and were imminent at many others. Intercurrent factors had much to do with determining frank carcinosis; and when the tendency to it was not marked their influence sometimes seemed crucial. Analogous instances of a graded alteration from papilloma to cancer are frequent in human pathology. The virus that gives rise to the rabbit papillomas must be looked upon as the primary cause of the cancers developing therefrom. Whether it is their proximate cause has yet to be determined

SELECTION WITH THE MAGNET AND CULTIVATION OF RETICULO-ENDOTHELIAL CELLS (KUPFFER CELLS)

Methods and apparatus are described where with living Kupffer cells can be procured from the liver of the rabbit and the dog for study and cultivation in vitro. Almost none of these cells can be dislodged from the normal liver by forcible perfusion; but after they have taken up finely particulate matter (India ink, iron oxide), they come away in great numbers. When they have phagocyted ferromagnetic iron oxide they can be selected with a magnet from amongst the blood elements present in suspension with them; and they are obtainable in quantity by this means. They do poorly when plated in a thin plasma clot, failing to multiply or to assume their characteristic shape; but they flourish when allowed to attach themselves to strands of lens paper bathed in serum that is frequently changed. Bacterial infection of serum cultures of Kupffer cells from normal rabbits and dogs occurs only as the result of secondary contamination of the materials, whereas it regularly develops in cultures from animals with fever induced by the injection of nucleic acid or of killed B. prodigiosus. Kupffer cells obtained under such conditions are abnormally active, and some can be washed out of the liver of sick animals in the absence of any preliminary phagocytosis of particulate matter. The facts have a bearing both on the conditions conducing to blood invasion and on the response of the Kupffer cells in the emergency. The characters of the isolated Kupffer cells and the results of tests of their presumptive functions will be described in later papers