bluuebunny/crossref_metadata_2025 huggingface dataset:
Ceramide Inhibits Antigen Uptake and Presentation by Dendritic Cells
Authors: Sallusto Federica , Nicolò Chiara , De Maria Ruggero , Corinti Silvia , Testi Roberto
Published: June 2004

Ceramides are intramembrane diffusible mediators involved in transducing signals originated from a variety of cell surface receptors. Different adaptive and differentiative cellular responses, including apoptotic cell death, use ceramide-mediated pathways as an essential part of the program. Here, we show that human dendritic cells respond to CD40 ligand, as well as to tumor necrosis factor-α and IL-1β, with intracellular ceramide accumulation, as they are induced to differentiate. Dendritic cells down-modulate their capacity to take up soluble antigens in response to exogenously added or endogenously produced ceramides. This is followed by an impairment in presenting soluble antigens to specific T cell clones, while cell viability and the capacity to stimulate allogeneic responses or to present immunogenic peptides is fully preserved. Thus, ceramide-mediated pathways initiated by different cytokines can actively modulate professional antigen-presenting cell function and antigen-specific immune responses.
The V–J Recombination of  T Cell Receptor-γ Genes Is Blocked in Interleukin-7 Receptor–deficient Mice
Authors: Maki Kazushige , Sunaga Shinji , Ikuta Koichi
Published: June 2004

IL-7R-deficient mice have severely impaired expansion of early lymphocytes and lack γδ T cells. To elucidate the role of IL-7R on γδ T cell development, we analyzed the rearrangements of TCR-α, β, γ, and δ genes in the thymus of the IL-7R-deficient mice. Southern blot analysis with a Jγ1 probe revealed that more than 70% of Jγ1 and Jγ2 alleles are recombined to form distinct Vγ1.2–Jγ2 and Vγ2–Jγ1 fragments in control mice. On the contrary, no such recombination was detected in the mutant mice. The rearrangements in the TCR-α, β, and δ loci were comparably observed in control and mutant mice. PCR analysis indicated that the V–J recombination of all the Vγ genes is severely hampered in the mutant mice. The mRNA of RAG-1, RAG-2, Ku-80, and terminal deoxynucleotidyl transferase (TdT) genes was equally detected between control and mutant thymi, suggesting that the expression of common recombination machinery is not affected. These data demonstrated that the V–J recombination of the TCR γ genes is specifically blocked in the IL-7R-deficient mice and suggested the presence of highly specific regulation for TCR γ gene rearrangement.
CD8β Increases CD8 Coreceptor Function and Participation in TCR–Ligand Binding
Authors: Renard Valery , Romero Pedro , Vivier Eric , Malissen Bernard , Luescher Immanuel F.
Published: June 2004

To study the role of CD8β in T cell function, we derived a CD8α/β− (CD8−/−) T cell hybridoma of the H-2Kd–restricted N9 cytotoxic T lymphocyte clone specific for a photoreactive derivative of the Plasmodium berghei circumsporozoite peptide PbCS 252-260. This hybridoma was transfected either with CD8α alone or together with CD8β. All three hybridomas released interleukin 2 upon incubation with L cells expressing Kd–peptide derivative complexes, though CD8α/β cells did so more efficiently than CD8α/α and especially CD8−/− cells. More strikingly, only CD8α/β cells were able to recognize a weak agonist peptide derivative variant. This recognition was abolished by Fab′ fragments of the anti-Kd α3 monoclonal antibody SF11.1.1 or substitution of Kd D-227 with K, both conditions known to impair CD8 coreceptor function. T cell receptor (TCR) photoaffinity labeling indicated that TCR–ligand binding on CD8α/β cells was ∼5- and 20-fold more avid than on CD8α/a and CD8−/− cells, respectively. SF1-1.1.1 Fab′ or Kd mutation D227K reduced the TCR photoaffinity labeling on CD8α/β cells to approximately the same low levels observed on CD8−/− cells. These results indicate that CD8α/β is a more efficient coreceptor than CD8α/α, because it more avidly strengthens TCR–ligand binding.
Different Interleukin-1β Converting Enzyme (ICE) Family Protease Requirements for the Apoptotic Death of T Lymphocytes Triggered by Diverse Stimuli
Authors: Sarin Apurva , Wu Ming-Lei , Henkart Pierre A.
Published: June 2004

Two cell permeable peptide fluoromethyl ketone inhibitors of Interleukin-1β converting enzyme (ICE) family proteases were tested as inhibitors of apoptotic cell death of T lymphocytes at various stages of differentiation. The CPP-32–like protease activity in apoptotic cell lysates was blocked by both the ICE inhibitor Cbz-Val-Ala-Asp(OMe)-fluoromethyl ketone (ZVADFMK) as well as its truncated analog Boc-Asp(OMe)-fluoromethyl ketone (BD-FMK), which failed to block ICE. In vitro apoptotic death in murine thymocytes triggered by the independent agents dexamethasone, etoposide, radiation, anti-Fas, and anti-CD3 was blocked equally well by BD-FMK and ZVAD-FMK, but not by the control reagent Cbz-Phe-Ala-fluoromethyl ketone. In activated T cell blasts, while anti-CD3/ Fas-induced death was almost completely inhibited by both ZVAD-FMK and BD-FMK, death induced by dexamethasone, etoposide, or irradiation was more sensitive to inhibition by BD-FMK. In the murine T cell line CTLL-2, apoptotic death induced by IL-2 withdrawal, etoposide, or dexamethasone was inhibited by BD-FMK, while ZVAD-FMK was without effect. These data indicate that ICEfamily proteases comprise a common functional step in distinct T cell apoptotic death pathways, but suggest that different family members are likely to be critical in various differentiated T cell types, even when triggered by the same stimulus.
PNEUMOCOCCUS HEMOTOXIN
Authors: Cole Rufus
Published: June 2004

Solutions of the bodies of pneumococci, obtained by dissolving them in dilute solutions of sodium cholate, by permitting them to undergo autolysis, or by first freezing, drying, and then grinding in salt solution, are actively hemolytic for rabbit, sheep, guinea pig, and human red blood corpuscles. The substance on which this hemolytic property depends is very labile, much of its activity is lost on passing through a filter, and it is destroyed by the action of trypsin. In its properties it corresponds to the substance contained in such solutions which causes the death of guinea pigs on intravenous injection. Its activity is prevented by the presence of minute amounts of cholesterin.

Following the injection of this solution into rabbits and sheep, the sera of these animals acquire increased power of inhibiting its hemolytic action. It therefore possesses antigenic properties.

It may therefore be concluded that the bodies of pneumococci contain a toxin that is hemolytic for red blood corpuscles. This substance is not simply a product of autolysis but undoubtedly exists preformed in the bacterial cell. However, it is not given up to the surrounding fluid as long as the bodies of the bacteria are intact. It may therefore be considered a hemolytic endotoxin.
THE PRODUCTION OF METHEMOGLOBIN BY PNEUMOCOCCI
Authors: Cole Rufus
Published: June 2004

1. Pneumococci in contact with hemoglobin transform this into methemoglobin. This reaction occurs only when the pneumococci are living; it is not induced by the culture fluid or by extracts of the bacteria.

2. The reaction does not occur when hemoglobin is added to an emulsion of washed pneumococci in salt solution. However, if minute traces of dextrose be added to such a mixture, the reaction quickly occurs. The dextrose may be replaced by any one of a number of other sugars, and also by certain other organic substances, if the latter are added in large amounts. Certain other organic substances are not able to replace dextrose, but it has been impossible to determine any special molecular configuration on which this property depends.

3. The formation of methemoglobin by pneumococci probably resembles the formation of methemoglobin by certain chemical substances, such as aminophenol.

4. From the work of others it is probable that the formation of methemoglobin is always a reaction of oxidation. In the formation of methemoglobin by reducing agents, the latter are first oxidized, this occurring better in the presence of oxyhemoglobin. In certain instances an alternate oxidative and reduction of the transforming agent occurs, so that the reaction is continuous.

The effect which the presence or absence of free oxygen has on the reaction with pneumococci suggests that this follows similar lines.

5. The reaction does not occur in the absence of oxygen. If the free oxygen be first removed, and then replaced, the reaction occurs more rapidly than if the oxygen had not been removed. The presence of free oxygen in excess slightly delays the reaction, possibly because of the inhibition of the reduction process which forms the first part of the reaction.

6. The explanation of this phenomenon of methemoglobin production is not only of importance so far as this special reaction is concerned, but also because it suggests an explanation for the manner in which pathological effects are produced by those bacteria which apparently produce no soluble toxin.
ON THE IMMUNIZATION OF ANIMALS WITH BACTERIAL PROTEOTOXINS (ANAPHYLATOXINS)
Authors: Zinsser Hans , Dwyer J. G.
Published: June 2004

Our experiments have shown definitely that guinea pigs, once injected with sublethal doses of bacterial proteotoxins (anaphylatoxins), acquire distinct tolerance to these poisons. The degree to which such resistance or tolerance is developed is never very high, in no case in our experiments exceeding the ability to withstand one and one half to twice the fatal dose of the poisons. During the three or four days immediately following the first injection the animals appear to be slightly less resistant than are normal controls, this depending probably upon the in jury done by the administered poison. Tolerance begins to be evident after from four to seven days, seems to be most highly developed in about two weeks, but lasts in a diminishing degree for at least as long as sixty days.

Our experience, in this respect, with the poisons resulting from the contact of active serum and bacteria is similar to that of Vaughan with the toxic protein split products obtained by chemical methods.

The development of increased resistance definitely established, the questions immediately arise: (1) Is this tolerance specific? And (2) can it be passively transferred, with the serum, to a normal animal? We have begun to seek answers for these problems but as yet our data are too meager to permit definite conclusions.

The significance of the existence of higher resistance in animals treated with proteotoxins is far reaching both in connection with anaphylaxis and with immunity in general. We are not inclined to attribute to it as predominant a part in anti-anaphylaxis as is assigned to it by Bessau. For, in the first place, tolerance to the poisons is never developed to a very high degree, and, moreover, it does not become evident until three or four days after the first injection, while anti-anaphylaxis develops almost immediately after shock. However, there seems to us to be strong presumptive evidence that such tolerance to the poisons may play an important and, possibly, a non-specific part in anti-anaphylaxis, the chief underlying and specific cause of this phenomenon being the exhaustion of antibodies, or desensitization in the sense of Besredka.

The relation of such tolerance to the resistance of the animal to bacterial infection is, of course, obvious if we accept the possibility of the production of such poisons in the injected body and their participation in the production of bacterial toxemia. We hope to throw more light on these relations in another paper dealing with the aggressin-like properties of the proteotoxins.
EXPERIMENTS ON THE RÔLE OF LYMPHOID TISSUE IN THE RESISTANCE TO EXPERIMENTAL TUBERCULOSIS IN MICE
Authors: Murphy James B. , Ellis Arthur W. M.
Published: June 2004

Mice either normal or splenectomized after exposure to X-ray are markedly more susceptible to bovine tuberculosis than are normal animals. Animals splenectomized a short time prior to inoculation are also more susceptible than normal, while those splenectomized eight to ten days before inoculation have about the same resistance as normal. The mice splenectomized three to four weeks before inoculation have a resistance increased over the normal, as has already been shown by Lewis and Margot. As X-ray in the doses used apparently affects only the lymphoid tissue and as the hypertrophy of the remaining lymphoid tissue after splenectomy is so rapid that the circulating lymphocytes may be much above the normal by the third week, it is concluded that this evidence, taken with the well known association of the lymphocytes with tuberculous lesions, points strongly to the lymphocyte as an important agent in the defensive mechanism against tuberculosis.
ON THE CAUSE OF THE LOCALIZATION OF SECONDARY TUMORS AT POINTS OF INJURY
Authors: Jones F. S. , Rous Peyton
Published: June 2004

The cause of the frequent localization of secondary tumors at points of injury is not known. Our work deals with this problem. For the experiments the peritoneal cavity has been employed as offering relatively uncomplicated conditions, and the fate of mouse tumor brought into contact with a peritoneal lining injured in various ways has been studied.

The injection of a suspension of mouse tumor into a healthy peritoneal cavity has little success as a rule compared with a similar injection into the subcutaneous tissue. We have found that the resistance of the peritoneal lining thus indicated can be largely if not completely abolished by the preliminary injection of a mechanical irritant (Kieselguhr, lycopodium). That the change thus brought about is independent of general immunity phenomena is shown by the fact that a local injury renders susceptible the part of the peritoneum immediately affected and that part only. Special tests show that the factor important in rendering the peritoneum more susceptible is the injury to the subendothelial connective tissue. Susceptibility persists after the endothelium has regenerated over the reacting connective tissue.

Schmidt has found that the cells of tumor emboli in the pulmonary arterioles are able to penetrate the endothelium of the vessel only after they have been provided with a stroma from the subendothelial connective tissue. Our findings are easily explained on the basis thus suggested. A connective tissue highly cellular and perhaps still proliferating as the result of injury may well elaborate the stroma for a tumor more rapidly than normal connective tissue. Tests of growth in vitro support this idea. Connective tissue reacting to an injury grows profusely and almost immediately when incubated in plasma, whereas normal tissue from the same region shows usually no growth whatever.

Dead tumor fragments in contact with the peritoneum cause a change favorable to the lodgment and growth of later tumor fragments. It seems not improbable that the peritoneal dissemination of certain human neoplasms may be accomplished indirectly through the death of the first tumor fragments cast off.

Our observations have been purposely confined to the effects of injury on the peritoneal lining ; but they seem to afford the basis for a generalization. The secondary localization of tumors at points of injury may be attributed with good reason to the presence at such points of an active connective tissue capable of elaborating a stroma rapidly and abundantly. For it is the proliferation of the subendothelial connective tissue to form a supporting stroma that determines the fate of free tumor cells, whether these lie on the peritoneum or within a vessel.
BACTERIAL ANTIFERMENTS
Authors: Jobling James W. , Petersen William
Published: June 2004

1. Intact bacteria probably resist tryptic digestion because of the absence of an exposed protein substrate.

2. Dried organisms resist digestion in a degree proportional to their content of unsaturated lipoids.

3. Lipoidal extractives reduce the resistance to tryptic digestion.

4. The extracted lipoids (saponified) are antitryptic in a degree proportional to their unsaturation.

5. The inactivation of the antiferment in Gram-negative organisms is probably due to changes in the degree of lipoidal dispersion.

6. Bacteria adsorb lipoids from the serum when incubated at 37° C. Such organisms when dried are found to be more resistant to tryptic digestion than untreated organisms.
IMMUNIZATION AGAINST THE ACTION OF SUBSTANCES INHIBITING TUMOR GROWTH
Authors: Fleisher Moyer S. , Vera Miguel , Loeb Leo
Published: June 2004

1. Through a set of preliminary injections of colloidal copper or hirudin, given from the second to the sixth day after transplantation, we can weaken the effect of injections of the same substances given from the ninth to the thirteenth day after transplantation.

2. Injections of colloidal copper given before the transplantation of the tumor lead to a weakening of the effect of injections given from the ninth to the thirteenth day after transplantation.

3. The same result can be obtained if we inject colloidal copper or hirudin into mice from the second to the sixth and from the ninth to the thirteenth day after transplantation, and use these tumors at the end of the series of injections for further transplantation into another set of mice; the developing tumors are more resistant to the action of colloidal copper or hirudin than new control tumors.

4. We may therefore conclude that the immunity has two sources: (a) it is based on changes taking place somewhere in the host organism; and (b) it is localized in the tumor cells themselves which transfer this immunity to the following generations of tumor cells.

5. The immunity acquired against colloidal copper does not protect noticeably against the action of hirudin, and vice versa. The immunity is therefore specific.

6. We discuss certain general conclusions which may be drawn from these experiments. We expect to test the validity of these results in further experiments.
THE EFFECT OF GENTIAN VIOLET ON PROTOZOA AND ON TISSUES GROWING IN VITRO, WITH ESPECIAL REFERENCE TO THE NUCLEUS
Authors: Russell D. G.
Published: June 2004

1. Gentian violet may be regarded as a true vital nuclear stain.

2. Embryonic and adult tissue of the frog will grow in vitro in the presence of gentian violet of a far stronger dilution than that necessary to kill many bacteria. In these experiments, for example, successful tissue growths were obtained when gentian violet 1 to 20,000 was used, yet Bacillus subtilis will not grow in 1 to 100,000 dilution and grows very badly in 1 to 1,000,000 dilution. This fact may simplify the technique of the growth of certain tissues by eliminating the risk of bacterial contamination.

3. The use of stains in the plasma in which tissue is grown will probably facilitate the study of nuclear growth.

4. Gentian violet appears to have a certain selective action on tissue similar to that exercised by the dye on bacteria. Certain observations made last year in this laboratory (too few to serve as more than a suggestion) seem to indicate that another dye (methylene blue) acted as a stimulant to the growth of connective tissue. These leads should be followed out and the effect of various stains studied in the hope of discovering dyes which will exercise a sharp selective action on growing tissue.

5. The growth of animal cells in a strength of dye much more than sufficient to kill many pathogenic organisms lends encouragement to efforts now being made in this laboratory to apply the observations on the bactericidal effect of gentian violet and allied stains to the treatment of disease. Moreover, the ability of growing cells to rid themselves of this dye would indicate that it may be possible to apply the dye to infected tissue and count on the cells to eliminate the material after its work had been done.
THE EFFECT OF VARIOUS TISSUE EXTRACTS UPON THE GROWTH OF ADULT MAMMALIAN CELLS IN VITRO
Authors: Walton Albert J.
Published: June 2004

The cultivation of cells in vitro affords a valuable means of estimating the effects of tissue extracts.

Tissue extracts have a definite effect upon the growth of adult mammalian cells in vitro.

The majority of tissue extracts stimulate the growth of connective tissue, but liver extract inhibits it.

The extracts are to a certain extent specific in their action upon the growth of parenchymatous cells. Some cells are stimulated by one extract and inhibited by another, and those extracts which inhibit one type of parenchymatous cell may stimulate another type.

Homogenous and autogenous extracts are equally efficacious in their action upon the growth of cells.

The extracts may be preserved for a short period of time without suffering any change in their power of affecting the growth of cells.
AGGLUTINATION PHENOMENA IN LOBAR PNEUMONIA
Authors: Chickering Henry T.
Published: June 2004

1. Agglutinins are present in the blood of patients suffering from lobar pneumonia during some stage of the disease in a large percentage (73.8 per cent.) of the cases due to pneumococci belonging in groups I, II, and IV.

2. In most very severe and fatal cases agglutinins cannot be demonstrated, and it is probable that their absence during the later days of the disease may have unfavorable prognostic significance.

3. No agglutinins are demonstrable by the technique employed in the blood of patients suffering from infection with Pneumococcus mucosus (group III).

4. In certain cases agglutinins may be demonstrable for only one day, and in other cases they may persist for several weeks.

5. When agglutinins are demonstrable they usually appear at about the time of the crisis.

6. It has not been possible to demonstrate that treatment with immune serum has any effect on the appearance of agglutinins.

7. The agglutinins present in cases due to organisms of types I and II are always specific for the type of organism causing the infection. In certain cases the agglutination reaction may be more active or appear earlier when the homologous organism is employed than when other organisms of the group are used in the test. In cases due to organisms of type IV, the serum never causes agglutination of any organism except the homologous one.
CULTIVATION OF THE SKIN EPITHELIUM OF THE ADULT FROG, RANA PIPIENS
Authors: Uhlenhuth Eduard
Published: June 2004

1. Fragments of skin taken from the back of the leopard frog were cultivated in a mixture of plasma and muscle extract of the same species.

2. A few hours after explanation, processes of activity are seen to arise, which finally lead to the formation of a compact epithelial rim around the fragment of skin.

3. These epithelial cells undergo gradual transformation into a spindle-shaped type of cell; in this form they resemble the spindle cells which have been described as connective tissue cells.

4. The growth of a rim of tissue around the explanted fragments of skin may be ascribed principally to the activity of a basal layer of epithelial cells, the units of which first advance into the medium as compact membranes by means of the so called epithelial movement, but which later become separated from the compact membrane, and having assume a spindle form, spread according to the manner of connective tissue cells.

5. In contradistinction to this basal layer, the cells of an upper and middle layer of epithelium upon separation from the fragment of skin and isolation in the nutritive medium, remain completely inactive.

6. The connective tissue of frog skin, for reasons not yet completely established, does not participate in the production of the rim of cells, possibly for the reason that it was early surrounded by the epithelium and was thus prevented from sending out cells into the medium.

7. The transformation of the epithelial cells into a type of cells of the spindle form is a result of the changes in the physicochemical conditions brought about by the life in vitro, which become similar to the physicochemical conditions normally characteristic of connective tissue.

8. The final stage of the explanted fragments of skin is a hollow epithelial sphere (cystic stage) filled with connective tissue.

9. During the cystic stage the epithelium again shows its normal polar differentiation, as a consequence of the physicochemical conditions which now approach normal.

10. These conditions also permit of the shedding of cells in a vertical direction, although previously the production of cells in a horizontal direction had already become impossible.
THE PATHOLOGICAL EFFECTS OF ATMOSPHERES RICH IN OXYGEN
Authors: Karsner Howard T.
Published: June 2004

In spite of numerous abnormalities or non-experimental lesions in the rabbit certain facts can be considered as established. It has been known for many years that pneumonia is produced by the more or less prolonged inhalation of high partial pressures of oxygen. The studies herein reported show that atmospheres containing 80 to 96 per cent oxygen under normal barometric pressure produce in 24 hours, or more commonly 48 hours, congestion, edema, epithelial degeneration and desquamation, fibrin formation, and finally a pneumonia, probably of irritative origin and to be described as a fibrinous bronchopneumonia. The important new points are the time relations of these changes and definition of the type of the pneumonia.

Other studies have noted slight passive congestion, but it is now established that this is to be accounted for in most cases by dilatation of the right side or of both sides of the heart. This congestion affects all the abdominal viscera and is accompanied by certain secondary changes such as cloudy swelling of the parenchymatous organs and phagocytosis of erythrocytes by endothelial cells of the mesenteric lymph nodes.

Although deficiency of oxygen may affect the hematopoietic system, the animals subjected to high oxygen percentages failed to show any demonstrable pathologic changes in blood, spleen, lymph nodes, or bone marrow, except for the presence of congestion.

This study is the first of a comprehensive series projected in and under the direction of the Carnegie Nutrition Laboratory. Different animals and various methods of attack will be employed in the investigation.
A STUDY OF THE GASTRIC ULCERS FOLLOWING REMOVAL OF THE ADRENALS
Authors: Mann Frank C.
Published: June 2004

Acute ulcers of the gastric mucosa are found in a large percentage of dogs and cats dying after adrenalectomy. These ulcers seem to develop during the moribund period. They are apparently peptic ulcers forming at the site of local hemorrhages in the gastric mucosa. They are true acute ulcers, usually penetrating to the muscularis mucosa with a total loss of epithelium. They develop in the absence of pancreatic secretion and bile. However, they appear to develop only in an acid medium.
A TRANSPLANTABLE CARCINOMA OF THE GUINEA PIG
Authors: Jones F. S.
Published: June 2004

An adenocarcinoma of the mammary gland of an old guinea pig has been successfully transplanted through eight successive series of animals. It now appears much earlier and grows more rapidly. The number of takes also has increased. In two instances metastasis to the regional lymph glands (inguinal) has been observed. Once microscopic metastases were found in the kidney. The so called precancerous changes observed in the breasts of women and mice suffering from mammary carcinoma were found in the mammary gland of the spontaneous tumor animal. It is hoped that the tumor may soon be utilized for experimental purposes.
THE PRESERVATION OF LIVING RED BLOOD CELLS IN VITRO
Authors: Rous Peyton , Turner J. R.
Published: June 2004

In order to determine the availability for functional uses of red cells kept in vitro by our methods, transfusion experiments have been carried out with rabbits by which a large part of their blood was replaced with kept rabbit cells suspended in Locke's solution. It has been found that erythrocytes preserved in mixtures of blood, sodium citrate, saccharose, and water for 14 days, and used to replace normal blood, will remain in circulation and function so well that the animal shows no disturbance, and the blood count, hemoglobin, and percentage of reticulated red cells remain unvaried. Cells kept for longer periods, though intact and apparently unchanged when transfused, soon leave the circulation. Animals in which this disappearance of cells is taking place on a large scale, remain healthy save for the progressing anemia. The experiments prove that, in the exsanguinated rabbit at least, transfusions of cells kept for a long time in vitro may be used to replace the blood lost, and that when the cells have been kept too long but are still intact they are disposed of without harm. The indications are that kept human cells could be profitably employed in the same way.
A CONTRIBUTION TO THE BIOLOGY OF PERIPHERAL NERVES IN TRANSPLANTATION
Authors: Ingebrigtsen Ragnvald
Published: June 2004

1. The Wallerian degeneration occurring in peripheral nerves by incubation in Ringer solution and serum does not occur in plasma.

2. Peripheral nerves incubated in plasma give rise to no growth. The same is true of peripheral nerves in a Wallerian degeneration up to the 4th day.

3. Peripheral nerves in Wallerian degeneration from the 5th day give rise to a growth of the syncytium of Schwann. In cultures from later stages there is a progressive growth of the same structure. It is evident that the proliferation of the cells of Schwann is directly produced by the degeneration of the axis cylinder and its myelin sheath.

4. In no case was growth of axis cylinders observed.

5. The growth of the syncytium of Schwann from degenerating nerves affords a basis for an anatomical conception of the centrifugal orientation of growing axis cylinders in regeneration.

6. Morphologically there is a striking resemblance between the syncytium of Schwann and neuroglia growing in plasma.
THE BACTERICIDAL PROPERTIES OF THE QUATERNARY SALTS OF HEXAMETHYLENETETRAMINE
Authors: Jacobs Walter A. , Heidelberger Michael , Amoss Harold L.
Published: June 2004

By the addition of substituted benzyl halides to hexamethylenetetramine, a series of quaternary salts of this base was obtained. These salts represent a new group of organic bactericides. The results obtained in the tests with these substances upon Bacillus typhosus have demonstrated the existence of direct relationships between chemical constitution and bactericidal action within the series.

The bactericidal character is directly attributable to the presence of the hexamethylenetetramine nucleus. The degree of the bactericidal action, however, is determined by the position, character, and number of the groups substituted in the benzene nucleus.

By the introduction of the methyl, chlorine, bromine, iodine, cyano, and nitro groups into the benzene nucleus of the parent benzyl hexamethylenetetraminium salt, the bactericidal power of this compound was notably enhanced. The substitution of these groups in the ortho position almost invariably resulted in substances which were more active than their meta or para isomers. The introduction of the methoxy group was without marked effect.

Several substances in which two hexamethylenetetraminium side-chains occurred were found to be the most active of the substances of this series when tested against Bacillus typhosus. Comparative tests with other bacterial types demonstrated that these compounds possessed a marked degree of specificity for Bacillus typhosus.
THE EFFECT OF DIGITALIS ON THE NORMAL HUMAN ELECTROCARDIOGRAM, WITH ESPECIAL REFERENCE TO A-V CONDUCTION
Authors: White Paul Dudley , Sattler Robert Ray
Published: June 2004

Digitalis was given by mouth to five normal young male adults in amounts ranging from 2.0 to 3.0 gm. of standardized leaves in the course of 7 to 10 days. The As-Vs interval was prolonged in four of the five subjects, the greatest prolongation occurring in the case of the subject who received the most digitalis and none at all in one who received only 2.0 gm. There was no prolongation to so great an interval as 0.2 second until 2.7 gm. had been taken. The effects of the digitalis on conduction time began 5 to 6 days after the drug had been started and after 1.5 to 1.8 gm. had been taken. The effects persisted for 1 to 2 weeks after the drug had been stopped. Atropine removed completely the effect of digitalis on A-V conduction. The slowing heart rate after exercise was accompanied by an enhancement of the defect in conduction. The change in conduction through digitalis was therefore almost entirely, if not entirely, due to increase of vagal tone and irritability.

Digitalis did not affect to an appreciable extent the Q-end of S and the Q-end of T intervals. Exercise and atropine both shortened the ventricular complex Q-end of T while the subject was under digitalis.

The amplitude of the T wave, especially in Lead II, was changed within 48 hours after digitalis had been started, a decrease then beginning which became greater as the drug was continued and which persisted until 10 to 19 days after the digitalis had been stopped. The change in the T deflection preceded by several days the change in conduction time. The T wave, therefore, in the normal subject as well as in the patient gives us the earliest indication of digitalis action.

The amplitudes of P, Q, R, and S were not materially influenced by the amounts of digitalis given.

The pulse rate in two subjects became lower than usual at night as the result of the digitalis; otherwise there was no evidence of vagal action on the sino-auricular node. Blood pressure was uninfluenced by the digitalis. Mild subjective sensations occurred in all the subjects during the administration of the drug.

A curious, hitherto undescribed, digitalis arrhythmia consisting of blocked auricular premature beats occurred in one subject after 3.0 gm. of digitalis had been taken.
THE INFLUENCE OF TETHELIN, AND OF OTHER ALCOHOL-SOLUBLE EXTRACTIVES FROM THE ANTERIOR LOBE OF THE PITUITARY BODY, UPON THE GROWTH OF CARCINOMATA IN RATS
Authors: Robertson T. Brailsford , Burnett Theodore C.
Published: June 2004

1. The hypodermic administration of tethelin increases markedly the rate of growth of the primary tumor and the tendency to form metastases in rats inoculated with carcinoma, in this, as in other respects, reproducing the action of the whole anterior lobe of the pituitary body.

2. Other alcohol-soluble extractives of the anterior lobe of the pituitary body, with the exception of the lecithin fraction, exert no appreciable effect upon the growth of carcinomata in rats.

3. The lecithin fraction, as in previously reported experiments in which we employed lecithin obtained from eggs, causes evident retardation of the growth of carcinomata in rats.
THE INTRAVENOUS INJECTION OF MAGNESIUM SULPHATE FOR ANESTHESIA IN ANIMALS
Authors: Auer J. , Meltzer S. J.
Published: June 2004

These experiments justify the following general conclusions.

By the intravenous injection of M/4 magnesium sulphate into dogs at a certain rate, a stage can be reached where the abdominal walls are completely relaxed and when section of the abdomen and stimulation of sensitive parts of the parietal peritoneum do not produce pain or elicit any reaction of the animal. At the same time spontaneous respiration may still be maintained within normal limits and the lid reflex be fair or even normal. In this stage intratracheal intubation for artificial respiration can be easily accomplished. This stage may be attained in 12 to 14 minutes when the rate of injection is about 3 cc. per minute. When this stage is once attained the rate of injection should gradually be reduced, otherwise, sooner or later, spontaneous respiration will be abolished, and by a further maintenance of the rate of injection all the skeletal muscles may become paralyzed.

When the injection of magnesium is continued for a longer period, the paralytic effects of the magnesium injection will set in, even when administered at a slow rate.

The paralysis of the respiratory function is readily met by intrapharyngeal insufflation, which is easily executed even without training in this procedure, or by the method of intratracheal insufflation, if executed by one trained in its management.

When the respiration of the animal is accomplished by insufflation, the paralytic effect of the magnesium may be abolished fairly rapidly by an intravenous injection of about 10 cc. of an M/8 calcium chloride solution; or it may disappear slowly, after the infusion of the magnesium solution is discontinued for some time. The latter mode of disappearance may be favorably accelerated by an intravenous infusion of 60 to 100 cc. of an M/4 solution of sodium sulphate.

The production of anesthesia by intravenous injection of magnesium sulphate should not be undertaken unless an apparatus for intrapharyngeal insufflation is at hand, because in exceptional cases the disappearance of spontaneous respiration may be one of the earliest consequences of the magnesium injection.

The injection of calcium chloride should not be employed in cases in which the subject shows cardiac insufficiency. In such instances, moreover, injections of magnesium should not be used for the purpose of anesthesia; at least not until greater experience has been acquired in the employment of this method.
AN EXPERIMENTAL STUDY OF THE ADDITIVE AND ANTAGONISTIC ACTIONS OF SODIUM OXALATE, AND SALTS OF MAGNESIUM AND CALCIUM IN THE RABBIT
Authors: Gates F. L. , Meltzer S. J.
Published: June 2004

The foregoing experiments establish firmly the following facts.

Subcutaneous or intramuscular injections of sodium oxalate in subtoxic doses, when administered to an animal which received a subminimal dose of magnesium sulphate, produce profound anesthesia and paralysis of long duration, although the usual effects of sodium oxalate alone are of a stimulating character. This fact is, in general, in harmony with the results reported by Starkenstein who, however, seems to have used the combination of the two salts in one solution; namely, that of magnesium oxalate.

The combined injections of subminimal doses of sodium oxalate and magnesium sulphate produce a strong reduction, or even, at times, a complete abolition of the conductivity of the motor nerve endings.

An intravenous injection of calcium salts brings on a recovery from the profound and prolonged effects of the combined action of sodium oxalate and magnesium sulphate, which is as prompt as is observed in experiments in which effective doses of magnesium alone were given. This fact is the more noteworthy, since depressions of long duration produced by prolonged continuous injections of magnesium solutions alone do not respond very promptly and effectively to calcium injections.

As will be recalled, the starting point for our investigation was the hypothesis that substances which are capable of precipitating calcium—a biological antagonist of magnesium—ought to be capable of increasing the depressive effect of magnesium. Our experiments proved that this assumption was correct. This would seem, therefore, to justify the interpretation that the augmenting action of sodium oxalate has its cause in the ability of the latter to precipitate calcium and thus increase within the body the amount of unantagonized magnesium. However, we wish to state expressly that this view is, for the present, still no more than a hypothesis and does not exclude other possible interpretations of our facts. As we pointed out it speaks against this hypothesis that oxalates do not produce phenomena of depression; the toxic symptoms produced by oxalates exhibit distinctly signs of increased and not of decreased irritability.
THE DISTRIBUTION OF TRYPAN-RED TO THE TISSUES AND VESSELS OF THE EYE AS INFLUENCED BY CONGESTION AND EARLY INFLAMMATION
Authors: Lewis Paul A.
Published: June 2004

In as far as the observations reported have a bearing on the movements of fluid within the eye, they are, for the most part, in accord with views at present generally accepted. On the other hand, we know of no other way in which it may be so readily demonstrated that simple and even temporary local circulatory changes may profoundly alter the distribution of substances from the circulating blood to the extravascular fluids and tissues. In the light of these observations, it would seem that such changes might easily account for marked idiosyncrasies in the action of poisonous drugs, and as well probably for other factors in drug action.
CHEMICAL VERSUS SERUM TREATMENT OF EPIDEMIC MENINGITIS
Authors: Flexner Simon , Amoss Harold L.
Published: June 2004

Claims of efficiency have been made at two widely separated periods for the chemical treatment of epidemic meningitis, in the first instance for lysol and in the second for protargol. The use of lysol was long since abandoned; the recommendation for protargol is based on a single series of cases, small in number. Because of the variable severity of epidemics of meningitis, small reliance can be placed on results of treatment limited in extent to small numbers of cases and to one locality. A more uniform and accurate measure of the value of a method of treatment is provided by animals infected experimentally with pathogenic cultures of meningococci.

Young guinea pigs respond in a definite manner to intraperitoneal inoculation of virulent meningococci. Neither protargol nor lysol proved to have any curative action on the experimental infection thus produced in these animals.

Monkeys respond in a characteristic manner to the inoculation of virulent cultures into the subarachnoid space. Protargol displayed no curative action on the experimental infection thus produced in these animals.

On the contrary, both lysol and protargol exert antileukotactic and antiphagocytic effects, and are also potent protoplasmic poisons, and the leukocytes with which they come in contact are injured and made to degenerate. According to the extent to which these harmful properties are exerted, the chemicals promote the advance rather than restrain the progress of meningococcic infection.

Recovery from meningococcic infection in man and animals is accomplished chiefly through the process of phagocytosis. The specific antiserum acts curatively by increasing the emigration of leukocytes, by promoting phagocytosis directly, and by agglutinating the meningococci, and also by neutralizing endotoxin. Any means which interfere with and reduce these essential processes retard or prevent recovery. Both lysol and protargol interfere with and diminish the emigration of leukocytes and the phagocytosis of meningococci, and neither possesses antitoxic power.

The mixture of antiserum with lysol and with protargol reduces to a certain extent the antileukotactic and antiphagocytic effect of the chemicals; but this action is insufficient to set aside wholly the injurious effects which they produce.

It follows, therefore, that whatever theoretical advantages might accrue from a bactericidal activity exerted by these chemicals independently of the type of meningococcus causing epidemic meningitis, is more than offset by the harmful effects which they cause.

Hence specific antiserum seems to provide the logical therapeutic agent with which to combat epidemic meningitis, since it is itself innocuous and promotes those processes essential to recovery from the disease. The problem up to the present has been that of producing an antiserum which represents the several types of the meningococcus, and this problem is now in a fair way to being solved.
Promotion of Neurite and Filopodium Formation by CD47: Roles of Integrins, Rac, and Cdc42
Authors: Miyashita Motoaki , Ohnishi Hiroshi , Okazawa Hideki , Tomonaga Hiroyasu , Hayashi Akiko , Fujimoto Tetsuro-Takahiro , Furuya Nobuhiko , Matozaki Takashi
Published: June 2004

Axon extension during development is guided by many factors, but the signaling mechanisms responsible for its regulation remain largely unknown. We have now investigated the role of the transmembrane protein CD47 in this process in N1E-115 neuroblastoma cells. Forced expression of CD47 induced the formation of neurites and filopodia. Furthermore, an Fc fusion protein containing the extracellular region of the CD47 ligand SHPS-1 induced filopodium formation, and this effect was enhanced by CD47 overexpression. SHPS-1–Fc also promoted neurite and filopodium formation triggered by serum deprivation. Inhibition of Rac or Cdc42 preferentially blocked CD47-induced formation of neurites and filopodia, respectively. Overexpression of CD47 resulted in the activation of both Rac and Cdc42. The extracellular region of CD47 was sufficient for the induction of neurite formation by forced expression, but the entire structure of CD47 was required for enhancement of filopodium formation by SHPS-1–Fc. Neurite formation induced by CD47 was also inhibited by a mAb to the integrin β3 subunit. These results indicate that the interaction of SHPS-1 with CD47 promotes neurite and filopodium formation through the activation of Rac and Cdc42, and that integrins containing the β3 subunit participate in the effect of CD47 on neurite formation.
Cystic Fibrosis Transmembrane Conductance Regulator Degradation Depends on the Lectins Htm1p/EDEM and the Cdc48 Protein Complex in Yeast
Authors: Gnann Andreas , Riordan John R. , Wolf Dieter H.
Published: June 2004

Cystic fibrosis is the most widespread hereditary disease among the white population caused by different mutations of the apical membrane ATP-binding cassette transporter cystic fibrosis transmembrane conductance regulator (CFTR). Its most common mutation, ΔF508, leads to nearly complete degradation via endoplasmic reticulum-associated degradation (ERAD). Elucidation of the quality control and degradation mechanisms might give rise to new therapeutic approaches to cure this disease. In the yeast Saccharomyces cerevisiae, a variety of components of the protein quality control and degradation system have been identified. Nearly all of these components share homology with mammalian counterparts. We therefore used yeast mutants defective in the ERAD system to identify new components that are involved in human CFTR quality control and degradation. We show the role of the lectin Htm1p in the degradation process of CFTR. Complementation of the HTM1 deficiency in yeast cells by the mammalian orthologue EDEM underlines the necessity of this lectin for CFTR degradation and highlights the similarity of quality control and ERAD in yeast and mammals. Furthermore, degradation of CFTR requires the ubiquitin protein ligases Der3p/Hrd1p and Doa10p as well as the cytosolic trimeric Cdc48p-Ufd1p-Npl4p complex. These proteins also were found to be necessary for ERAD of a mutated yeast “relative” of CFTR, Pdr5*p.
The Basolateral Targeting Signal of CD147 (EMMPRIN) Consists of a Single Leucine and Is Not Recognized by Retinal Pigment Epithelium
Authors: Deora Ami A. , Gravotta Diego , Kreitzer Geri , Hu Jane , Bok Dean , Rodriguez-Boulan Enrique
Published: June 2004

CD147, a type I integral membrane protein of the immunoglobulin superfamily, exhibits reversed polarity in retinal pigment epithelium (RPE). CD147 is apical in RPE in contrast to its basolateral localization in extraocular epithelia. This elicited our interest in understanding the basolateral sorting signals of CD147 in prototypic Madin-Darby canine kidney (MDCK) cells. The cytoplasmic domain of CD147 has basolateral sorting information but is devoid of well-characterized basolateral signals, such as tyrosine and di-leucine motifs. Hence, we carried out systematic site-directed mutagenesis to delineate basolateral targeting information in CD147. Our detailed analysis identified a single leucine (252) as the basolateral targeting motif in the cytoplasmic tail of CD147. Four amino acids (243-246) N-terminal to leucine 252 are also critical basolateral determinants of CD147, because deletion of these amino acids leads to mistargeting of CD147 to the apical membranes. We ruled out the involvement of adaptor complex 1B (AP1B) in the basolateral trafficking of CD147, because LLC-PK1 cells lacking AP1B, target CD147 basolaterally. At variance with MDCK cells, the human RPE cell line ARPE-19 does not distinguish between CD147 (WT) and CD147 with leucine 252 mutated to alanine and targets both proteins apically. Thus, our study identifies an atypical basolateral motif of CD147, which comprises a single leucine and is not recognized by RPE cells. This unusual basolateral sorting signal will be useful in unraveling the specialized sorting machinery of RPE cells.