Electrokinetic properties and mitogen responsiveness of mouse splenic B and T lymphocytes following hydrocortisone treatment.

CBA mice recieved a single intraperitoneal injection of hydrocortisone acetate (OHC) in a dose of 125 mg/kg body weight. At various times therafter, electrophoretic mobility (EPM), surface immunoglobulin (SIG) and in vitro DNA synthetic reactivity to concanavalin A (ConA), phytohemagglutinin (PHA), lipopolysaccharide (LPS) and tuberculin (PPD) were investigated on splenic lymphocytes. OHC was found to deplete rapidly the spleen to a minimum of 18% of control cellularity by day 4 posttreatment. At this time, the proportions of low mobility (LM) and SIG-bearing lymphocytes (B cells) were reduced respectively to 28% (control 54%) and 20% (control 45%). The proportion of high mobility (HM) lymphocytes (T cells) was increased to 72% (control 45%). While the mean EPM of LM cells (0.71) was only slightly and transiently reduced, that of HM cells was significantly augmented (1.24) over control value (1.16). This latter finding was interpreted as indicating the selective removal by OHC of a T cell subpopulation with a mean EPM around 1.10. Changes in mitogenic responsiveness were consistent with these alterations of B and T cell compartments. Despite a marked drop in spontaneous 3H-thymidine uptake, the absolute response to T cell mitogens ConA and PHA remained relatively unchanged. By contrast, the reactivity to B cell mitogens LPS and PPD was strongly depressed. Starting by day 12, regeneration and normalizaiton of lymphocyte populations proceeded slowly and were not achieved before day 26-34.


Studies on immune responses to parasite antigens in mice. V. Different susceptibilities of hypothymic and intact mice to Babesia rodhaini.

Hypothymic BALB/c.nu/nu mice are more resistant than intact BALB/c.nu/+ mice to Babesia rodhaini and a proportion survive a dose of infected blood which is uniformly lethal to nu/+ mice. This proportion of nu/nu survivors is not affected by administration of an anti-Babesial drug, whereas the majority of nu/ + mice develop a long-lasting resistance to infection. The data suggest that T cell dependent activities are involved both in the acceleration of parasitaemia and in the development of drug-assisted resistance.


Inhibition of IgE production of mice by non-specific suppressor T cells.

SWR adult normal splenic T lymphocytes injected into irradiated syngeneic mice along with immune spleen cells can suppress IgE formation by the immune cells. Spleen cells from 1- or 3-week-old mice, however, are not effective in abrogating IgE synthesis. The T lymphocytes which are induced to become suppressors for IgE are hydrocortisone-resistant and anti-thymocyte serum-sensitive. Normal SJL mice, a poor reagin-producing strain, do not appear to have more suppressor cells or cells which are more easily stimulated to become suppressor cells than a good reagin-producing strain (SWR).


DNA replication and repair in a human melanoma cell-line resistant to ultra-violet-radiation.

The effect of ultra-violet (U.V.)-irradiation on DNA replication was studied in a U.V.-resistant, human melanoma cell-line (MM96). Semi-conservative synthesis of DNA was decreased about five-fold by a U.V.-dose of 100 ergs/mm2. The size of DNA fragments synthesized in irradiated cells at short times after U.V. was smaller than those synthesized in unirradiated cells. Elongation of these fragments occurred with time, and 6 hours after irradiation cells synthesized DNA in fragments of the same size as obtained in unirradiated cells. In this post-replication repair process, elongation appeared to involve de novo synthesis and was not inhibited by theophylline.


Immune responses during human schistosomiasis mansoni. I. In vitro lymphocyte blastogenic responses to heterogeneous antigenic preparations from schistosome eggs, worms and cercariae.

In vitro lymphocyte blastogenesis assays were performed using peripheral blood lymphocytes obtained from patients with schistosomiasis mansoni. Their infection was well characterized both clinically and in regard to the duration and intensity of Schistosoma mansoni infection. Subjects who were either not infected with any helminths or who were negative for S. mansoni but infected with other helminths provided two control groups. Cultures were exposed to various concentrations of heterogeneous soluble antigens prepared either from S. mansoni eggs, worms, or cercariae. In this series there was no statistical correlation between the intensity of infection (as determined by eggs/ml of feces) and the degree of cell-mediated reactivity observed by lymphocyte blastogenesis to any of the antigenic preparations. Individual patient lymphocyte responsiveness varied considerably. However, analysis of the data by groups, based upon the longevity of their S. mansoni infection, demonstrated different patterns of reactivity in regard to the antigen preparations. Responses to the egg antigens were only present early in infection. In contrast, reactivities stimulated by either the worm or cercarial preparations increased in a direct relationship to the duration of S. mansoni infection.


Gamma-irradiated chymotrypsin-like proteins. I. Structural changes.

The chymotrypsin-like proteins (chymotrypsin-CT,chymotrypsinogen-CTG, trypsin-T and modified chymotrypsins-at Met 192-MCT and at Tyr 146, 171-TCT), gamma-irradiated in the presence of air, were investigated. Irradiation leads to the unfolding of the native structure of CT-like proteins both in solution and in the dry state, which was shown by the tryptophan fluorescence, viscosimetry and microcalorimetry. The radiation yield of unfolded molecules Gconf was estimated and compared with (1) the rate constants for the reactions of OH-radicals with the proteins as determined by the p-nitrosodimethylaniline, (2) general stability of protein globule using the difference of the energies of the unfolded and globular conformations and (3) the radiation yield of tryptophan destruction in proteins-G-trp. There was a correlation between the values of Gconf and G-trp. The ratio G-trp/Gconf, which defines the number of destroyed tryptophan residues for one unfolded protein molecule, was constant within the limits of error. For CT, MCT, TCT and CTG, this ratio was on the average 3-2, and for T it was 2-2 residues. These facts point to the role of tryptophan destruction in the unfolding of the native structure of CT-like proteins on irradiation.


Influence of a 1400-gauss magnetic field on the radiosensitivity and recovery of EMT6 cells in vitro.

EMT6 mouse mammary tumour cells in vitro were exposed to an almost uniform 1400-gauss magnetic field during or after irradiation with 120 kV X-rays. Exposure of unirradiated control cultures to this field for up to 48 hours did not alter the viability or growth of the cells. Exposure of exponentially-growing cultures to the magnetic field during irradiation did not alter the survival curve. Exposure of exponentially-growing culturesto the magnetic field between two doses of 500 rad of X-rays did not alter significantly the pattern or magnitude of the recovery from sub-lethal damage. Exposure of plateau phase cultures to the magnetic field after irradiation did not alter significantly the pattern or magnitude of recovery from potentially-lethal damage. The effects of a short exposure to an almost uniform magnetic field of this strength on the production and repair of radiation damage appear to be minimal in this system.


Uracil metabolism in golden hamster after irradiation.

The catabolism of uracil and the total balance of excreted radioactivity were studied in golden hamsters after a peroral application of 14C-uracil. Twenty-four hours after administration most of the radioactivity taken up appeared in expired carbon dioxide. The percent proportion of radioactivity in carbon dioxide was independent of the amount of uracil administered. On the other hand, the percentage of radioactivity excreted in urine depended on the amount of uracil taken up, high doses of the compound causing up to eight-fold increase in urine-excreted radioactivity. Most of the exogenously-administered uracil was catabolized within the first 5 hours. Irradiation had no substantial effect on the dynamics of uracil catabolism. Analysis of urine revealed that most urine-excreted radioactivity is in the form of uracil. On peroral application of high doses of uracil to irradiated hamsters, their urine was found to contain barbituric acid which originated from uracil.


A change in the oxygen effect throughout the cell-cycle of human cells of the line NHIK 3025 cultivated in vitro.

NHIK 3025 cells were synchronized by repeated mitotic selection. The S-phase was determined by 3H-thymidine incorporation and scintillation counting. By comparing the age-response surves of aerobic cells irradiated with 500 rad with those of extremely hypoxic (less than4 p.p.m. O2) cells irradiatedwith 1500 rad, it was found that the sensitizing effect of oxygen was not constant throuhgout the cycle. It was significantly higher in S, G2 and mitosis than in G1. No significant sensitizing effect of 120 p.p.m. O2 (compared with less than4 p.p.m.O2) was found on cells in G1 when the cells were irradiated with 1500 rad. In S, G2 and mitosis, however, the sensitizing effect of oxygen at 120 p.p.m. is considered to be significant. Experiments performed with cells irradiated with 2000 rad incontact with either less than4 p.p.m. O2 or 80 p.p.m. O2 showed the same trend, little sensitizing effect in G1 and higher in S, G2 andmitosis. Dose-response curves for cells in mid-G1 and mid-S under aerobic and extremely hypoxic conditions were well fitted by the formula S=exp (-alphaD-betaD2). From the dose-response curves it was conculded that the change in the sensitizing effect of oxygen throughout the cell-cycle only appeared for low doses (in the dose region where alpha dominates). The sensitizing effect of oxygen on cells in mid-G1 was found to be increasing with increasing dose.


Modification of the radiosensitivity of barley seed by post-treatment with caffein. IV. Effect of the moisture content of seed and storage temperature after irradiation.

The oxygen-dependent damage which develops in barley seeds with approximately 7-8 per cent moisture content disappears after post-irradiation storage in vacuo for 48 hours at 40 degrees C and for 24 hours at 50 degrees C. When the diration of storage at 40 degrees C is extended to 384 hours, oxygen-independent damage becomes potentiated. There is oxygen-dependent damage in seeds of approximately 13.3 per cent moisture content and after the seeds have been stored in vacuo at 50 degrees C, the oxygen-dependent damage begins to increase by 168 hours, and it is very significantly potentiated by 192 hours. Under these circumstances, caffeine acts as a radioprotector only as long as the precursors of oxic damage are present in the seeds. Once these sites are lost, caffeine acts only as a radiosensitizer. The oxygen-independent damage which increases with storage at high temperature is further potentiated by caffeine.


Dose-rate and oxygen effects in models of lipid membranes: linoleic acid.

Cellular membranes have been suggested as possible loci for the development of the oxygen effect in radiobiology. Unsaturated lipids from membranes are subject to very efficient radiation-induced peroxidation, and the deleterious effects generally associated with lipid autoxidation could be initiated by ionizing radiation. Oxidative damage in lipids is characterized not only by high yields but also by a profound dose-rate effect. At dose-rates of X-irradiation below 100 rad/min, a very sharp rise occurs in oxidative damage. This damage has been quantified spectrophotometrically in terms of diene conjugation (O.D. 234 mm) and chromatographically in terms of specific 9- and 13-hydroperoxide formation in linoleic acid micelles. Radical scavenging experiments indicate that hydroxyl radical attack initiates the oxidative damage. Dimethyl sulphoxide is exceptional in that it does not protect, but sensitizes, linoleic acid to radiation induced peroxidation. The yields of hydroperoxides are substantial (G=10--40) and can be related to biological changes known to be effected by autoxidizing lipids.


Ultrastructural events in the cytoplasmic death of lethally-irradiated human lymphocytes.

Normal human peripheral-blood lymphocytes were irradiated with a dose of X-rays and processed for electron microscopic examination at different times after irradiation. A localized protrusion of the plasma membrane of the irradiated lymphocytes was observed in samples fixed as early as 15 min after irradiation, suggesting that the injury to the plasma membrane could have occurred during or immediately after irradiation. This was followed by fenestration of the plasma membrane, rarefaction of the cytoplasm and accumulation of cytoplasmic organelles in the centrosphere region. Localized distention of the outer nuclear envelope occurred after 2 hours and invagination of the inner nuclear membrane after 4 hours of irradiation. By 24 hours, the cytoplasmic and nuclear ultrastructural integrity was lost. The study suggested that, for high doses of X-radiation, the plasma membrane of the human peripheral-blood lymphocytes was the most sensitive target.


Endonuclease activities in extracts of Micrococcus luteus that act on gemma-irradiated DNA.

Several protein fractions containing endonuclease activity against gemma-irradiated DNA (gamma-endonuclease) were isolated from M. luteus. The crude extract was eluted on a phosphocellulose column and chromatographed on TEAE cellulose and subsequently on hydroxyapatite. Five peaks of gamma-endonuclease were obtained from each preparation. Repeated experiments showed comparable chromatographic behavior of the fractions. There was no detectable activity of U.V.-endonuclease in the fractions with gamma-endonuclease but a small contamination of endonuclease against unirradiated DNA and against DNA with apurinic sites. The gamma-endonuclease is stimulated by, but is not dependent on, magnesium. Several tests for endonuclease activity have been used: the analysis of strand breaks in calf-thymus DNA or in PM2 DNA, and the determination of end-groups formed by endonuclease, either 3'OH end-groups or phosphomonoester end groups. From the results obtained it can be assumed that the strand breaks induced by the gamma-endonuclease carry 3'OH and 5' phosphate end groups.


Chromosome aberration yields induced in human lymphocytes by 15 MeV electrons given at a conventional dose-rate and in microsecond pulses.

Yields of unstable chromosome aberration were analysed in human lymphocytes after in vitro exposure to 15 MeV electrons. Two dose-effect curves were prepared. In one, doses of 44 to 742 rad were given at 100 rad/min, and in the other doses of 53 to 764 rad were each delivered in single microsecond pulses. No significant difference could be found between the two sets of data when analysed in terms of the quadratic model of aberration production. Good agreement was observed with other dose-response studies in this laboratory, in which human lymphocytes were exposed to 250 kVp X-rays and 60CO gamma-rays at conventional rates of 100 and 50 rad/min, respectively. Comparison with the results of a low-LET dose-rate experiment shows that the yield of dicentric aberrations remains constant overa wide range, i.e. 25 to 6X 10(9), 100 to 1-5 X 10(10), and 150 to 3 X 10(10) rad/min, respectively, for doses of 100, 250 and 500 rad. Radiochemical consumption of oxygen occuring in the lymphocytes during the single microsecond exposures may amount to less than 5 per cent of the total oxygen present in the blood samples, immediately before irradiation. The data also indicate that the ultra-high dose-rates currently available are insufficient to overcome the therapeutic problem of hypoxic radioresistant tumour cells.


Interactions of alkyl sulphates with bovine-serum albumin studied using eaq--as a probe.

The reactions of hydrated electrons produced during pulse radiolysis habe been used to investigate the binding of a range of alkyl sulphates to bovine-serum albumin. Binding to ten high-affinity sites is detectable for all compounds (methyl, hexyl, octyl, decyl, and dodecyl sulphates) studied. Sodium dodecyl sulphate, in contrast to the other analogues, causes large increases in the reactivity of BSA as a result of further binding. Possible mechanisms for this increase are discussed.


Radioresistance of mongolian gerbils. Fast neutrons.

Seventy-six 8 week old Mongolian gerbils were exposed to acute, whole-body fast neutrons produced by The University of Michigan 83-in. cyclotron. Groups of seven or eigth gerbils were given doses between 485 and 881 rad at 25 rad per minute. The LD 50/30 determined by probit analysis was 750 rad, with 95 per cent fiducial limits of 733 and 776. For the 50 per cent mortality level, an r.b.e. of fast neutrons compared with cobalt-60 of 1-45 was determined. For the same end-point, the r.b.e. for fast neutrons compared with X-rays is 1-33.  Mortality data, body-weight and microhaematocrit changes are discussed.


Neonatal haemophilus aphrophilus meningitis.

Case report of a neonatal meningitis due to Haemophilus influenzae. The treatment with ampicillin was ineffective because of insensitivity. This case demonstrates the importance of a proper bacteriological identification in order to avoid ineffective or delayed treatment.


Intramural hematoma of the alimentary tract in two hemophilic children.

The occurrence of an intramural hematoma of the alimentary tract is reported in two hemophilic children. In both cases, the hematomas may be the result of a mild unrecognized trauma. The first patient presents large duodenal hematomas with secondary rupture into the retroperitoneal space. Death occurs despite medical and surgical treatment. The second patient presents an intramural hematoma of the colon, which is treated medically. In both cases factor VIII inhibitors developed during the course of therapy. Indications for medical or surgical treatment are discussed.


Rectal wall bleeding--an overlooked source of massive lower gastrointestinal hemorrhage.

Two cases of acute massive bleeding from the rectum are described. In both cases, the diagnosis was made angiographically. Some points of angiographic technique are discussed. In both cases, there had been previous negative sigmoidoscopy. Care must be taken to include the entire rectum on the films obtained during injection of the inferior mesenteric artery regardless of findings on sigmoidoscopy.


Aneurysm of the superior hemorrhoidal artery: an unusual cause of massive rectal bleeding.

A case of massive rectal hemorrhage from a previously unreported source is presented. Localization of the bleeding site was made angiographically after failure of proctoscopy to demonstrate the lesion. Careful evaluation of the rectal region in patients with massive hemorrhage is indicated.


The effect of colony stimulating factor on the synthesis of ribonucleic acid by mouse bone marrow cells in vitro.

The effect of granulocyte-macrophage colony stimulating factor (GM-CSF) on the synthesis of RNA in liquid cultures of mouse bone marrow, spleen, thymus, peritoneal, peripheral blood leukocytes and lymph node cells was investigated. GM-CSF appeared to stimulate RNA-synthesis in syngeneic bone marrow cells within ten minutes of adding it to the culture. In the presence of GM-CSF bone marrow cultures maintained their initial rate of RNA synthesis for approximately ten hours. GM-CSF had no apparent effect on the uptake of 3H-uridine into bone marrow cells. This stimulation was still observed in the presence of puromycin and cycloheximide, but was abrogated by actinomycin D. The magnitude of the stimulation was not affected by the density of cells between 1 and 20 x 10(6) cells/ml but was slightly smaller at 0.1 and 40 x 10(6) cells/ml. Increasing concentration of GM-CSF (up to 2 X 105 units per ml) led to increased stimulation of RNA synthesis in bone marrow cells, but a significant stimulation could be detected at concentrations as low as 800 units/ml. GM-CSF did not significantly stimulate RNA synthesis in spleen, thymus, mesenteric or subcutaneous lymph node cells. However a small stimulation was observed in peripheral blood leukocytes and peritoneal cells. Autoradiographic studies showed that GM-CSF stimulated RNA synthesis in blast cells, myelocytes, metamyelocytes and polymorphs. Nucleated erythroid cells showed no increased labeling with GM-CFS. Labeling in lymphoid-like cells was highly variable but the level of labeling did not appear to be influenced by GM-CSF.


Comparisons between direct microscopic and cultural methods for recognition of Corynebacterium vaginale in women with vaginitis.

The frequency with which clue cells could be detected in Gram-stained vaginal smears and/or cervical Papanicolaou (Pap) smears was compared with the frequency of Corynebacterium vaginale (Haemophilus vaginalis) isolation in a group of 236 female patients, of whom 221 had vaginitis. Vaginal clue cells were found most often in women from whom C. vaginale was isolated (P = 0.00006) whereas, conversely, clue cells in cervical Pap smears were reported more frequently in women with negative cultures for this organism (P = 0.006). C. vaginale isolations were made more frequently from women with both vaginal and cervical clue cells reported (P = 0.000088). However, the combined false positive-false negative vaginal clue cell rate in the patients studied was 36.5%. Neither the detection of vaginal clue cells nor the isolation of C. vaginale was significantly affected by whether or not patients had trichomoniasis (P = 0.25). Trichomonas vaginalis detection in cervical Pap smears and vaginal isolation were related (P = 0.00005), whereas the same relationship was not significant for fungi (P = greater than 0.05).


New differential medium for the isolation of Corynebacterium vaginale.

A new differential medium for isolation of Corynebacterium vaginale is described. This opaque medium containing 1% corn starch allows detection of C. vaginale by the zones of clearing developing around the colonies.


Etiology of nongonococcal urethritis. Evidence for Chlamydia trachomatis and Ureaplasma urealyticum.

Chlamydia trachomatis, Ureaplasma urealyticum (T-mycoplasma), and Hemophilus vaginalis have previously been considered possible etiological agents in nongonococcal urethritis (NGU). In this study, current C. trachomatis infection was confirmed by culture and (or) micro-immunofluorescence serology in 26 of 69 men experiencing afirst episode of NGU, and 1 of 39 with no urethritis. Serum IgM immunofluorescent antibody to chlamydia was demonstrated in 16 of 20 men with chlamydia culture positive NGU, and 3 of 39 with chlamydia culture negative NG, and none of 34 with no urethritis. 9 of 10 culture positive men with less than or equal to 10 days symptoms developed immunofluorescent antibody seroconversion in paired sera. U. realyticum was isolated significantly more often and in significantly higher concentration from first voided urine from chlamydia-negative cases of NGU than from chlamydia-positive NGU. Ureaplasmacidal antibody titers increased fourfold in six men, four of whom had negative cultures for for unreaplasma. H. vaginalis  was isolated from c9 of 33 men with no urethritis and 2 of 69 with NGU. C. trachomatis is susceptible, and U. urealyticum is resistant to sulfonamides. A 10-day course of sulfisoxazole therapy produced improvement in 13 of 13 chlamydia-positive, unreaplasma-negative, and only 14 of 29 chlamydia-negative, unreaplasma-positive NGU cases (P less than 0.002). Thus, culture, serology, and response to therapy support the etiologic role of chlamydia in NGU. Quantitative culture and response to therapy suggest U. unrealyticum may cause many cases of chlamydia-netative NGU.


Unusual complication of nasogastric esophageal intubation-erosion into an aberrant right subclavian artery.

The case history is presented of a seventeen year old female with a complicated postoperative course following a cesarean section. The patient expired following a massive upper gastrointestinal hemorrhage secondary to erosion of an indwelling nasogastric tube through the esophagus into an aberrant right subclavian artery. Emphasis is placed on an aggressive diagnostic approach to this problem using endoscopy.


Afferents to the optic tectum of the leopard frog: an HRP study.

Following unilateral HRP injections in the optic tectum of Rana pipiens, HRP-positive cells were seen in three pretectal nuclei: bilaterally in the dorsal posterior nucleus; in the dorsal half of the ipsilateral posterior nucleus; and ipsilaterally in the large-called pretectal nucleus. HRP-positive cells were also seen ipsilaterally in the anterodorsal, posterodorsal and posteroventral tegmental fields, the nucleus isthmi, and the dorsal gray columns of the cervical spinal cord; bilaterally in the suprapeduncular nucleus, a paramedian cell group dorsal to the interpeduncular nucleus; and in the deep layers of the contralateral tectum. In addition, evidence for a bilateral ventral preopto-tectal projection was seen in half the experimental animals. No tectal afferents from telencephalic or rostal thalamic areas were seen. Both the ascending and descencing tectal efferent fibers were also filled with reaction product. The pale reaction indicative of terminating tectal efferents was seen in the dorsal pretectum, partially overlapping the lateral nucleus and uncinate neuropil; in the core of nucleus isthmi; and in the superior olive.


Rearrangements of the retinotectal projection in Rana pipiens after unilateral caudal half-tectum ablation.

When the caudal half-tectum is ablated and the optic nerve is cut in adult Rana pipiens, recordings from optic nerve terminals show that the entire visual field comes to be represented in retinotopic order on the remaining rostral half-tectum (compression). In contrast, if the caudal half-tectum is ablated but the optic nerve is left intact, no compression of the retinotectal projection results. Instead, the terminals displaced from the ablated tissue form a permanently disorganized projection to the rostral half-tectum superimposed on the unaltered representation of those parts of the retina which normally project there. The receptive field locations of tectal neurons in both groups of animals show that the altered retinotectal projections make functional synapses. This conclusion is further supported by behavioral data, which show that the accuracy of prey-catching movements is altered in both groups of frogs. The anomalous retinotectal maps can be interpreted by means of a model which includes polarity cues derived from the tectum and ordering cues derived from repelling interactions among fiber terminals.


Effects of reserpine on retention of escape reversal in mice: absence of state-dependent learning.

A discriminated escape training paradigm was used to study the effects of reserpine on learning and memory in mice. Intraperitoneal injection of reserpine before reversal training had no effect on acquisition but did produced a time-and dose-dependent impairment of retention test performance 10 days later. These results suggested that reserpine may have interfered with some aspect of memory storage. Retention impairments observed when a 2.0 mg/kg reserpine injection was given 2 hr before reversal training were not attenuated by readministering the drug before testing, a finding that provides no support for a state-dependency interpretation. Furthermore, animals treated with reserpine exhibited inferior retention of previous training, regardless of the pharmacological state present during that learning. This was interpreted as a drug-induced impairment of memory retrieval. In addition, performance during the initial discriminated escape training session suggested that reserpine may also impair acquisition under some conditions. In the last experiment, it was found that when the catecholamine precursor L-dihydroxyphenylalamine (100 mg/kg) and the indole amine precursor D,L-5-hydroxytryptophan (125 mg/kg) were both given after reserpine treatment, subsequent retention performance was not significantly impaired. The results are discussed in terms of the possible roles of biogenic amines in arousal, learning, and memory.


Characteristics of the immature cells involved in T cell-mediated enhancement of syngeneic tumor growth.

Enhancement of tumor growth was observed when non-sensitized thymocytes were injected together with tumor cells into syngeneic mice, although this tumor enhancement was less pronounced than that caused by tumor-sensitized T lymphocytes. The cells within the thymus which are responsible for this tumor enhancement were found to be rapidly dividing and to be absent from the thymus a day after cortisone administration. At a longer time interval the cortison-depleted thymus was repopulated by dividing cells which exhibited tumor-enhancing reactivity. The characteristics of these cells suggest that they are in the early stages of thymic processing. The enhancing thymocytes were sensitive to treatment with the thymic humoral factor which functions in T cell maturation, and their enhancing activity was cancelled by such treatment. These results are compatible with our hypothesis that exposure of immature T cells to a tumor stimulus may lead to tumor enhancement whereas interaction between mature T lymphocytes and tumor cells may be required for tumor inhibition.


The cutaneous basophil response to phytohemagglutinin in chickens.

A cellular infiltrate rich in basophils was observed in chickens in skin sites injected locally with the mitogen PHA. These infiltrating metachromatically granulated cells exhibited features common to mast cells of some species (monolobed nucleus), but also resembled basophils of other species in that they circulated in the blood, and they responded to the PHA mitogen by infiltrating skin test sites. Previous literature suggests that the chicken has a single metachromatic granulated cell and our data support this notion. PHA, a known T cell mitogen, may act by causing the stimulated T lymphocyte to produce a lymphokine that is responsible for the attraction of basophils to the test site.


Splenic modifications induced by cyclophosphamide in C3H/He, nude, and "B" mice.

The spleen cell population of adult C3H/He mice injected with a single sublethal dose of cyclophosphamide (CY) has been analyzed. An initial phase of spleen atrophy is followed by a considerable hypertrophy, and a progressive return to normal. During the phase of spleen atrophy, both B and T cell compartments are depleted, as estimated by the percentages of cells killed by anti-Thy 1-2 and anti-Ig antisera plus complement. During the stage of regeneration, the percentage of Ig + cells increases rapidly, and at the peak of splenomegaly, the percentage of Ig + cells is high whereas almost no Thy 1-2 + cells are detectable. Progresively, the spleen cell content returns to the original values. In thymo-deprived mice (nude mice and B mice) the percentage of null cells increases during the stage of regeneration, and B mice develop a large number of Ig +-bearing cells. Histologic examination shows that follicles (B-dependent areas) disappear 1 to 2 days before periarteriolar sheaths (T-dependent areas). At the peak of splenomegaly the architecture of the spleen is destroyed, and the interstitial tissue is composed of a dense and uniform layer of lymphoid cells. Progressively, the architecture returns to normal. In nude mice, the disappearance of follicles, and the appearance of a homogenous layer of lymphocytes has been observed. When analyzed for their pattern of electrophoretic mobilities (E.M.), spleen cells from untreated mice reveal two peaks of E.M. 0.80 and 1.15 micron x s-1 x V-1 x cm-1. After CY treatment, during the step of splenic hypertrophy, these two peaks disappear, and a single peak of intermediate mobility appears. In T-deprived mice, a single peak of the same mobility is detected at this stage. The nature and origin of cells which appear during the phase of regeneration are unclear, but their appearance in T-deprived mice argues against thymo dependence. These spleen cells have the ability to suppress the response of normal spleen lymphocytes to T and B cell mitogens.


Evidence that Con A induces cytotoxicity in the same subclass of T cells as does alloimmunization.

We have studied the induction of cytoxic activity in murine T cells by the T cell mitogen Con A. Here we report the results of experiments that indicate that this cytotoxicity develops in the same class of T cells potentially activatable to cytotoxicity by immunization with allogeneic cells. Cytotoxic activity does not result from activation of cells of the T-helper class by PHA, and extensive reduction of the proportion of cells of the T-helper class by in vivo treatment with ATS does not comparably reduce the cytotoxicity developed in response to Con A. The Con A-activated cytotoxic cell sediments as a large cell. Furthermore, spleen cell populations previously immunized to alloantigens in vivo develop greatly increased cytotoxicity specific for the alloantigen of the immunizing haplotype after culture with Con A in vitro.


Purification and properties of human lymphocyte activating factor (LAF).

Lymphocyte-activating factor (LAF) has been shown to be produced by LPS-stimulated human adherent cells (monocytes) and peripheral leukocytes, but many non-macrophage cell lines failed to produce LAF. Other macrophage activators including latex microspheres, antigen-antibody complexes, and barium sulfate induce the production of LAF. There is a delay of 6 hr before significant amounts of LAF activity appear in the supernatant medium and maximum activity is found after 12 to 24 hr. Chromatography of concentrated crude supernatant fractions containing LAF activity on Sephadex G-100 gave two peaks of activity (approximately 85,000 and 13,000 daltons). The latter constitutes the major activity and has been purified at least 500-fold with Sephadex G-100, anion exchange, and adsorption chromatography. Optimal stimulation with LAF induces mitosis in 10% of murine thymocytes. The purified activity is sensitive to chymotrypsin and is not affected by treatment with sodium periodate, sulfhydryl reagents, and phenylmethanesulfonylfluoride. The response of thymocytes to LAF decreases with age after 10 weeks and thymocytes obtained from animals injected with cortisone or tumor-bearing animals have an increased responsiveness to LAF.


Studies on antigen-induced arthritis in mice. II. Immunologic correlates of arthritis susceptibility in mice.

Antigen-induced arthritis was developed in mice as a model of human rheumatoid arthritis by using methylated bovine serum albumin (mBSA) as antigen. It was found that most strains were susceptible, whereas CBA mice were resistant. We therefore investigated the humoral and cell-mediated immune responses to mBSA in resistant mice (CBA) and susceptible mice (exemplified by C57BL) to determine whether these were associated with susceptibility to arthritis. The resistant strain (CBA) differed from the suceptible strains in the following respects. First, there was a lower humoral immune response to mBSA as measured by passive hemagglutination, but this could be overcome by a larger immunogenic dose. Secondly, there were differences in response to low doses of DNP-mBSA after mBSA carrier preimmunization. Thirdly, there were striking differences in delayed-type hypersensitivity (DTH) to mBSA as determined by a radioisotopic assay in vivo; the response of CBA mice occurred early, at 5 days, declined quickly, and was weaker, whereas that of C57BL mice developed later and was long sustained. Genetic studies of the DTH response with hybrids and backcrosses showed an oligogenic control of immune responsiveness, with one gene being linked to the H-2b allele of the susceptible C57BL mice, and another being independent of the H-2 complex. Our findings indicate that in mice, susceptibility to antigen-induced arthritis with mBSA correlates with a higher responder state to this antigen, and that T cells are the major if not the only determinant of the high responder state.


Studies on antigen-induced arthritis in mice. III. Cell and serum transfer experiments.

Antigen-induced arthritis in mice occurs after immunization and subsequent intraarticular challenge with methylated bovine serum albumin (mBSA). In adoptive transfer experiments, susceptible C57BL mice and resistant CBA mice were compared in their capacity to express delayed-type hypersensitivity (DTH) by ear assay, and to express arthritis. The expression of DTH could be transferred incrementally by lymphoid cells in C57BL mice, but not in CBA mice. Both immune lymphoid cells and, to a much lesser extent, serum transferred the capacity to develop arthritis in C57BL mice. The reactivity of transferred cells was abolished by anti-Thy-1 but enhanced by enrichment for T cells with anti-immunoglobulin columns. If this model disease can be equated with human rheumatoid synovitis, the lesions in the human disease would be an expression of a T cell-dependent activity.


Inability of choleragenoid-sensitized cells to induce T cell-mediated cytolysis.

Murine splenocytes and tumor cells bind cholera enterotoxoid (choleragenoid). Four hours after sensitization, choleragenoid-coated cells were lysed in the presence of anti-cholergenoid serum and complement, indicating that the binding was stable. Choleragenoid-coated cells were unable to sensitize spleen cells from normal or choleragenoid primed syngeneic mice into displaying a cytotoxic effect against choleragenoid-coated target cells in the T cell-mediated cytotoxicity assay. Cells coated with both choleragenoid and trinitrophenyl (TNP) groups did sensitize syngeneic spleen cells to display a cytotoxic effect against target cells bearing choleragenoid and TNP or TNP alone, but not choleragenoid alone. These data demonstrate that the mere binding of a foreign component to lymphoid cells is not sufficient to allow sensitization of cytotoxic T cells.


Studies on the role of the thymus and T cells in the in vivo suppression of delayed hypersensitivity (desensitization): radiosensitivity of the mechanism inducing nonspecific anergy.

Guinea pigs immunized with two or more antigens can have their ability to manifest delayed hypersensitivity (DH) reactions to all these antigens temporarily blocked by the administration of large (mg) amounts of one or more of these antigens 9 days after immunization. This nonspecific anergy is called desensitization. This study presents evidence for the induction of the desensitized state by an active, radiosensitive, immunoregulatory mechanism involving the peripheralization of thymocytes. Desensitization was associated with 1) a marked reduction in thymic weight; 2) an increase in mature T cells in the peripheral blood; 3) decreased responsiveness of the lymphocytes in the spleen to concanavalin-A; and 4) markedly reduced numbers of mono-nuclear cells, basophils, and polymorphs at the skin sites of specific and nonspecific desensitization. Small doses of whole-body irradiation which left DH capacity intact prevented nonspecific desensitization, but did not prevent specific desensitization, suggesting that a radiosensitive cell was involved in the production of anergy.


The role of the macrophage as the stimulator cell in contact sensitivity.

In this study we examined the requirement for the type of stimulator cell for thymus-derived (T) lymphocyte activation to simple chemical haptens. T cells from picryl chloride-immune guinea pigs were challenged in vitro with various trinitrophenyl (TNP)-conjugated syngeneic stimulator cells and the extent of activation was determined by an increase in DNA synthesis. Hapten-specific T cell activation occurred with TNP-conjugated peritoneal exudate cells (PEC) and purified macrophages but not with TNP-conjugated erythrocytes, thymocytes, or nonadherent lymph node cells or PEC. In addition, T cell activation also occurred with TNP-conjugated guinea pig leukemia cells, but only in the presence of macrophages. Furthermore, it was shown that macrophages were required to process and/or present TNP-conjugated leukemia cell antigens rather than simply providing a growth-promoting function. These results suggest that a macrophage-like stimulator cell is required for hapten-specific T cell activation and that this particular stimulator cell may be important in contact sensitivity.


Specific binding of T lymphocytes to macrophages. I. Kinetics of binding.

Peritoneal exudate lymphocytes obtained from immune guinea pigs and cultured for 1 week on antigen-pulsed autologous macrophages were tested for their ability to bind to fresh antigen-pulsed autologous macrophages or to macrophages pulsed with an irrelevant antigen. Up to 30% of the lymphocytes bound to macrophages bearing the relevant antigen whereas only 2 to 5% remained nonspecifically bound to macrophages after vigorous washing. Specific binding was observed in cultures as early as 1 hr. Analysis of the kinetics of binding suggests that the observed nonspecific binding is not a step in specific binding. The possibility that weaker antigen-independent association between lymphocytes and macrophages precedes specific binding cannot be excluded. No evidence was obtained that serum antibody adsorbed to the macrophage or T cell plays a role in this cell interaction or that the T cell can bind antigen directly. We suggest that the observed specific binding represents the initial event in stimulation of T lymphocytes by antigen.


Sequential proliferation induced in human peripheral blood lymphocytes by mitogen. I. Growth of 1000 lymphocytes in feeder layer cultures.

A culture system is described in which 1000 human peripheral blood lymphocytes diluted in 2.5 x 10(5) mitomycin-treated autologous cells respond to phytohemagglutinin (PHA). Proliferation data, including 3HTdR uptake, cell survival counts, and mitotic indices, indicate that this inoculum expands from 1000 to 40,000 cells by day 7, suggesting five or six sequential cell divisions. Chromosome markers in allogeneic cultures demonstrate that the dividing cells are derived from the original 1000 cells and not from the "feeder layer" of mitomycin-treated lymphocytes. The time course of proliferation in this system is similar to that in other human lymphocyte culture systems with a low percentage of responding cells, as in the response to PHA of cells from patients with chronic lymphocytic leukemia or the response of normal lymphocytes to antigens. The conditions provided by the feeder layer which permit proliferation of this small number of lymphocytes are not precisely known, but erythrocytes, heat-killed lymphocytes, or inert particles do not provide a satisfactory substitute.


Pathogenesis of experimental allergic orchitis. III. T lymphocyte requirement in local adoptive transfer by peritoneal exudate cells.

In experimental allergic orchitis (EAO), a lesion characterized by mononuclear invasion of seminiferous tubules can be adoptively transferred within 1 to 4 days by testicular injection of peritoneal exudate cells (PEC) from syngeneic strain 13 guinea pigs (GP) immunized with homologous testicular antigens in complete Freund's adjuvant (CFA). This study examined the role of T lymphocytes, macrophages, and polymorphonuclear neutrophils (PMN) in the adoptive transfer. Guinea pig PEC contained 7% T lymphocytes, rare B lymphocytes, and over 90% of macrophages and PMN. After T lymphocytes were depleted by rabbit erythrocyte (E) rosette and Hypaque-Ficoll gradient centrifugation, cell preparations that contained 73% of original macrophages and 15% original T lymphocytes were obtained, and these cells did not transfer EAO (0 of 18 testes). In contrast, cell preparations enriched in T lymphocytes by nylon wool column or E rosette contained 1.5% of the original macrophages and 59% of the original T lymphocytes transferred EAO to 70% of the testes, starting at 1.5 x 10(6) T lymphocytes per testis. The number of T lymphocytes correlated with the incidence of adoptive transfer; the correlation existed regardless of the number of macrophages or PMN present. Finally, EAO was adoptively transferred to recipients that had total-body irradiation. The results indicate that (a) T lymphocytes are capable of transferring lesions of EAO, (b) in the transfer, the T lymphocytes did not function as helper T cells, since the transfer need not involve participation of host lymphoid cells, and (c) by inference, testis antigen-reactive T lymphocytes exist.


Potentiation of experimental meningitis due to Haemophilus influenzae by influenza A virus.

When Haemophilus influenzae type b was given intranasally to infant rats, a very large dose was required to produce histologic evidence of meningitis in even half of the animals tested; meningitis developed in 16 of 31 rats that received 10(7) viable bacteria at the age of five days. However, when the animals first received influenza virus, the dose of bacteria required to produce meningitis was reduced 100-fold; meningitis occurred in 10 of 21 rats given virus at two days and 10(5) viable bacteria at five days. These results suggest that prior viral infection of the upper respiratory tract may be a factor in the pathogenesis of haemophilus meningitis.


Cell-mediated immune responses in humans after induced infection with influenza A virus.

Cell-mediated immune responses were examined in 19 normal volunteers after intranasal administration of three strains of influenza A virus. Eight volunteers manifested respiratory tract illness along with fourfold rises of serum antibody and/or virus shedding. Samples of peripheral venous blood were obtained before and two days, five days, and four weeks after challenge. During acute illness, infected volunteers showed lymphopenia, which persisted for up to four weeks after challenge. The lymphopenia involved thymus-derived, bone marrow-derived, and null cells. Blastogenic responses of lymphocytes to stimulation with phytohemagglutinin, concanavalin A, and streptokinase-streptodornase were depressed during acute illness, and responses to phytohemagglutinin and concanavalin A remained depressed at four weeks after infection. Thus, influenza infection in humans can result in prolonged depression of numbers and functions of circulating lymphocytes.


Fertilization of immature frog eggs: cleavage and development following subsequent activation.

Frog eggs are normally fertilized after reaching metaphase II. When eggs are inseminated prior to that, several sperm enter, but entry does not activate the egg. When such inseminated, immature eggs were maintained until they became mature and then were artificially activated, the eggs began to cleave. The cleavage furrows were irregular and often multiple, but the eggs developed to blastulae or partial blastulae. About 2 leads to 5% of the eggs developed to tadpoles. Typical asters were not associated with the entering sperm; rather, asters appeared only after activation. The sperm nucleus often formed chromosomes which were attached to small spindles. It is clear that sperm which remain for a time in unactivated egg cytoplasm, retain their ability to promote cleavage and development. Aster formation required not only sperm centrioles but also activated egg cytoplasm. Sperm which entered either near the equator or in the animal half of mature eggs usually produced normal cleavage furrows. Sperm which entered the animal half of immature eggs produced multiple animal half furrows when the egg was subsequently activated. In contrast, sperm which entered near the equator of immature eggs often failed to induce furrowing on subsequent activation or produced unusual equatorial furrows. The difference in the type of furrow between eggs inseminated in the animal half or at the equator is interpreted as a consequence of dissociating sperm entry from the cortical contraction which occurs in activation.


Quantitive studies of the reactions to horizontal angular accelerations in axolotls. II. head-turning reflexes in animals with a supernumerary pair of labyrinths.

In axolotls (Ambystoma mexicanun) the labyrinths and the associated parts of the medulla were doubled artificially. In these so-called tandem-heads the vestibular afferent fibres from both labyrinths on one side united within the medulla to form common bundles. The head-turning reflexes following impulse acceleration and during long-lasting acceleration were measured quantitatively and compared with those for normal animals. The form and the time-course of the reactions were almost identical in both groups. Tandem-heads showed a linear relationship between stimulus intensity and reaction strength, parallel to that in normal animals but with a greater reaction for a given stimulus. Consequent to this shift in the relationship, there was a significant decrease in the reaction threshold. The removal of one horizontal semicircular canal in tandem-heads proved that both pairs of labyrinths were functionally connected with the brain. It was suggested that during ontogenesis there exists a kind of specificity in the connexion of vestibular fibres. From the parallel shift of the intensity functions it was concluded that the input from both pairs of labyrinths in tandem-heads is not simply accumulate but compared with a reference parameter, which is also double in tandem-heads.


H-2 restriction of suppressor T-cell induction by hapten-modified lymphoid cells in tolerance to 1-fluoro-2,4-dinitrobenzene contact sensitization.

Studies using hapten-modified lymphoid cells as tolerogens for 1-fluoro-2,4-dinitrobenzene contact sensitization have shown that BALB/c(H-2d) mice can be made phenotypically tolerant by dinitrophenyl (DNP) on either syngeneic or allogeneic mouse lymphoid cells (DNP-LC). However, suppressor T-cell induction (Ts) in these mice (as demonstrated by adoptive transfer to syngeneic recipients) was restricted to H-2 identity between the DNP-LC and the donor mouse. It was also shown that identity at the right end of the H-2 complex was sufficient for Ts induction. In addition, this restriction was also demostrated in CBA (H-2 K) mice and for tolerance in the 1-chloro-2,4,6-trinitrobenzene contact sensitivity system using trinitrophenyl-modified lymphoid cells.


Secondary in vitro responses of T lymphocytes to non-H-2 alloantigens self-H-2-restricted responses induced in heterologous serum are not dependent on primary-stimulating non-H-2 alloantigens.

The role of non-H-2 alloantigens, specifically Mls locus products, in secondary in vitro T-cell-mediated cytotoxicity has been studied. Splenic T lymphocytes, activated against Mls locus alloantigens in primary-mixed cultures and isolated by velocity sedimentation gradient separation techniques, were used as responding populations in secondary mixed leukocyte cultures (MLCs) and cell-mediated lympholysis (CML). Such T-cell clones could be shown to exhibit either "self"-H-2-restricted or anti-Mls locus-specific reactivity, with this dichotomy of reactivity depending only on the primary culture conditions. Mls locus-activated T lymphocytes generated in cultures supplemented with homologous serum exhibited specific memory responses in MLC, yet remained incapable of effecting target cell destruction against Mls locus antigens or against "self"-H-2-structures in CML. In contrast, activated T-cell clones generated in the presence of heterologous serum displayed H-2-restricted reactivity in both secondary MLC and CML. H-2-restricted MLC activation was controlled by products of the H-2 serologically defined regions. Although heterologous serum was a necessary (and sufficient) entity for development of H-2-restricted responses, evidence argues against the possibility that heterologous serum acts via modification of cell surface components.


Immunosuppressive factor(s) extracted from lymphoid cells of nonresponder mice primed with L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) II. Cellular source and effect on responder and nonresponder mice.

The synthetic terpolymer of L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) fails to stimulate development of GAT-specific antibody responses in nonresponder strains of mice, but does stimulate the development of GAT-specific suppressor T cells that inhibit the development of normal anti-GAT antibody responses to GAT complexed to methylated bovine serum albumin (GAT-MBSA). Furthermore, extracts prepared from lymphoid cells of GAT-primed, but not control, nonresponder mice inhibit the development of antibody responses to GAT-MBSA by normal nonresponder mice. This suppression is specific, dose-dependent, and can be readily analyzed in vitro. The suppressive factor is a T-cell product. An extract from GAT-primed DBA/1 mice inhibits the response to GAT-MBSA by spleen cells from histoincompatible strains of mice that are nonresponders to GAT, but not strains that are responders to GAT.


Mesenteric lymph node B lymphoblasts which home to the small intestine are precommitted to IgA synthesis.

The fate of mesenteric lymph node lymphoblasts labeled with either [125I]iododeoxyuridine or [3H]thymidine can be studied after intravenous transfer into syngeneic mice both by measurement of radioactivity in various organs and by combined immunofluorescence and autoradiography of recipient tissues. Many of the lymphoblasts home to the lamina propria of the small intestine within hours of transfer; of these, many visibly secrete IgA. To determine whether the cells that will ultimately secrete IgA are already committed to IgA synthesis before their arrival in the gut, mesenteric lymph node cell populations were treated with various class-specific antisera to mouse immunoglobulins before transfer. Treatment with antiserum to IgA, plus complement, reduced the fraction of injected label recovered from the recipients' intestines, and also reduced the proportion of donor (labeled) cells containing IgA. We conclude that mesenteric lymph nodes are probably the principal source of IgA-secreting plasma cells in the lamina propria of the gut, and that the cells become committed to IgA synthesis and develop cell surface IgA before emigrating. This IgA is apparently synthesized by the cells that bear it since it is not removed by extensive rinsing at 37 degrees C, a maneuver that elutes passively adsorbed immunoglobulin.


Nature of the antigenic complex recognized by T lymphocytes II. T-cell activation by direct modification of macrophage histocompatibility antigens.

In order to analyze the molecular structures involved in T-cell recognition we developed an in vitro primary response against alloantisera bound to histocompatibility antigens in which nonimmune guinea pig T cells can be sensitized and subsequently challenged in tissue culture with antisera-treated macrophages. If macrophages were incubated with alloantisera directed against the I-region-associated (Ia) antigens of the guinea pig major histocompatibility complex (MHC) T cells could be sensitized to the antisera bound to macrophage Ia determinants. Anti-Ia-treated syngeneic macrophages in the first and second cultures elicited specific T-cell activation, as measured by increased DNA synthesis, to the antisera-induced immunogenic determinants. Similarly, antiIa-treated allogeneic macrophages also specifically stimulated T cells to antisera bound to allogeneic Ia determinants while reducing the mixed leukocyte reaction. Antisera to the B.1 antigens of the guinea pig MHC, the homologue of the mouse H-2K or H-2D antigens, also elicited specific T-cell activation that did not cross-react with that produced by the anti-Ia alloantisera. Furthermore, the anti-B.1-induced stimulation appeared to be associated with the Ia antigens of the macrophage used for priming since (2 x 13)F1 T cells sensitized with anti-B.1-treated parental macrophages could be restimulated only with the parental macrophage used for initial sensitization, and not with those of the other parent. Since the parental strain 2 and strain 13 guinea pigs express serologically identical B.1 antigens and differ only by Ia antigens of the MHC, this observation suggests that both B.1 and Ia antigens may be included in the immunogenic complex recognized by T cells. However, we cannot rule out the possibility that this restriction is due to other genetic differences between strain 2 and strain 13 guinea pigs that is unrelated to the I-region. We interpret these findings as showing that macrophage Ia antigens may serve to directly present antigens bound to the Ia molecule, and possibly indirectly aid in the presentation of antigens bound to other membrane components, such as the B.1 antigens.


Mechanisms of suppression of cytotoxic T-cell responses in murine lymphocytic choriomeningitis virus infection.

The cytotoxic T-cell response to lymphocytic choriomeningitis (LCM) virus infection was suppressed either in vitro or in vivo by addition of a high level of syngeneic virus-infected cells or syngeneic cells from congenital LCM virus carriers to the environment of the responding cells. This effect was not duplicated by formaldehyde-fixed carrier cells, nor could it be accounted for by 'cold' target competition by carrier cells at the level of the cytotoxicity assay. Conversely, suppression was produced in vivo by water-lysed, ultrasonically treated carrier cell suspensions, or by a large dose of LCM virus equivalent to that contained in the carrier cells. Thus a high level of infectious virus was a common factor in all observed examples of suppression. Based upon this, the following hypothesis, a form of 'forbidden clone deletion,' was proposed to account for virus-specific cytotoxic T-cell tolerance in LCM virus congenital carriers, or in high dose suppression. A high level of virus in lymphoid tissues, while not cytopathic per se, may result in infection of all or most T cells; this then may lead to deletion either via 'suicide' of individual, infected, cytotoxic T cells with receptors specific for virus-induced antigenic patterns on their own surface membranes, or by mutual lysis of two adjacent T cells.


Immunological studies of Aging. III. Cytokinetic basis for the impaired response of lymphocytes from aged humans to plant lectins.

The basis for the age-associated defect in the response of lymphocytes to plant lectins has been studied. Using three independent assays we have shown that the number of mitogen-responsive cells is markedly reduced in lymphocyte preparations from old persons. In addition, studies using colchicine bloock and thymidine pulse techniques have revealed a failure of mitogen-responsive cells from old persons to expand into a proliferating pool of lymphocytes as is observed when lymphocytes from young persons are cultured with phytohemagglutinin. Thus, the impaired response of lymphocytes from old persons to mitogens is attributable to a reduced number of mitogen responsive cells and their failure to undergo clonal expansion.


Helper T cells are required for the polyclonal stimulation of cytotoxic T cells by concanavalin A.

Concanavalin A stimulation of T-cell cytotoxicity has been shown to be absolutely dependent on helper T-cell collaboration. Thymocytes stimulated with ConA do not differentiate to yield cytotoxic effector cells. However, thymocytes cocultured with irradiated spleen cells as helpers and ConA yield high levels of cytotoxicity. The helper cell bears theta antigens on its surface, is not an adherent cell, and does not require any adherent cell functions in our culture conditions. The ConA-dependent helper cells appear to be polyclonal in specificity. Thus, polyclonal stimulation of cytotoxicity by ConA requires T helper-T precursor collaboration in analogy to antigen-specific T helper-T precursor interactions. Unlike the antigen-specific interacitons, the ConA-driven cytotoxicity does not appear to require linked associative recognition for induction of cytotoxicity.


Regulation of B-cell proliferative responses to lipopolysaccharide by a subclass of thymus T cells.

When thymus cells which are unresponsive to LPS are combined with numbers of peripheral lymphoid cells giving minimal responses to LPS, synergistic incorporation of [3H]thymidine occurs. Synergy requires that both components proliferate, but most of the augmented response is the result of peripheral cell proliferation. The thymus cell is a T cell of variable density, low in thy-1.2 antigen, not concanavalin A responsive, present in the major thymus subpopulation, and may be from lipopolysaccharide (LPS)-unresponsive strains. The peripheral cell is sensitive to anti-IgG or IgM plus complement (C'), resistant to anti-Thy-1.2 and C', exhibits adherence properties of B lymphocytes, and must be from LPS-responsive strains. Synergistic responses depend on critical thymus/peripheral cell ratios, inhibition occurring at high peripheral cell numbers. The data provide evidence that B-cell proliferative responses to LPS may be regulated by a subclass of thymus T cells.


Receptors for IgG: subclass specificity of receptors on different mouse cell types and the definition of two distinct receptors on a macrophage cell line.

To evaluate subclass specificity and aggregate size requirements of IgG receptors on mouse cells, we measured binding of radiolabeled monomeric and BDB-aggregated mouse myeloma proteins fractionated into various sizes by means of gel filtration. Monomers, tetramers, and high molecular weight (approximately 10(7) daltons) aggregates were used. The various cells and cell lines studied could be segregated into three patterns of reactivity: (a) Macrophage and macrophage-like cell lines bound monomer IgG2a preferentially; high molecular weight IgG aggregates bound as follows: IgG1 = IgG2b = IgG2a. (b) Lymphoid lines D2N and S49 showed no capacity to bind monomer IgG2a; high molecular weight aggregates bound as follows: IgG1 = IgG2b less than IgG2a. (c) Other Thy-1-positive lymphoid cell lines (EL4 and L5178) and normal T and B cells showed no capacity to bind monomer IgG; high molecular weight IgG aggregates bound to a lesser extent than to cells of the first two categories in the following manner: IgG1 less than IgG2b greater than or equal to IgG2a. The variable pattern of reactivity of the macrophage-like cell lines with monomer and aggregated IgG suggested that two distinct receptors for IgG were present: one capable of binding IgG2a and another capable of binding all aggregates. Further evidence for this hypothesis was obtained by analysis of the inhibitory capacity of different IgG subclasses on the binding of aggregated IgG and monomer IgG2a to P388 cells. Inhibition of monomer IgG2a binding was effected only by monomer or aggregated IgG2a, whereas inhibition of binding of aggregated IgG1 or IgG2b was noted with aggregates of all three subclasses with some preferential inhibition by monomer IgG2b being observed. Furthermore, monomer IgG2b binding was preferentially inhibitable by monomer IgG2b. It is postulated from these data that two receptor sites are present on this macrophage-like cell line, one reactive with aggregates of all three subclasses as well as monomer IgG2b, and another receptor specific for monomer IgG2a which also binds aggregated IgG2a. Support of this concept was obtained by trypsinization experiments in which the binding of monomer IgG2a was markedly decreased by trypsin treatment of cells, whereas the binding of aggregated IgG2b was unaffected by this treatment.


Transfer of experimental allergic encephalomyelitis in Lewis rats using supernates of incubated sensitized lymph node cells.

Supernates derived from incubated lymph node cells of Lewis rats sensitized to guinea pig spinal cord-Freund's adjuvant transfer experimental allergic encephalomyelitis (EAE) to syngeneic recipients. EAE supernatant transfer activity (EAE-STA) is not demonstrable in supernates derived from LNC of control donors not sensitized to nervous tissue. After addition of brain antigen to active supernates, EAE-STA is not longer demonstrable.


Desensitization and recovery at the frog neuromuscular junction.

The time course of carbachol-induced desensitization onset and recovery of sensitivity after desenitization have been compared at the frog neuromuscular junction. The activation-desensitization sequence was determined from input conductance measurements using potassium-depolarized muscle preparations. Both desensitization onset and recovery from desensitization could be adequately described by single time constant expressions, with tauonset being considerably shorter than taurecovery. In nine experiments, tauonset was 13+/-1.3 s and taurecovery was 424+/-51 s with 1 mM carbachol. Elevating the external calcium or carbachol concentration accelerated desensitization onset without changing the recovery of sensitivity after equilibrium desensitization. Desensitization onset was accelerated by a prior activation-desensitization sequence to an extent determined by the recovery interval that followed the initial carbachol application. The time course of return of tauonset was closely parallel to, but slower than the time course of recovery of sensitivity. These results are consistent with a cyclic model in which intracellular calcium is a factor controlling the rate of development of desensitization.


Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction.

The properties of Na channels of the node of Ranvier are altered by neutral, amine, and quaternary local anesthetic compounds. The kinetics of the Na currents are governed by a composite of voltage- and time-dependent gating processes with voltage- and time-dependent block of channels by drug. Conventional measurements of steady-state sodium inactivation by use of 50-ms prepulses show a large negative voltage shift of the inactivation curve with neutral benzocaine and with some ionizable amines like lidocaine and tetracaine, but no shift is seen with quaternary OX-572. However, when the experiment is done with repetitive application of a prepulse-testpulse waveform, a shift with the quaternary cations (applied internally) is seen as well. 1-min hyperpolarizations of lidocaine- or tetracaine-treated fibers restore two to four times as many channels to the conducting pool as 50-ms hyperpolarizations. Raising the external Ca++ concentration also has a strong unblocking effect. These manipulations do not relieve block in fibers treated with internal quaternary drugs. The results are interpreted in terms of a single receptor in Na channels for the different drug types. Lipid-soluble drug forms are thought to come and go from the receptor via a hydrophobic region of the membrane, while charged and less lipid-soluble forms pass via a hydrophilic region (the inner channel mouth). The hydrophilic pathway is open only when the gates of the channel are open. Any drug form in the channel increases the probability of closing the inactivation gate which, in effect, is equivalent to a negative shift of the voltage dependence of inactivation.


Regional differences of respiration in the bullfrog brain based on cell density.

The comparison of analogous and homologous regions of the anuran and mammalian brains, according to their rate of oxygen uptake per unit weight of DNA, has revealed a lack of correspondence between the respective brain regions. This discrepancy between corresponding regions was observed during incubation either in low-potassium or in high-potassium Ringer. Per unit weight of DNA, the rate of cellular respiration in the amphibian hindbrain exceeded that of the thalamus-midbrain, and cells in the latter region exceeded those in the telencephalon. Hindbrain values were only higher if based on unit weight of DNA, and were actually lower on a wet weight basis. This pattern contrasted with a uniform rate of oxygen consumption for the homologous regions of the mammalian brain. Such inequalities between the regional brain metabolism of two different classes of vertebrates clearly illustrate the unique evolutionary history of both forms. The intensity of potassium-stimulated oxygen uptake in the three brain regions of the amphibian was interpreted as probably being proportional to the number of glial cells in each area. The smallest percentage of stimulation in the hindbrain may signify fewer glia, and the highest percentage of stimulation in the mid- and forebrain may indicate more numerous glia. Histological descriptions of ependymal glia in consecutive regions of the anuran brain appear to confirm this distribution of non-neuronal cells.


Permeability of the endplate membrane activated by acetylcholine to some organic cations.

The ability of various organic cations to depolarize the ACh-activated endplate membrane in the absence of Na ions was examined on frog sartorius muscle by measuring the endplate potential on the muscle surface with the moving electrode technique. The ACh-activated endplate membrane was very permeable to ammonium and its methyl and hydroxy derivatives, and moderately permeable to guanidine derivatives and Tris (hydroxymethyl) aminomethane. The permeability of alkylol derivatives of ammonium diminished progressively with increase in molecular size. The present results suggested that the endplate ionic channels can be represented by a pore of about 6.4 A in diameter.


Family in which Duchenne's muscular dystrophy and protan colour blindness are segregating.

A family is recorded in which Duchenne's muscular dystrophy and protan colour blindness are segregating. Of 4 members of the second generation at least one is a recombinant. The lod scores have been calculated and added to those already published.


Mixed connective tissue disease in childhood. A clinical and serologic survey.

Mixed connective tissue disease is a syndrome with overlapping clinical features of SLE, scleroderma, and polymyositis. Only one other child with MCTD has been described in detail. In this study 14 children with MCTD are described. Each had overlapping clinical findings that evolved over an extended period of observation, and all 14 had high serum titers of speckled ANA and antibodies to RNP. A serologic survey of 127 children with various rheumatic diseases confirmed the specificity of high titer of speckled ANA and antibodies to RNP for MCTD in children. Significant cardiac and renal involvement, and thrombocytopenia, may be more common in affected children than in adults with MCTD, may lead to longer therapy with higher doses of a corticosteroid, and may contribute to a more serious prognosis than in adults.


Acute respiratory illness in children with acute lymphoblastic leukemia.

Ten of 70 children (14%) with acute lymphoblastic leukemia developed severe interstitial pneumonitis within three weeks after induction of central nervous system prophylactic therapy. The clinical picture was characterized by fever, cough, progressive dyspnea, and hypoxemia with complete resolution in one to three weeks, except in one patient who died during the acute illness from respiratory failure. P. carinii organisms were found in the lung tissue of only one patient. The etiology of the pneumonitis in the other nine children was probably viral, acquired or activated during a period of lymphopenia and immunosuppression. The morbidity and potential mortality from the pneumonitis warrants early recognition by open lung biopsy and intensive supportive therapy.


Fenbufen, a new anti-inflammatory analgesic: synthesis and structure-activity relationships of analogs.

One hundred analogs of fenbufen were prepared and tested using the carrageenan, polyarthritis, and UV erythema anti-inflammatory tests and the 2-phenyl-1,4-benzoquinone writhing and inflamed paw pressure analgesic tests. Only three retained the same full spectrum of activity as fenbufen: dl-4-(4-biphenylyl)-4-hydroxybutyric acid, dl-4-(4-biphenylyl)-1,4-butanediol, and 4-biphenylacetic acid. Fenbufen had the same spectrum of activity as aspirin, phenylbutazone, and indomethacin in the five tests. In addition, dose-response derived potencies show fenbufen more potent than aspirin and at least as potent as phenylbutazone in all five tests. Two related compounds were generally similar.


Conduction-blocking concentrations of anesthetics increase with nerve axon diameter: studies with alcohol, lidocaine and tetrodotoxin on single myelinated fibers.

The equilibrium blocking concentrations of benzyl alcohol, lidocaine and tetrodotoxin just sufficient to block nerve impulse conduction were determined on myelinated single fibers of the bullfrog. For all three anesthetics it was found that the fastest conducting fibers (45 m/sec; about 18 micron diameter) required about 4 times higher blocking concentrations than the slowest fibers (8 m/sec; about 3 micron diameter). The drugs did not affect the frog sciatic nerve length constant (2 mm), using tetrodotoxin to block the action potential. In agreement with Uehara's single fiber study using urethane (Uehara, Y.:Jap. J. Physiol. 10: 267-274, 1960), it is concluded that smaller myelinated fibers are more sensitive to anesthetic blockade.


Slow bleach-induced birefringence changes in rod outer segments.

1. Time resolved birefringence measurements reveal complex structural changes in rod outer segments following a bleaching flash. 2. The detailed character of the observed changes depends upon osmotic integrity of the outer segment envelope membrane. Rod outer segments with intact envelope membranes show a fast initial loss of intrinsic birefringence simultaneous with the formation of metarhodopsin II followed by a slower secondary loss. A subsequent birefringence increase to higher than the dark-adapted level is partially correlated with the formation of retinol. Rod outer segments with ruptured envelope membranes show the initial and secondary losses, but the subsequent recovery only reaches the dark-adapted level. Retinol does not form in such organelles. 3. The slow birefringence changes in intact rod outer segments were qualitatively different when Na+ salts were replaced by equimolar K+ salts in the bathing medium. 4. Glycerol appears to influence both the rate and magnitude of metarhodopsin III formation, and of the spectrally silent secondary birefringence loss.


Background adaptation in the rods of the frog's retina.

1. Aspartate-isolated photoresponses of the red rods to flashes and steps of light have been recorded, both in the presence of and without background lights of varying strength. 2. The results are interpreted in terms of a model of rod outer segment adaptation, where the three model parameters correspond to the adaptation processes associated with the transmitter release, the transmitter background concentration and the plasma membrane leakage, respectively. 3. The stimulus-response function deviated somewhat from the Michaelis equation U/Umax=I/(I + IH). During light-adaptation the operating curve, the stimulus-response function plotted in a log-log diagram, retained approximately its shape while moving strongly to the right along the log intensity axis and to a lesser degree downwards (Umax-decrease). 4. The movement of the operating curve was such that the rods approximately obeyed Weber's law. In the cases of flash and step of light stimuli the movement of the operating curve was about the same. 5. When a moderate background light was turned on a large decrease of sensitivity was first observed. During a period 0-5-1 min the sensitivity increased towards the stationary value. After extinguishing the background light the dark sensitivity returned in 0-5-1 min and then a period of hypersensitivity lasting typically 1 min was observed. 6. The experimental results, as interpreted according to the model, indicate that light-adaptation decreases q, the number of transmitter molecules released by one bleached rhodopsin molecule. 7. There is probably an adaptation process also in the rod inner segment, which increases the sensitivty of the rod to transient stimuli.


Specific patterns of neuronal connexions involved in the control of the rabbit's vestibulo-ocular reflexes by the cerebellar flocculus.

1. In anaesthetized albino rabbits, the occurrence of Purkinje cell inhibition on canal-ocular reflexes was surveyed with a reflex testing method. 2. Test reflexes were elicited by electrical stimulation of the semicircular canals. The results were appaised by recording potentials and tension from extraocular muscles. Twelve reflexes were defined in terms of the receptor canal and the effector muscle. 3. Conditioning electrical stimuli were applied to the flocculus, the inferior olive, and optic pathways at the retinae, optic chiasm, pretectal area and upper medulla. 4. The conditioning stimulation at the ipsilateral flocculus induced depression in six of the twelve canal-ocular reflexes; four of the six arose from the anterior canal and the remaining two from the horizontal canal. 5. The effect of stimulation of the contralateral inferior olive was similar to that of the ipsilateral flocculus, though less clear in two of the four reflexes from the anterior canal because of a contaminating effect. 6. The two reflexes from the horizontal canal were depressed by stimulation of the ipsilateral optic pathway which reached the ipsilateral flocculus via the contralateral pretectal area and inferior olive. 7. The four reflexes from the anterior canal were affected by stimulation of optic pathways in a different manner from each other. One was depressed from the contralateral retina via the ipsilateral pretectal area, while another was depressed from the ipsilateral retina via the contralateral pretectal area, though only occasionally. The third reflex was depressed from the ipsilateral pretectal area but not from the retina. The fourth was affected from neither the retina nor the pretectal area. 8. On the basis of latency measurements, it was concluded that the depression of canal-ocular reflexes was due to inhibition of relay neurones of the testing reflexes by flocculus Purkinje cells which were activated either directly, or indirectly through olivocerebellar climbing fibre afferents. 9. The above conclusion was supported by the observation that the depression induced by stimulation of the inferior olive and optic pathways was abolished by acute destruction of the ipsilateral flocculus. 10. The possible functional significance of the specific patterns of connexions from flocculus Purkinje cells to canal-ocular reflex pathways is discussed, and specialization among flocculus Purkinje cells in relationship with vestibulo-ocular reflexes is postulated.


[An intramural hematoma of the small intestine, during anticoagulant therapy: radiological course. Concerning one case].

The authors present a case of intramural hematoma of the small intestines during anticoagulant treatment. With reference to this case, they study the frequency, etiopathogenesis and anatomy of this hematoma and particularly look at the radiological manifestations. In this respect they distinguish three stages in the evolution. The first, when the straight X-ray of the abdomen and barium followthrough demonstrate an axial stenosis of the small intestines with dilation of the proximal loops; the second (between the 7th and 20th days) when the loop affected by the hematoma takes on a characteristic "palissade" or "spring" -like sausage appearance; finally the third (after the 3rd week), when only thickening of the haustrations persists with progressive return to normal. The radiological diagnosis is discussed, not only with intramural hematomas of the small intestines of other etiologies (traumatic, during pancreatitis, during disorders in hemostatis), but also with conditions giving rise to similar radiological pictures: malabsorption, inflammatory conditions, etc.


Childhood lymphoblastic cancer: subgroups defined by nonhuman primate antisera to human lymphatic leukemia cell antigens.

Lymphoblasts from 23 children with acute lymphocytic leukemia (ALL) and 10 with lymphoblastic lymphoma (LBL) were studied by complement-dependent microcytoxicity tests with two nonhuman primate antisera defining leukemia-associated and lymphoma-associated antigens. Cells form 15 patients with ALL and 1 with LBL reacted only with antiserum to chronic lymphatic leukemia (CLL). These group-I patients were predominantly female. Most were pancytopenic and lacked mediastinal widening and T-cell markers; lymphoblasts from 15 were periodic acid-Schiff-positive. Cells from 8 male patients reacted only with antiserum to converted lymphosarcoma (LS). All these group-II patients expressed T-cell markers; 5 had mediastinal enlargement and 2, an abdominal mass. Six of the 8 were PAS-negative. Cells from 9 patients reacted with both antisera. The group-III patients demonstrated some characteristics of each of the above groups. Patients whose lymphoblasts reacted with CLL antiserum presented with clinical and laboratory features indicative of a good prognosis, i.e., ALL with PAS positivity and no T-cell markers or localized mass. Patients whose cells reacted with LS antiserum often had bad prognostic features: mediastinal or abdominal mass, expression of T-cell markers, and PAS negativity. These antisera appear able to differentiate childhood ALL from LBL. The distinction is important prognostically and perhaps therapeutically.


Normal antibody-dependent killer cell function in patients with chronic lymphocytic leukemia.

Unfractionated mononuclear peripheral blood leukocytes (PBL) and nylon wool-nonadherent (B-cell-depleted and T- and null-cell enriched) cells from normal control individuals and untreated patients with chronic lymphocytic leukemia (CLL) were tested for killer cell function in an antibody-dependent cell-mediated cytotoxicity assay. Killer cell activity was present in unfractionated cells from normal individuals and was enriched after removal of adherent cells. Target cell killing by unfractionated mononuclear cells from CLL patients was deficient in 5 of 6 patients tested, but after removal of adherent cells it was approximately equal to that of normal nonadherent cells. Our results indicate that the apparent deficit of killer cells in unfractionated PBL from some CLL patients is due to dilution of killer cells and not to an intrinsic defect in the function of these cells, the presence of suppressor cells in the adherent population, or suppression of killer cell function by serum factors.


Bone marrow colony-forming cells in mice with virus-induced lymphoid leukemia: relation to serum colony-stimulating activity and blood granulocytes.

Mice with advanced lymphoid leukemia have elevated peripheral blood granulocytes and elevated serum colony-stimulating activity, which promotes the in vitro growth of granulocyte and/or macrophage colonies. The number of bone marrow precursor cells of the in vitro granulocyte and/or macrophage colonies varied from normal to 10% of normal. The elevation of colony-stimulating activity correlated best with a combination of increased blood granulocytes and a deficiency of bone marrow precursor cells, which suggested that colony-stimulating activity is a leukopoietin that increases the efficiency and rate of production of granulocytes.


Effects of x irradiation on a temperate bacteriophage of Haemophilus influenzae.

The inactivation of bacteriophage HP1c1 by X rays in a complex medium was found to be exponential, with a D0 (the X-ray exposure necessary to reduce the survival of the phage to 37%) of approximately 90 kR. Analysis of results of sucrose sedimentation of DNA from X-irradiated whole phage showed that the D0 for intactness of single strands was about 105kR, and for intactness of double strands, it was much higher. The D0 for attachment of X-irradiated phage to the host was roughly estimated as about 1,100 kR. Loss of DNA from the phage occurred and was probably due to lysis of the phage by X irradiation, but the significance of the damage is not clear. The production of single-strand breaks approaches the rate of survival loss after X irradiation. However, single-strand breaks produced by UV irradiation, in the presence of H2O2, equivalent to 215 kR of X rays, showed no lethal effect on the phage. Although UV-sensitive mutants of the host cell, Haemophilus influenzae, have been shown to reactivate UV-irradiated phage less than does the wild-type host cell, X-irradiated phage survive equally well on the mutants as on the wild type, a fact suggesting that other repair systems are involved in X-ray repair.


New developments in cardiothoracic surgery.

New and innovative developments in cardiothoracic surgery include the pulmonary effects of certain inotropic drugs, the role of patent ductus closure in neonatal respiratory distress syndrome, the use of immunostimulating agents as adjuvants in the treatment of cancer of the lung, ingenious operative procedures to correct transposition of the great vessels and aortic stenosis, and improved methods to protect and assist the heart during cardiac operations.


Coronary bypass surgery for unstable angina pectoris. Long-term survival and function.

The first 81 patients to undergo coronary artery bypass surgery for unstable angina pectoris at Standford Hospital have been observed for a mean of 40.8 months. Surgical mortality was 8.5%, and perioperative incidence of myocardial infection was 16%. The mean 18-month follow-up showed two early cardiac deaths and 12 additional myocardial infarctions. Sixty-seven percent of the patients were angina-free, and the condition of none was worse. After a mean of 40.8 months, two late cardiac deaths and two myocardial infarctions had occurred. Complete relief of angina was present in 51%;22% had unstable or worsening angina. The probability of survival from time of operation to four months after surgery was 88.8% +/- 3.5%, and this remained unchanged until the two late deaths, which decreased survival probability to 83.8% +/- 4.8% at 43 months. The two late cardiac deaths and the 22% incidence of patients with worsening angina may reflect progression of the atherosclerotic process, late graft occlusion, or both.


Acute reversible myocardial infarction after blood transfusion in the aged.

Seven elderly cases with reversible electrocardiographic changes simulating acute myocardial infarction in the absence of gross myocardial infarction on postmortem examination were observed following the blood transfusion. The underlying diseases were cancer of gastrointestinal tract or gall bladder in 4, gastric ulcer in 2, and 1 of pseudomembranous enterocolitis. The electrocardiogram revealed the abnormal Q waves with monophasic ST elevation and following coronary T inversion. These findings lasted only for 2 to 7 days and returned to the previous normal tracings. The hematocrit was elevated from 28.9 to 47.7 after the blood transfusion of 800 to 1,800 ml. The disseminated intravascular coagulation was shown in 5 cases. GOT levels were within normal ranges except 1 case. Pathological findings in cases with recent electrocardiographic changes were characterized by the mural thromboses, extending into the myocardium through the Thebesian vein. The focal small necroses of the adjacent myocardium or around the thrombosis of small vessels were also observed. In the later phase the fine interstitial fibrosis took place after the resorption of the thrombi and necrotic foci. From these clinical and pathological findings we proposed a new concept of reversible myocardial infarction induced from the hypercoagulability, disseminated intravascular coagulation, and elevated hematocrit.


Anomalous origin of left coronary artery from pulmonary artery. Case report and review of literature concerning teen-agers and adults.

An adult with angina was found to have anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). Review of the literature regarding this anomaly in teen-agers and adults disclosed only 25 cases diagnosed during life. Eighteen additional cases of ALCAPA in this age group have been diagnosed post mortem. In this report, we will review the management of teen-agers and adults in whom ALCAPA was correctly diagnosed during life. We shall also describe the eighth case of successful aorta-left coronary artery grafting with the saphenous vein in this age group. This case brings the total in the literature to 44. Of those patients offered surgical therapy, 13 underwent successful ligation of the anomalous artery. Saphenous vein grafts were employed in 8. Five did not undergo ligation or saphenous vein grafting. There was one death. It would appear that saphenous vein grafting is the definitive means of surgically correcting ALCAPA, because it restores the dual coronary circulation.


Postoperative chest wound infections in patients requiring coronary bypass. A controlled study evaluating prophylactic antibiotics.

A controlled study investigating clean chest wound infections in 904 patients undergoing myocardial revascularization was performed. Four hundred fifty-one patients received systemic antibiotics before and after the operation, and 453 patients received no prophylactic systemic antibiotics. The infection rate was 1.10 per cent and 1.76 per cent, respectively, indicating no statistical difference between the two groups. Preoperative skin preparation and subsequent local antibiotic wound irrigation may be the most important factors in preventing clean wound infection.


The histocompatibility complex and rheumatic diseases.

Histocompatibility typing has assumed an increasingly important role as a clinical and research tool in rheumatic diseases. The HLA antigens which are serologically defined (A and B series) are being used most extensively for clinical work, but the role of other immunologic determinants in the HLA complex is being evaluated. These include D-locus (MLC) determinants, several complement components, and immune response genes which have been well characterized in the mouse, but not in man. The products of the major histocompatibility complex are inherited in a simple Mendelian fashion as a series of co-dominant alleles. Large population studies have characterized the frequencies of various alleles, and family studies have allowed tentative mapping of the various loci within the complex on the sixth chromosome in man. A number of diseases which are considered to be autoimmune in nature are now known to be associated with specific HLA antigens. Of these disease associations, the strongest and best studied are the seronegative spondyloarthropathies which are highly associated with the B27 antigen. Included in this group are ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, colitic arthropathy, Yersinia arthritis and a small group of juvenile rheumatoid arthritis patients with features of ankylosing spondylitis. The clinical application of tissue typing or B27 testing is most helpful in regard to difficult diagnostic problems in patients with early or atypical seronegative spondyloarthropathy. Its value as an indicator of prognosis, and its value in counselling family members is not well established. There are many interesting hypotheses regarding pathogenetic mechanisms of these rheumatic diseases based on susceptibility factors related to the major histocompatibility complex. An abnormal immune response gene within the complex is probably a key feature of the mechanism, but the exact details are little more than speculative at this point.


[Ulcerative colitis - indications for surgery and methods of treatment (author's transl)].

Morphology, clinical signs and symptoms as well as surgical therapy of ulcerative colitis are discussed comparing own findings with results reported in the literature. Case reports are given of 48 patients with special emphasis on indications for surgical treatment, methods of surgery and complications. Timing of surgery and medical pretreatment do play a decisive role. The treatment of choice today is proctocolectomy with terminal ileostomy in one session; more serious complications as well as transition into a carcinoma can thus be avoided. In some acute cases a fistula-operation may be indicated for short-term relief.


[Clinics and management of radiation injuries of small bowel and colon(author's transl)].

In the Surgical and Gynecological Departments of the University of Mainz, Medical School, 50 patients were operated between 1964-1976 for mechanical and paralytical  ileus and intestinal bleeding caused by radiation injury of the bowel. Diagnosis depends on the history of radiation therapy. At operation we have seen a recurrence of gynecological and other malignant growths only two times. Intestinal resection with anastomosis is the preferred method for the management of such radiation injuries. The postoperative dehiscence of the intestine was noticed only five times. In order to prevent higher mortality rates, operation should be carried out as soon as possible.


Growth of measles virus in various human lymphoid cell lines.

Neurovirulent TYCSA strain and attenuated Schwarz strain of measles virus and Halle strain of subacute sclerosing panencephalitis (SSPE) virus replicated in cultures of human lymphoid cell lines of the T-cell type, MOLT-3, MOLT-4 and CCRF-CEM. TYCSA and Halle strains grew rapidly, but Schwarz strain grew slowly in these cell lines. Furthermore, these three strains established persistent infection in CCRF-CEM cells but not in the other cell lines. In these persistently infected cultures an almost entire population of cells were shown to be infected and infectious virus was produced constantly for over 100 days. Cells persistently infected with Schwarz strain contained nucleocapsid structures in both the nucleus and cytoplasm and produced low titered infectious virus, whereas nucleocapsid structures were observed only in the cytoplasm of cells persistently infected with either TYCSA or Halle strain and the titers of infectious virus produced from these cells were high.


The experience of a haematemesis and melaena unit: a review of the first 513 consecutive admissions.

This report is of the results of management in a haematemesis and melaena unit at Prince Henry's Hospital, Melbourne. The unit was established in October, 1972, in response to unpublished data for the decades 1950 to 1959 and 1960 to 1969, which showed a mortality of about 15%. In the 39 months to December, 1975, 513 patients were received into a semi-intensive care setting. The unit staff consisted of a group of four surgeons and four physicians working a weekly roster. Primary care and liaison were the responsibility of the gastroenterology registrar. The basic diagnostic measure taken was the routine early use of fibreoptic duodenoscopy. The unit was set up with an agreed policy of management of the common causes of haematemesis and melaena, and data were prospectively recorded in a form suitable for computer analysis in every case. Of the 513 admissions, 378 were of males and 135 were of females. Forty-five patients died, giving an overall admission mortality of 8-8. There were 143 admissions for bleeding duodenal ulceration, 102 for acute peptic ulceration, 47 for chronic gastriculceration, 43 for oesophageal varices, 33 for Mallory-Weiss syndrome and 45 for less common causes of upper gastrintestinal bleeding. In 100 cases the source of bleeding was not discovered. Of the 143 patients admitted for chronic duodenal ulcer, either patients died, giving a mortality of 5-6%; 72 patients underwent operation, with an operative mortality of 9-7%. Of the 47 admitted with bleeding gastric ulcer, nine died (19-1%), while 26 came to operation; the operative mortality was 26-9%. There were 102 admissions for acute peptic ulceration, with an overall mortality of 11-7% (12 patients); 16 patients came to operation, with an operative mortality of 43-7%. Eleven deaths occurred in the 43 patients admitted for bleeding oesophageal varices (25-6%), with 10 patients coming to operation; the operative mortality was 30-0%. An age of greater than 50 years and shock on admission were the most significant factors for poor prognosis in this group of patients.


Coronary artery surgery in Australia, 1975-1976. A report by the National Heart Fundation of Australia.

This is a report of a register of Australian experience in coronary artery bypass graft surgery over a 12-month period from October 1, 1974, to September 30, 1975. It provides data on results up to discharge from hospital. There were 967 patients and 58 (6%) hospital death.


The future of cardiac surgery in Australia. A prediction from a 15 year experience.

Statistics are presented which demonstrate that the load of congenital heart surgery in Australia is between 900 and 1,000 cases per year. For valvular heart surgery the load is also approximatley 1,000 cases per year. About 800 to 900 operations are undertaken annually to institute cardiac pacing. The number of operations for coronary artery disease has increased in an explosive manner from less than 100 cases in 1970 to more than 1,000 cases in 1975. The implications of this marked increase in operation for coronary artery disease is of paramount importance for future planning in cardiac surgery.


Relation of protease inhibitor phenotypes to obstructive lung diseases in a community.

To examine the relative risk for the development of obstructive lung disease in persons heterozygous for alpha1-antitrypsin deficiency, we determined protease inhibitor phenotypes in 2944 subjects in a general community population. Phenotype M was found in 89.5 per cent, MS in 7.1 per cent, and MZ in 3.0 per cent of the population. There were two persons of phenotype Z and six of phenotype SZ. The study also included respiratory questionnaires and spirometry. There were no statistically significant differences in the prevalence of respiratory symptoms and diagnoses or of ventilatory impairment among the three major phenotype groups (M, MS and MZ), nor were there differences in the rates of deterioration of function with age or smoking. Consequently, we do not consider population screening for heterozygous alpha1-antitrypsin deficiency to be worthwhile.


T and B lymphocytes in uremic patients with type B hepatitis infection.

Peripheral T and B lymphocytes were measured in (1) hepatitis B surface antigen (HBsAg)-positive, (2) HBsAg-negative uremic patients on chronic hemodialysis (CHD) therapy, and (3) patients with type B chronic active viral hepatitis (CAVH). When compared to normals, a decrease in the absolute number of T and B lymphocytes was detected in both CHD groups. CAVH patients had a decrease in the total number of T lymphocytes. When expressed as percentage of T lymphocytes, normals and HBsAg-negative CHD patients had similar values, while a decrease was detected in both HBsAg-positive CHD and CAVH patients. Also, in the latter two groups, hepatitis B virus infection resulted in an increase in the total number and percentage of null cells.