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Pulmonary granuloma size, anergy, serum and lung angiotensin converting enzyme (ACE) levels, and responsiveness to captopril therapy were measured in both pulmonary hypersensitivity granuloma (HSG) and foreign body granuloma (FBG) murine models. The kinetic development of the granuloma was similar in both models, peaking at 3 days and resolving by 14 days. The granuloma size of the FBG model was significantly larger than the HSG model at 1 and 3 days. The FBG model further differed from the HSG model in that anergy was observed at 3 days and lung ACE levels were increased at 1, 7, and 14 days. In the HSG model anergy was not observed and lung ACE levels were significantly elevated only at 1 and 7 days. Furthermore, the HSG model was shown to be responsive to captopril therapy whereas the FBG model was not. This study shows that two murine pulmonary granuloma models, although displaying similar growth and resolution kinetics, differ in terms of granuloma size, anergy, lung ACE activity, and responsiveness to captopril therapy, suggesting that the mechanism(s) involved in the inflammatory response of the two models may be different.

We have shown previously that cytoplasmic extracts from actively dividing lymphoid cells are capable of inducing DNA synthesis in isolated nuclei. One of the factors involved in this activity, ADR, appears to be a greater than 90 kDa heat-labile protease. Cytoplasmic extracts prepared from nonproliferating lymphocytes express little to no ADR activity. However, ADR activity can be generated in these extracts by brief exposure to a membrane-enriched fraction of spontaneously proliferating, leukemic human T lymphoblastoid (MOLT-4) cells. This suggests that ADR activity is present in the resting cytoplasm in an inactive or precursor form. This in vitro generation of ADR activity can be inhibited in a dose-dependent manner by the isoquinolinesulfonamide derivative, H-7 (1-(5-isoquinoline-sulfonyl)-2-methylpiperazine dihydrochloride), an inhibitor of both cyclic adenosine monophosphate (cAMP)-dependent protein kinases and protein kinase C (PKC). However, more specific inhibitors of cAMP-dependent protein kinases, including N-[( 2-methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H8) and N-(2-gua-nidinoethyl)-5-isoquinolinesulfonamide (HA-1004), had little to no effect on the in vitro generation of ADR activity. Furthermore, membranes from MOLT-4 cells depleted of PKC by long-term exposure (24 h) to phorbol esters and calcium ionophores were unable to induce ADR activity in resting peripheral blood lymphocytes extracts. The results of these studies suggest 1) ADR activity is present in resting cell cytoplasm in an inactive or precursor form; and 2) ADR activity can be induced in this resting cytoplasm through a mechanism involving a membrane-associated protein kinase, possibly PKC. The ability of alkaline phosphatase to deplete the activity of preformed ADR suggests the possibility that ADR itself is phosphoprotein.

The systemic injection of high doses of antigen into a previously immunized animal results in a state of transient anergy with respect to cell-mediated immune responses. This phenomenon is known as desensitization. The results presented here demonstrated that serum interleukin 2 (IL-2) activity was found transiently in desensitized mice at early stage (3 hr after the challenge). Subsequently, these mice could not develop in vivo (footpad swelling) and in vitro (lymphocyte proliferation) manifestations of cell-mediated immune responses 1 day after the challenge. Antigen-nonspecific and specific suppression of IL-2 production was observed in desensitized mice. The serum from 3 hr-desensitized mice containing endogenous IL-2 activity showed a marked suppressive effect on IL-2 production. Exposure of lymph node cells to IL-2 was capable of inhibiting IL-2 production in vitro. Additionally, in vivo administration of exogenous IL-2 into preimmunized mice led to the failure of development of footpad responses to antigen. These results suggest that IL-2-dependent regulatory mechanisms of T cell-mediated immune responses play an important role in the immunosuppression of desensitized mice.

Those who dislike speculation about past and future can usually see an end to the situation which has induced such relative breaks in the normal scheduling of life; they can consider plans for when they get out of hospital, or prison, or home on holiday. There are still bills to be paid, visits to relations to be arranged, home coming parties to be organised during those times when one is absent from the normal run of life. The ordinary temporal scheduling of one’s affairs is kept in the background of one’s mind by the continued operation of such financial, domestic and social matters. When twenty years of one’s time is taken away, even these routine matters disappear. The landscape of time, the past and the future, and the actual significance of the present moment insistently occupy the mind. The prisoners in E-Wing found Victor Serge’s description of this obsessive state the most accurate.

rheumatic drugs had failed. The ACR response and success rates for patients receiving leflunomide treatment (52% and 41%, respectively) and methotrexate treatment (46% and 35%, respectively) were significantly higher than those for patients receiving placebo (26% and 19%, respectively) (P,.001), and they were statistically equivalent, with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy. X-ray analyses demonstrated less disease progression with leflunomide (P#.001) and methotrexate (P = .02) therapy than with placebo. Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo (P,.001 and P,.05, respectively). Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints, skin rash, and reversible alopecia. Asymptomatic transaminase elevations resulted in treatment discontinuations for 7.1% of patients receiving leflunomide therapy, 1.7% of patients receiving placebo, and 3.3% of patients receiving methotrexate therapy. Conclusions: Clinical responses following administration of leflunomide, a new therapeutic agent for the treatment of RA, were statistically superior to those with placebo and equivalent to those with methotrexate treatment. Both active treatments improved signs and symptoms of active RA, delayed disease progression as demonstrated by x-ray films, and improved function and health-related quality of life. Arch Intern Med. 1999;159:2542-2550

Thomas G. Blomberg & Stanley Cohen, eds. Punishment and Social Control: Essays in Honor of Sheldon L. Messinger. Foreword by Philip Selznick. Hawthorne, NY: Aldine de Gruyter, 1995. x + 318 pp. $46.95. Chris Clarkson & Rod Morgan, eds. The Politics of Sentencing Reform. New York: Oxford University Press, Clarendon Press, 1995. vi + 287 pp. $59.00. Todd R. Clear. Harm in American Penology: Offenders, Victims, and Their Communities. Albany: State University of New York Press, 1994. xvi + 242 pp. $74.50 cloth; $24.95 paper. Michael Tonry. Malign Neglect: Race, Crime and Punishment in America. New York: Oxford University Press, 1995. Pp. xii+233. $25.00 cloth; $11.95 paper. Michael Tonry. Sentencing Matters. New York: Oxford University Press, 1996. Pp. vii + 222. $29.95 cloth. The primary principle underlying the physician's oath is nonmaleficence: "first, do no harm." These five books present the best contemporary thinking about trends in criminal sentencing and philosophies of punishment; taken together, they of fer the physicians' wise counsel to modern politicians, judges, and citizens across the globe. The caution is especially germane because debates about sentencing reform-indeed, debates about crime and justice generally-occur in the wider context of postindustrial social change. To comprehend both the manifest and the latent functions of punishment and how the courts can or cannot impose just sanctions on people convicted of crime, we must take account of the world from which the offenders and the courts themselves come. These five books all provide rich consideration of issues related to inequality and the political choices we make about punishment. All five volumes present thoughtful overviews of how penal philosophies have changed over the past 25 years, offered either as theoretical reflections or as legislative histories and impact evaluations. All five present sober analysis of sentencing reforms that have not only failed to reduce disparities among various racial and economic classes but also have exacerbated the tension between equal treatment in the courts and the drive to process tremendous numbers of offenders from the urban underclass. The link between inequality and current sentencing policies is a primary subject in Clear's Harm in American Penology and Tonry's Malign Neglect. Clear chronicles the tremendous boom in size and power of "the penal harm machine" over the past two decades, and he asks and answers the question: Why did this happen? By contrast, Tonry's starting point is the jurisprudence of sentencing, not corrections, although he arrives at the same question and answer that Clear does. Both implicate crime-control ideologues in inflaming the extraordinary punitiveness of the American public, and doing so while including an unspoken but very real degree of racism in their ideology. While Clear and Tonry believe that these arguments and agendas have produced a contemporary obsession with harsh punishment, other scholars whose work is reviewed here contend that "popular punitiveness"1 is a preexisting cultural characteristic springing from a variety of sources. Social inequality is not the explicit focus of the other works reviewed here, all of which seek to explain sentencing and how it has changed, although race and inequality are constant subterranean themes. Tonry's Sentencing Matters, for instance, is an encyclopedic compendium of sentencing theory and reform in the United States, beautifully written and organized around a set of eight prescriptions for change that Tonry says are the logical outcomes of studying the reforms. In Sentencing Matters, Tonry's scholarly "good cop" book, and Malign Neglect, his angry "bad cop" political book, the aim is to get American politicians to confess to malpractice in setting up the sentencing reforms of the past two decades and to do penance by repealing the worst of these laws. …

L'A. etudie les relations entre crime et politique. Il s'interesse plus particulierement a la criminologie et porte son attention sur l'ouvrage de D. Matza : « Becoming deviant » publie dans les annees 1960 qui souligne le decalage entre criminologie et politique en matiere criminelle. Il presente, d'autre part, la nouvelle de John Le Carre « The Night manager » ou celui-ci s'efforce de montrer que le trafic de drogue et d'armes constitue la nouvelle menace. Il estime que ces deux ouvrages constituent deux vues complementaires quant aux rapports entre politique et criminalite. Il etudie le lien qui unit systeme politique et systeme de controle social, la nature de la criminalite, les phenomenes de corruption, le crime organise international, la criminalite politique. Il s'efforce de comprendre ce qu'il faut entendre par nouvelle victimisation

The policy of lustration is set in the context of responses to abuses of power by previous regimes. Using examples from three recent forms of social reconstruction (in Latin America, the former communist states, and South Africa), the author reviews the “justice in transition” debate. How do societies going through democratization confront the human rights violations committed by the previous regime? Five aspects of this debate are reviewed: (1) truth: establishing and confronting the knowledge of what happened in the past; (2) justice: making offenders accountable for their past violations through three possible methods: punishment through the criminal law, compensation and restitution, and mass disqualification such as lustration; (3) impunity: giving amnesty to previous offenders; (4) expiation; and (5) reconciliation and reconstruction. A concluding discussion raises the implications of the subject for the study of time and social control.

Background: This study was developed to compare the incidence of endoscopically diagnosed ulcers in elderly patients taking nabumetone, ibuprofen, or concomitant ibuprofen/misoprostol. Further research is indicated to better establish the clinical relevance of these endoscopy findings. Methods: We conducted a prospective, multicenter, randomized, endoscopist-blinded, 12-week study involving 171 patients with osteoarthritis aged 60 years and older. Patients were randomized to receive nabumetone, 1000 mg (n=58); ibuprofen, 600 mg four times daily (n=53); or ibuprofen, 600 mg four times daily, administered concomitantly with misoprostol, 200 μg four times daily (n=60). Endoscopy was performed at baseline and at weeks 2, 6, and 12. Endoscopy results were scored on a scale of 1 to 9. Significant ulcers were defined as breaks in the mucosa greater than 5 mm with appreciable depth. Results: Of the 171 randomized patients, 148 completed the study. There was no significant difference in the incidence of significant ulcers between the nabumetone group and the ibuprofen/misoprostol group (one vs zero). There were significantly fewer significant ulcers in the nabumetone and ibuprofen/misoprostol groups than in the ibuprofen monotherapy group (one and zero vs eight; P P Conclusions: Nabumetone is equivalent in ulcerogenicity to concomitant ibuprofen/misoprostol and is significantly less ulcerogenic than ibuprofen alone. (Arch Intern Med. 1993;153:2565-2571)

New data are reported on the multiphoton detachment process in a fast beam of H− ions. The angle-tuned relativistic Doppler shift is used to vary the photon energy of a focused (~10 GW/cm2) 10.6-μm CO2 laser beam from ~0.05 to ~0.4 eV in the rest frame (CM frame) of the fast ions. The ions are produced at 800 MeV (β = v/c = 0.84) by the Los Alamos Meson Physics Facility linear accelerator at Los Alamos and experience ~1-psec pulses in the CM frame as they cross the laser beam focus. Peaks in the detachment signal corresponding to each order for two- to six-photon processes are observed. At modest laser intensity in the gigawatt-per-square-centimeter range, observed shifts of the apparent two-photon threshold are found to be not more than 30–50% of the expected maximum shift, based on the value of the ponderomotive potential. Experimental uncertainties are due mainly to imprecise knowledge of the maximum laser intensity. The data analysis and modeling of the expected threshold shape experiments are continuing.

In crude homogenates of the submaxillary gland of the male mouse, epidermal growth factor activity is found almost entirely in a high molecular weight complex. The complex has a molecular weight of about 74,000 and appears to be composed of 2 molecules of epidermal growth factor (6,045 molecular weight) and 2 molecules of a binding protein (29,300 molecular weight). The complex is stable only in the range of pH 5.0 to 8.0, and its behavior during isoelectric focusing, gel filtration, and ultracentrifugation suggests that it may be in a slow equilibrium with its subunits. In addition, the complex appears to undergo a concentration-dependent aggregation. The biological activity of the high molecular weight complex is proportional to its fractional content of the low molecular weight factor. No evidence was found which indicated that the binding protein might affect the biological activity of the low molecular weight epidermal growth factor. It is postulated that the high molecular weight form of epidermal growth factor is an enzyme-product complex. The substrate is presumed to be the epidermal growth factor precursor which is recognized by a specific arginine esterase, the binding protein.

B19 parvovirus is the etiologic agent of fifth disease and transient aplastic crisis. In natural infections, B19 antigen and DNA have been detected in sera early in the course of aplastic crisis and only rarely in fifth disease. We have found B19 DNA in circulating cells of infected patients by DNA dot blot with a virus-specific probe: in four of four sickle cell patients with aplastic crisis, in one asymptomatic sibling, and in one normal adult with fifth disease. Only two of the sera showed B19 DNA. High-molecular weight intermediate forms were detected by Southern analysis of DNA extracted from cells, thus indicating active replication of virus in cells rather than passive adsorption to their surface membranes. Separation of cells into high- and low-density fractions resulted in a concentration of the virus DNA in the granulocytic fraction.

Heparin was studied in a dose range of 1 to 100 units/ml for its ability to interfere with migration inhibitory or chemotactic activity of lymphokine preparations. Heparin was found to inhibit macrophage and neutrophil chemotaxis but not macrophage migration inhibition. The dose range for these effects is similar to the in vivo concentrations necessary to suppress cutaneous reactions of delayed hypersensitivity. These results, taken in conjunction with previous studies, suggest that macrophage chemotactic factor may play a more significant role than macrophage migration inhibitory factor in the expression of cutaneous reactivity.

The $^{1}\mathrm{P}^{\mathrm{o}}$ shape resonance of ${\mathrm{H}}^{\mathrm{\ensuremath{-}}}$ has been studied in moderate motional electric fields by Doppler-tuning the photon energy absorbed by a 650-MeV ${\mathrm{H}}^{\mathrm{\ensuremath{-}}}$ beam crossed by the fourth-harmonic beam of a Nd:YAG laser (YAG denotes yttrium aluminum garnet). The resonance parameters are remarkably insensitive to electric fields in the range from 120 to 240 kV/cm. Our measurements reveal that the width of the shape resonance may decrease from its zero-field value, on average, by (3.3\ifmmode\pm\else\textpm\fi{}0.9)% in this electric field regime. This observation contradicts the (naive) expectation that perturbation of the resonance by an electric field should promote more rapid decay, and hence greater width. Interpretations are given in terms of (a) Stark mixing with narrower singlet states and (b) tunneling through the potential barrier in hyperspherical coordinates.

Stable cell lines expressing the human epidermal growth factor (EGF) precursor have been prepared by transfection of mouse NIH 3T3 cells with a bovine papillomavirus-based vector in which the human kidney EGF precursor cDNA has been placed under the control of the inducible mouse metallothionein I promoter. Synthesis of the EGF precursor can be induced by culturing the cells in 5 mM butyric acid or 100 microM ZnCl2. The EGF precursor synthesized by these cells appears to be membrane associated; none is detectable in the cytoplasm. The size of the EGF precursor expressed by these cells is approximately 150-180 kDa, which is larger than expected from its amino acid sequence, suggesting that it is posttranslationally modified, presumably by glycosylation. The EGF precursor was also detected in the conditioned medium from these cells, indicating that some fraction of the EGF precursor synthesized by these transfected cells may be secreted. Preliminary data suggest that this soluble form of the EGF precursor may compete with 125I-labeled EGF for binding to the EGF receptor. These cell lines should be useful for studying the processing of the EGF precursor to EGF as well as determining the properties and possible functions of the EGF precursor itself.

Effect of plasma sodium concentration on diluting segment sodium reabsorption. Studies were performed in dogs undergoing water diuresis to evaluate the effect of extracellular volume expansion on diluting segment sodium reabsorption and how alterations in plasma sodium concentration may modify this effect. Urinary volume (V) was used as an index of delivery and free water clearance (C H 2 O ) was used to approximate sodium reabsorption in the diluting segment. In the majority of studies, abolishment of antidiuretic hormone secretion was accomplished by supraoptic-hypophyseal ablation. This model was found to produce a steady level of urinary hypotonicity of less than 70 mOsm/kg for at least five hours. These animals were then expanded with either 0.9% NaCl (group 1—hypernatremic expansion) or 0.45% NaCl (group 2—normonatremic expansion). In both groups C H 2 O /glomerular filtration rate (GFR) rose to a V/GFR of 20% and then remained constant as delivery increased to 38%. In contrast, in the group 3 studies (hyponatremic expansion), normal or acute diabetes insipidus (DI) dogs which were hyponatremic during expansion (P Na = 122 mEq/liter) had a continued increase in C H 2 O /GFR as V/GFR rose as high as 40%. When factored for P Na , absolute sodium reabsorption was also greater at high rates of delivery in the hyponatremic studies. This enhanced sodium reabsorption in the diluting segment in the group 3 studies could not be accounted for by differences in volume expansion, medullary or papillary solutes, serum potassium concentration or GFR when compared to groups 1 and 2. It is suggested that hyponatremia per se increases sodium reabsorption in the diluting segment. Effet de la concentration de sodium plasmatique sur la reabsorption de sodium par le segment de dilution. Ce travail a ete entrepris chez le chien soumis a une diurese aqueuse afin d'evaluer l'effet de l'expansion du volume extracellulaire sur la reabsorption du sodium par le segment de dilution et l'influence des modifications de la concentration plasmatique du sodium sur cet effet. Le debit urinaire (V) a ete utilise comme un temoin de la quantite delivree au segment de dilution et la clearance de l'eau libre (C H 2 O ) a evalue la reabsorption de sodium dans ce segment. Dans la majorite des cas la suppression de la liberation d'hormone anti-diuretique a ete obtenue par hypophysectomie supra-optique. Ce modele s'est revele capable de realiser un etat stationnaire d'hypoosmolalite urinaire inferieure a 70 mOsm/kg pendant au moins cinq heures. Les animaux ont ete soumis a une expansion secondaire soit avec NaCl 0,9% (Groupe 1, expansion hypernatremique) ou 0,45% (groupe 2, expansion normonatremique). Dans les deux groupes C H 2 O /GFR augmente jusqu'a ce que V/GFR atteigne 20% puis reste constant alors que le debit delivre au segment de dilution augmente jusqu'a 38% de GFR. A l'oppose, dans le groupe 3 (expansion hyponatremique), des chiens normaux ou en etat de diabete insipide hyponatremiques au cours de l'expansion (P Na = 122 mEq/litre) ont une augmentation continue de C H 2 O /GFR pendant que V/GFR augmente jusqu'a 40%. Quand P Na est pris en compte, la reabsorption absolue de sodium est elle aussi plus importante pur les debits eleves chez les chiens hyponatremiques, Cette exaltation de la reabsorption du sodium par le segment de dilution dans les etudes du groupe 3 ne peut etre expliquee par des differences de l'expansion, du contenu en substances dissoutes de la medullaire ou de la papille, de la kaliemie ou du GFR avec les groupes 1 et 2. Il est suggere que l'hyponatremie, par elle-meme, augmente la reabsorption du sodium par le segment de dilution.

Cytoplasmic extracts, prepared from continuously proliferating lymphoblastoid cells, as well as mitogen-activated normal lymphocytes, contain an extractable factor capable of inducing DNA synthesis in isolated quiescent nuclei. This factor is not detectable in resting cells. It is nondialyzable, precipitable by 30–50% saturated ammonium sulfate, and inactivated by trypsin. It is heat sensitive, but stable to cold and lyophilization. The molecular weight of the factor is greater than 100,000. This Cytoplasmic activator of nuclear DNA replication is not released from the cell, and has no effect on intact cells. This suggests that it serves as an intracellular mitogenic signal in replicating cells.

Macrophage migration inhibitory activity has been detected in the sera of six of eight patients with hepatic dysfunction following transplantation (renal or hepatic) and immunosuppression. Three of these individuals had detectable Australia antigen. Serum MIF activity bore an interesting temporal relation to parameters of hepatic disease, especially serum glutamic oxaloacetic transminase (SGOT) levels. Elevations of serum MIF preceded elevations of SGOT by approximately 5–10 days. This suggests that cell-mediated immune mechanisms may have not been beneficial, but rather may have contributed to the underlying hepatic pathology.

Although we have focused on desensitization as an experimental model, the findings obtained suggest mechanisms by which physiological control of cell-mediated immunity is attained. Thus, such regulation may occur either at the stage of expression of lymphokine activity or at the level of lymphokine production itself. The former may involve unique suppressor molecules, but as indicated above may be due to the inflammatory lymphokines themselves. The latter appears to involve suppressor systems similar to those operative in antibody formation. Over and above any specific model for regulation, the findings presented here suggest that local fluctuations in lymphokine distribution can modulate immunologically induced inflammatory responses, either through alterations in chemotactic gradients, or by other mechanisms as yet unknown.

Lipocortin-I (p35) is a unique calcium- and phospholipid-binding protein of the lipocortin/calpactin family. Although several possibilities have been suggested, functions for the individual proteins of this family are not yet known with certainty. As an initial step in the identification of the biological function(s) of p35, we have used immunohistochemical methods to define precisely many of the cellular phenotypes that contain p35 in vivo. In all organs where p35 is found, we have observed a striking distribution of p35-positive cells. Typically it is highly enriched in a limited range of differentiated cell types while apparently totally absent from most others. Our identification of specific p35-positive cell types in vivo will now set limitations on likely possibilities for functions of this protein and thereby permit a more logical approach to the determination of its true function.

The effect of human epidermal growth factor (hEGF), a 5,400 molecular weight polypeptide isolated from human urine, on the growth of human foreskin fibroblasts (HF cells) was studied by measuring cell numbers and the incorporation of labeled thymidine. The addition of hEGF to HF cells growing in a medium containing 10% calf serum resulted in a 4-fold increase in the final density. The presence of hEGF also promoted the growth of HF cells in media containing either 1% calf serum or 10% gamma globulin-free serum. The addition of hEGF to quiescent confluent monolayers of HF cells, maintained in a medium with 1% calf serum for 48 hours, resulted in a 10- to 20-fold increase in the amount of 3H-thymidine incorporation after 20-24 hours. The stimulation of thymidine incorporation was maximal at an hEGF concentration of 2 ng/ml, was dependent on the presence of serum, and was enhanced by the addition of ascorbic acid. In confluent cultures of HF cells, subject to density dependent inhibition of growth, hEGF was able to stimulate DNA synthesis more effectively than fresh calf serum. Human EGF stimulated DNA synthesis in quiescent cultures, however, regardless of cell density. The addition of rabbit anti-hEGF inhibited all effects of this growth factor on HF cells.

Trypsinization of P815 mastocytoma cells interferes with their ability to bind to endothelial monolayers in vitro, suggesting the involvement of proteins in cell-cell binding. Binding is also dependent upon divalent cations. Incubation of tumor cells with tunicamycin, which blocks protein glycosylation, or the monosaccharide N-acetyl-D-glucosamine could also inhibit binding. In addition, antibodies prepared against whole P815 cells had the ability to interfere with tumor cell binding. The protein fragments released from P815 cells by trypsin interfered with the binding of fresh P815 cells to endothelium. Moreover, those fragments as well as CHAPS extracts of tumor cell membranes were able to neutralize the inhibitory effect of an anti-P815 antibody on tumor cell-endothelial cell binding. These observations, taken together, strongly suggest the presence of adhesion molecules on the tumor cell. The anti-P815 antibody preparation could also inhibit endothelial binding of an unrelated tumor. Ehrlich ascites (EA). In addition, membrane preparations of EA could neutralize the antibody's effect on intact P815, and membrane preparations of P815 could neutralize the antibody's effect on EA. These observations suggest that there are common epitopes on these tumor cells and raise the possibility that a variety of tumors may share common mechanisms for attachment to endothelium. This, in turn, raises the possibility that monospecific antibodies against such epitopes might be useful agents for interfering with metastasis in vivo.

The three disulfide bridges in epidermal growth factor have been identified by the isolation of three unique cystinyl peptides obtained by thermolytic digestion. The cysteic acid-containing peptide pairs derived from each of the cystinyl peptides were isolated. Their amino acid compositions were in agreement with those predicted from the known amino acid sequence of epidermal growth factor. The cysteinyl residues in positions 6 and 20, 14 and 31, and 33 and 42 were linked as disulfides in this 53 amino acid residue polypeptide.

A factor that can inhibit the migration of tumor cells without cytotoxic effect (TMIF) is present in supernatants of activated lymphocytes. In the present experiments, we demonstrate that similar activity can be found in the serum of appropriately immunized animals. As is the case for macrophage migration inhibitory factor (MIF), TMIF activity appears only transiently after challenge with antigen. TMIF is also found in the serum of tumor-bearing animals. In this situation, activity persists from Day 7 postinoculation until the time of death. Although previous studies have demonstrated that TMIF and MIF are distinct, these results show that TMIF activity parallels serum migration inhibitory activity against macrophages. In the present experiments, the animals were given a lethal dose of tumor cells. However, it is likely that by virtue of its biologic properties, TMIF might have a protective effect under other experimental conditions.

Guinea pig basophils obtained from blood or bone marrow have been studied for their chemotactic responsiveness. Chemotactic factors for basophils include a substance (lymphokine) present in culture fluids from antigen-stimulated lymphocytes, a material generated in zymosan-activated guinea pig serum, a C5 cleavage factor, and a bacterial factor. When compared with homologous neutrophils and monocytes, basophils respond most rapidly to a chemotactic stimulus. The lymphokine basophil chemotactic factor is physicochemically similar to the previously described monocyte chemotactic factor but appears to be distinct from it as well as MIF and neutrophil chemotactic factor present in the same fluids. Part of the evidence for this is the ability to detect basophil chemotactic factor in the absence of other lymphokine activities under appropriate experimental conditions. More evidence, specifically relating to the monocyte factor, is that monocytes can adsorb basophil chemotactic activity but not vice versa. This latter observation may have implications for the mechanism whereby the accumulation of basophils is controlled and limited in vivo. In addition, it was noted that specific antigen could also suppress basophil chemotaxis. Although the mechanism of this phenomenon is unclear, it could serve as a second means by which basophil accumulation may be controlled in the intact animal. Taken together, these observations provide further definition of the chemotactic behavior of basophils in general, and underscore some of the ways in which lymphocytes can influence basophils through lymphokine-dependent mechanisms.

Histones specifically phosphorylated at either tyrosine (phospho-Tyr-histones) or serine and threonine (phospho-Ser-histones) were prepared and tested as substrates for so-called alkaline and protein phosphatases. Three different preparations of alkaline phosphatase (calf intestine, bovine liver, and Escherichia colg dephosphorylated phospho-Tyr-histones at 5-10 times the ratet hey dephosphorylated phospho-ser-histones. It was concluded that the p-nitrophenyl phosphatase and phospho-Tyr phosphatase activities reside in the same protein on the basis of high performance liquid chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, inhibition of both activities by Pi and EDTA but not fluoride, and inhibition of phospho-Tyr phosphatase activity by p-nitrophenyl phosphate. Phosphoprotein phosphatase from rabbit muscle, which had little if any p-nitrophenyl phosphatase activity, dephosphorylated phospho-Ser-histones at 16 times the rate it dephosphorylated phospho-Tyrhistones. Thus, the ratio of the pseudo-first order rate constants for dephosphorylation of phospho-Tyr-histones/ phospho-Ser-histones was approximately 100 times higher for alkaline phosphatases compared to the rabbit muscle protein phosphatase. Membrane proteins from A-431 cells (phosphorylated at tyrosine) were more effective substrates than phospho-Tyr-histones as substrates for alkaline phosphatase; this was not the case for protein phosphatase. Phospho-Tyr phosphatase activity of the alkaline phosphatases was optimal in the pH range of 7-8. The so-called alkaline phosphatases, then, may be a group of membrane-bound glycoproteins that represent a class of phosphoprotein phosphatases that show selectivity for proteins phosphorylated at tyrosine residues.

The present study was undertaken in an effort to elucidate the mechanism(s) responsible for desensitization, making use of both cutaneous and peritoneal manifestations of delayed hypersensitivity as parallel assay systems in the guinea pig model. Particular emphasis was placed on investigating the possibility of passively transferring desensitization with serum factors and attempting to characterize these. Our data support the hypothesis of an inhibitory environment in the anergic animal: The desensitized state was successfully transferred to immune recipients by the systemic administration of desensitized serum as measured by both skin testing and macrophage disappearance reaction (MDR). Transfer of the desensitized state is not due to residual antigen in donor sera and is nonspecific. Partial characterization of the serum inhibitor indicated that it is nondialyzable, heatstable at 56 °C for 30 min, but destroyed by heating at 80 °C for 60 min. Sephadex G-100 chromatography located the inhibitory activity in the size range of 10,000–45,000 daltons. Larger molecular weight fractions were devoid of inhibitory activity, suggesting that antibodies or immune complexes are not responsible for the effect observed and the inhibitory serum component is not associated with macroglobulins. The physicochemical properties of the desensitizing factor, and our previous finding that intravenous injection of lymphokines leads to transient cutaneous anergy, suggest that the desensitizing substances may represent endogenous lymphokines in the general circulation.

Physical, chemical, and enzymatic properties of the protein which binds epidermal growth factor (EGF) have been examined. A molecular weight of 29,300 was determined from sedimentation equilibrium studies, in agreement with a value of 30,000 calculated from the s020, w (2.83 S) and D020, w (8.73 x 10-7 cm2 s-1). It has an E1%1 cm at 280 nm of 15.6 and the isoelectric point is 5.6. The circular dichroic spectrum indicates a major nonhelical character with a minor amount of α helical structure. The amino acid composition was determined. No free sulfhydryl groups were detected. Hexosamine analysis revealed the presence of glucosamine and galactosamine. EGF-binding protein was found to be an arginine esterase with a restricted substrate specificity. Kinetic studies of the catalytic hydrolysis of Nα-benzoyl-l-arginine ethyl ester revealed a Km of 130 µm and a pH optimum in the range of pH 7.8 to 8.5, where the specific activity is approximately 390 µmoles per min per mg. This arginine esterase is not identical, but is related antigenically, to the arginine esterases associated with the nerve growth factor complex. The EGF-binding protein is postulated to function in the enzymatic liberation of active EGF from an inactive precursor.

The response to external electric fields of the $^{1}\mathrm{P}^{\mathrm{o}}$ resonance ``dip'' in the ${\mathrm{H}}^{\mathrm{\ensuremath{-}}}$ photodetachment continuum cross section below the n=3 hydrogenic excitation threshold is investigated. Using the relativistic (\ensuremath{\beta}=0.806) 650-MeV ${\mathrm{H}}^{\mathrm{\ensuremath{-}}}$ beam at the Clinton P. Anderson Meson Physics Facility (LAMPF) in Los Alamos, the fourth harmonic (266 nm) of a Nd:YAG laser (where YAG denotes yttrium aluminum garnet) is Doppler shifted to provide a continuously tunable photon beam in the rest frame of the ions. The magnetic field from pulsed Helmholtz coils, surrounding the photon-${\mathrm{H}}^{\mathrm{\ensuremath{-}}}$ interaction point provides a Lorentz-transformed barycentric electric field. As the magnitude of the external field is increased, there is no observed shift in the photon energy to excite the resonance ${E}_{o}$, 12.650\ifmmode\pm\else\textpm\fi{}0.001 eV, until quenching occurs at a field strength of 2.36 MV/cm. The effective strength of the resonant state is consistent with a linear decrease with increasing field. The line shape index q is constant within statistical uncertainty, until the resonance disappears. There is evidence that the width of the resonance remains constant at fields below 1.25 MV/cm. It then broadens at higher fields before the resonance quenches.

We have investigated the effect of vanadate on the phosphoserine- and phosphotyrosine-specific phosphoprotein phosphatase activities of A-431 cell membranes and have found that micromolar concentrations of vanadate strongly inhibit the membrane-dependent dephosphorylation of histones containing phosphotyrosine but that they do not inhibit the dephosphorylation of histones containing phosphoserine and phosphothreonine. In addition, the dephosphorylation of endogeneous membrane proteins of A-431 cells (which are known to be phosphorylated at tyrosine residues) was inhibited by vanadate. These results show that vanadate is a potent and selective inhibitor of phosphotyrosyl-protein phosphatase.

NIH 3T3 cells were transfected with cDNA corresponding to human kidney prepro-epidermal growth factor (preproEGF) under control of the inducible mouse metallothionein promoter. The synthesis of recombinant human EGF precursor by these cells has provided us with a model system for analysis of the structure and activity of this precursor. In transfected cells, the precursor was present as an intrinsic 170-kilodalton membrane protein as well as a soluble protein in the extracellular medium; both forms were N glycosylated. Glycosylation of the EGF precursor was determined by (i) the direct incorporation of [3H]mannose and [3H]glucosamine, (ii) metabolic labeling in the presence or absence of glycosylation inhibitors, (iii) enzymatic cleavage of the precursor by N-glycanase or endoglycosidase II, and (iv) lectin chromatography. Recombinant human preproEGF was purified by affinity chromatography, using wheat germ lectin and antibodies to human EGF. The intact precursor was biologically active. Purified preparations of preproEGF (i) competed with 125I-labeled EGF for binding to the EGF receptor in intact fibroblast cells, (ii) activated the intrinsic tyrosine kinase activity of the EGF receptor in membrane preparations, and (iii) sustained the growth of a mouse keratinocyte cell line that is dependent on EGF for growth. These results suggest that proteolytic processing of the precursor may not be essential for its biological function.

Opening ParagraphIt has long been a cliché in the social sciences to talk about the insulation of disciplines and sub-disciplines from each other. We all know what it is like tostudy a phenomenon – poverty, crime, the family – from within one academic paradigm and then come across a quite different view of the ‘same’ phenomenon. The result is usually self-pity: ‘If only I had known what they were up to’ or ‘If only they knew what I was up to’.