Possible nitrosodimethylamine formation in comparative in vitro nitrosation experiments with six different tetracycline antibiotics. The hydrochlorides of tetracycline, minocycline, chlorotetracycline, anhydrochlorotetracycline, desmethylchlorotetracycline, oxytetracycline and doxycycline were reacted with sodium nitrite for two hours at 37 degrees C in aqueous buffer solutions at pH 2 and 4 under simulated stomach conditions. NDMA formation was detected from minocycline, doxycycline, oxytetracycline and anhydrochlorotetracycline by GLC and GLC-MS analysis. NDMA formation from minocycline and dodxycycline was blocked by ascorbic acid. The catalytic effect of sodium thiocyanate for NDMA formation from minocycline and nitrite was investigated. The different reactivities of the tested tetracyclines towards nitrite in acidic solutions (NDMA formation from minocycline, doxycycline, oxytetracycline and no NDMA formation from tetracycline, chlorotetracycline and desmethylchlorotetracycline) may be understood from stereochemical considerations. The failure of dealkylative nitrosation reactions in the latter tetracyclines is explained by the formation of intramolecular hydrogen bridge linkages between epidimethylamino groups at C-4 and OH groups at C-6. This hypothesis was proved by the observations of NDMA formation from anhydrochlortetracycline and sodium nitrite at pH 2.


Non-volatile N-nitroso compounds in human feces. A bacterial mutagen has been detected in ether extracts of freeze-dried feces of humans on Western diet. Several types of evidence suggest that nitroso compounds are present in human feces and the mutagen could be a nitroso compound. Ascorbic acid supplement in the diet reduces the levels of both the mutagens and nitroso compounds in the feces.


An assessment of human exposure to N-nitroso compounds. Current knowledge on human exposure to N-nitroso compounds is reviewed. Four exposure routes are considered: ingestion, inhalation, dermal and in vivo. The relative importance of various N-nitrosation mechanisms is discussed.


Comprehensive analytical procedures for the determination of volatile and non-volatile, polar and non-polar N-nitroso compounds. The first comprehensive analytical procedures for the quantitative analysis of N-nitroso compounds are described. The scheme divides N-nitroso compounds into four major, overlapping categories: volatile (Class I), non-volatile, low polarity (Class II), non-volatile, non-ionic, high polarity (Class III) and non-volatile, ionic, high polarity (Class IV). Existing analytical techniques for each class of compound are integrated into an organized and logical sequence of analysis to allow all classes of compounds to be determined. TEA-GC is used for the volatile compounds and TEA-HPLC for the non-volatile. It is emphasized that the coincidence of retention time in either TEA-GC alone or TEA-HPLC alone cannot be taken as sufficient evidence for the identification of N-nitroso compounds, especially for samples from complex matrices. Independent techniques are required to confirm these results. The confirmatory techniques used frequently in our laboratory are: (1) spectroscopic analysis (IR, NMR, UV and MS), (2) formation and identification of derivatives, and (3) parallel TEA-GC/TEA-HPLC techniques. These procedures are now used at Thermo Electron for the comprehensive screening of environmental samples.


Analytical determination of N-nitroso compounds in pesticides by the United States Environmental Protection Agency--a preliminary study. Lijinsky, Eisenbrand and others have demonstrated the formation of N-nitroso derivatives of certain secondary amine pesticides under specified experimental conditions. Partly based on these studies and on reports of the industrial discharge of N-nitrosos compounds from several chemical manufacturing facilities the Environmental Protection Agency (EPA) has issued several reports on the nitroso problem, including a report by a special ad hoc committee under the Administrator's Science Advisory Board (1976). Unexpectedly high N-nitrosoalkylamine residues found in several pesticide products (Fine et al., 1976) have prompted EPA to conduct a survey, initially of approximately 70-80 pesticides that potentially were representative of the following three routes of contamination: 1. industrial process formation and carryover; 2. in situ (container) nitrosation and 3. utilization of contaminated amines in the manufacturing process. Environmental formation was not studied in this survey. Duplicate samples were analysed by two different laboratories using GC and HPLC interfaced with Hall, UV and chemiluminescent (TEA) detectors. Results of some analyses of this continuing survey are presented. Based partly on the results of this study, the Agency has decided to conduct risk-benefit analyses on pesticides suspected of containing N-nitroso contaminants, with special consideration given to oncogenic and mutagenic potential. The analytical results of the study are discussed, as is the cooperative effort within the Agency.


Chemical studies on tobacco smoke LIX. Analysis of volatile nitrosamines in tobacco smoke and polluted indoor environments. Chemical-analytical data were presented illustrating that the mainstream smoke of tobacco products contains traces of volatile N-nitrosamines. The quantity of volatile nitrosamines in the sidestream smoke of cigarettes and cigars exceeds that in the mainstream smoke by at least a factor of 10. This observation led to model studies and analysis of air in bar cars of trains, in a local bar and other indoor atmospheres polluted by tobacco smoke. The results showed that, during one hour in a smoke-polluted indoor environment, one may inhale volatile nitrosamines in quantities equal to those in the mainstream smoke of 0.5-30 cigarettes. It is emphasized that there are, at present, no epidemiological data linking human respiratory cancers to volatile nitrosamines.


Chemical studies on tobacco smoke LVI. Tobacco specific nitrosamines: origins, carcinogenicity and metabolism. Tobacco contains specific carcinogenic nitrosamines which are derived from nicotine. These compounds may be among the causative agents for the various cancers (lung, oral cavity, oesophagus, bladder and pancreas) which are associated with tobacco usage. The major tobacco specific nitrosamine is N'-nitrosonornicotine (NNN), which has been detected in both unburned tobacco (0.3-90.6 ppm) and cigarette mainstream smoke (137-238 ng/cig.). Studies with labelled precursors showed that the major source of NNN formed during curing of tobacco was nicotine, rather than nornicotine. The transfer rate of NNN from tobacco to mainstream smoke was 11.3%; about half the NNN present in smoke therefore originated from tobacco, with the remainder being formed during smoking. Model studies of the reaction of nicotine and nitrite showed that, in addition to NNN, two other nitrosamines, 4-(N-methyl-N-nitrosamino)-4-(3-pyridyl)-1-butanal (NNA) and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were formed. Analysis of tobacco revealed the presence of NNK in chewing tobacco and snuff (0.6-2.4 ppm). A comparative bioassay of NNN, NNK and NNA in strain A mice indicated that NNK was more tumorigenic than NNN and that NNA was inactive. NNN, which had previously been shown to induce oesophageal and nasal cavity tumours in rats, also was a moderately active carcinogen in the Syrian golden hamster, giving tracheal tumours. A study of the metabolism of cyclic nitrosamines was initiated. Metabolic alpha-hydroxylation of nitrosopyrrolidine, which is thought to be the critical step in activation of this compound, was demonstrated by detection in vitro and in vivo of 2-hydroxytetrahydrofuran, which was the product of decomposition of alpha-hydroxynitrosopyrrolidine. The metabolism of the related cyclic nitrosamine, NNN, is currently under investigation, with emphasis on metabolites resulting from alpha- and beta-hydroxylation. These analytical and metabolic studies are intended to clarify the possible relationship of tobacco-specific nitrosamines and site-specific cancers in tobacco users.


Absorption, tissue deposition and passage into eggs of N-nitrosodimethylamine in hens. The experiments were performed on 262 laying hens divided into 8 groups: 5 groups of hens were given orally N-nitrosodimethylamine (NDMA) in single doses of 30, 10, 3, 1 and 0.1 mg/kg of body weight, two groups received tap water containing 2 and 5 mg NDMA/kg, provided ad libitum for 20 consecutive days, and one group of layers served as a control. Birds were selected at random and sacrificed at one or two day intervals and NDMA content was determined in blood, muscles, liver, brain and in collected eggs. The highest concentrations of NDMA were found 24-36 hours after dosing in all investigated tissues and eggs. A single oral dose of 0.1 mg NDMA/kg produced tissue levels up to 0.06 mg/kg and resulted in excretion of detectable amounts of the carcinogen in eggs for up to 6 days. After large doses, 10 mg and 30 mg NDMA/kg, concentrations in corresponding tissues reached 6.0 and 12.7 mg/kg, and the presence of NDMA in eggs could still be detected after 12 and 14 days. Birds receiving NDMA in drinking water showed increasing NDMA concentrations in all analysed tissue and eggs. After 12 days, the highest levels were found in eggs, blood and brain. Practical implications of the results must be evaluated from the point of view of human safety.


The intake of nitrate, nitrite and volatile N-nitrosamines and the occurrence of volatile N-nitrosamines in human urine and veal calves. A hundred samples of total diets, 19 samples of cheese (mainly Dutch), a total of 30 samples of muscle, fat liver, kidney, blood and fried meat from experimental veal calves (fed daily with 0.6 or 300 mg of potassium nitrate per kg b.w.) and 14 samples of urine of patients medicated with massive amounts of ammonium nitrate (up to an equivalent of 180 mg potassium nitrate per kg b.w.) have been analysed with GC-TEA for their content of the following N-nitrosamines: NDMA, NDEA, NDPA, NDBA, NPIP, NPYR and NMOR. NDMA was frequently found, but always in the sub micrograms per kg range, except for two diets (1.2 and 1.7 microgram/kg). Other N-nitrosamines were sporadically found in the same concentration range, except for one diet (NPYR, 1.9 microgram/kg). No correlation was found between NDMA content and the composition of diets or the nitrate load of patients or veal calves. Mean daily intake of NDMA, potassium nitrate and sodium nitrite from total diets was calculated to be 0.5 microgram, 215 mg and 7.7 mg respectively. N-nitrosamine recoveries from the various samples were determined mostly at the 1 microgram/kg level. Contents of potassium nitrate and sodium nitrite are reported for 124 samples of various vegetables, 94 samples of canned baby food and 48 samples of human saliva, collected at various times after the intake of meals. Some kinds of vegetables showed high to very high nitrate contents, for example, purslane, red beets, spinach and lettuce. Only traces of nitrite were found in the vegetables. Salivary nitrite content was shown to be highly dependent on the dietary intake of nitrate and increased up to 60 times its initial value after the consumption of vegetable-rich meals.


Nitrosobenzylmethylamine, zinc deficiency and oesophageal cancer. In an earlier study, we found reduced levels of zinc in the blood, hair and oesophageal tissue from patients with oesophageal cancer, compared with those in matched control subjects. Using a rat model, dietary zinc deficiency was found to increase the incidence and shorten the lag time for oesophageal tumour induction by NBMA. Zinc levels were also lower in samples of serum, hair, oesophagus and testis of the zinc-deficient rats, treated with the carcinogen or untreated, compared with the control rats, treated or untreated.


The permeability of laboratory gloves to selected nitrosamines. Samples of laboratory gloves of various composition and thicknesses were used as barriers between 0.136 M solutions of nitrosamines (dimethyl-, ethylmethyl-, diethyl-8 n-butylmethyl-, di-n-propyl-, di-iso-propyl- and di-sec-butyl- in dichloromethane, acetone, ethanol and double-distilled, deionized water) and water. The concentration of permeated nitrosamine was measured periodically. Nearly all gloves tested were permeable to the nitrosamine solutions. The results indicate that: (1) gloves should not be assumed to provide full protection, (2) gloves should be discarded immeidately following overt contamination and (3) gloves should not be reused.


Diffusion of nitrosamines through protective gloves. A simple experimental demonstration of the permeability of protective gloves to volatile nitrosamines has been carried out. Rubber and polyvinyl chloride (PVC) gloves were turned inside out and the fingers filled with dilute solutions of nitrosamines in hexane. The outer faces of the fingers were washed with water at various times and the nitrosamine content of these washings determined. From these measurements the proportions of the various nitrosamines passing through the gloves were calculated. For both types of gloves N-nitrosopyrrolidine (NPYR) permeated the fingers most rapidly and to the greatest extent. Only a relatively small amount of N-nitrosodibutylamine (NDBA) was transmitted. It was also established that the rubber gloves themselves did not contain any of the common volatile nitrosamines; N-nitrosomethylphenylamine and N-nitrosodiphenylamine were also absent.


The analysis and source of 1-diphenylmethyl-4-nitrosopiperazine in 1-diphenylmethyl-4-[(6-methyl-2-pyridyl) methyleneamino]piperazine: a case history. Analytical methods were developed to determine whether there was less than one ppm of II in IV. Purified IV contained a compound with the same GC retention time as authentic II on OV-17 and Silar 10C columns, using a FID or a nitrogen/phosphorus detector. The GC-coupled mass spectra contained major peaks at m/e 251 and 167 and the GC-coupled methane CI spectra gave the quasi-molecular ion, m/e 282. However, the CI selected ion monitor indicated three compounds at m/e 282. The nitrosamine II was separated from IV by HPLC on muBondapak C18. The GC-coupled mass spectra of the HPLC nitrosamine fraction had peaks at m/e 251 and 167 and other peaks for a compound of greater MW than II, although the GC retention times were the same. Evidence for II and a decrease in the detection limit to one ppm was obtained with a TEA interfaced with a HPLC. To determine if II was formed from IV, it was exposed to ozone at -78 degrees C in methylene chloride. The DSC, IR and NMR of the product were coincident with those of the standard of II. In other experiments, IV in methylene chloride was exposed to light and dry air in the presence and absence of methylene blue. The PMR and 13C NMR of the product formed in the presence of methylene blue were the same as that of II. It is postulated that this nitrosamine was formed by a singlet oxygen mechanism.


Electronic properties of the nitrosamine function. The addition of a chiral alcohol, such as l-menthol or R-(-)-2-octanol, to an achiral nitrosamine causes a dissymmetric perturbation of the symmetrical chromophore and a Cotton effect is evident in the circular dichroism curve at the wavelength of ultraviolet absorption of the nitrosamine function. The intensity (ellipticity) of this induced circular dichroism is concentration dependent and appears to result from a weak 1:1 complex of nitrosamine and alcohol. The implications of these observations for structural studies are considered.


Histological and cytological technique for the quantitation of cultured human bone-marrow cells:formation of aggregates. A bone-marrow culture system is described that provides a simple, quantitative and rapid assessment of marrow bone cells in vitro. Aggregation of bone-marrow cells, an in vitro phenomenon, occurs within 24 hr of culture and is observed utilizing Millipore filters. Daily quantitation shows both an increase in the number and a change in the morphology of these aggregates. The maximum number of aggregates is achieved on the 2nd or 3rd day of incubation. Histologically, aggregates are composed of myeloid, mononuclear and mesenchymal fibroblastic cells. Mesenchymal cells form a matrix for apposed mononuclear and myeloid cells. Scanning electron micrographs show intimate cell contact and spreading by the marrow cells. Fluctuation of the absolute numbers of various cell types are observed. The system can be utilized for long-term culture of bone marrow.


Differing effects of isoleucine deficiency on the toxicity of MNNG for 10T1/2 and CHO cells. Isoleucine deficiency sensitizes C3H 10T1/2 cells to the cytotoxic effects of MNNG. Synchrony of proliferation is not required for this effect since it occurs prior to full growth arrest and subsequent establishment of synchronous proliferation after refeeding in complete medium. Furthermore, confluence arrest of proliferation of 10T1/2 cells does not affect their cytotoxic response to MNNG, although they proliferate synchronously after replating at low density. In contrast, the toxicity of MNNG for CHO cells is not altered by isoleucine deficiency, even though these cells are readily synchronized by refeeding in complete medium after transient isoleucine deficiency.


Changes in isoperoxidases during shoot formation in tobacco callus. Shoot formation in tobacco (Nicotiana tabacum L.) callus is accompanied by an increase in peroxidase activity which takes a form similar to a sigmoid curve. The "stationary" phase coincides with the period of organ formation. Characteristic changes in isoperoxidase pattern are found in the shoot-forming part of the callus. These changes are different from those in the nonshoot-forming part or in gibberellin-treated tissue, which does not form shoots.


The cytogenetic, proliferative and viability effects of four bacteriophages on human lymphocytes. Certain bacteriophages have been found in live virus vaccines, while a few others have been associated with disease states. Some of these phages have produced abnormal growth of eukaryotic tissue cultures. For this reason bacteriophages phiX-174, MS2, T2 and an isolate from live virus vaccines, phiV-1, were incubated with human cell cultures for examination of chromosomal effects, cell proliferation and viability. Mitogen-stimulated lymphocytes and human embryonic kidney tissue cultures showed no increase in chromosomal abnormalities for high doses of phage-infected versus control cultures. Tritiated-thymidine uptake, correlated with mitotic indices for phage-treated lymphocyte cultures, indicated a reduction in cell division, while 51-chromium release studies showed no cell death occurring in these cultures. This suggested that inhibition of DNA synthesis was occurring in some cells. The presence of phage in the supernate of cells that were exposed to phage suggested the possibility of phage attachment to the plasma membranes of lymphocytes, which may in turn affect the suppression of DNA synthesis.


[Antibiotic treatment of gynecologic and obstetric infections (author's transl)]. 1. Obstetric and gynecologic infections especially ascending intrauterine infections, pelvic inflammatory disease (PID) and postoperative infections are usually polymicrobial infections involving enterobacteria and anaerobes. 2. The antibiotic treatment of these infections must primarily be active against the two groups of organisms mentioned. Semisynthetic penicillins, cephalosporines or aminoglycosides combined with clindamycin or one of the new large spectrum penicillins, or cephalosporines alone proved to be effective. In addition to the antimicrobial therapy surgical intervention is very often required in postoperative infections after obstetric and gynecologic surgery and for pelvic abscesses. 3. For treatment of infections in pregnancy specific side effects of antimicrobial agents concerning the mother and the fetus have to be considered. Transfer of the antibiotic to the fetus and the amniotic fluid in sufficiently high concentrations is mandatory for the treatment of intrauterine infections. 4. In cervicitis and salpingitis the possibility of a gonococcal infection has to be kept in mind.


[Indirect hemagglutination test for detection of toxoplasma antibodies (author's transl)]. A micromethod with stable reagents for the simple and rapid detection of toxoplasma antibodies with the indirect hemagglutination test (IHAT) is presented. The results obtained with this method are compared with the titers in the dye test and complement-fixation test and with two IHAT-kits recently offered by commercial firms. We propose to use the IHAT as a supplementary reaction to the methods commonly in use. The relationship between the Sabin-Feldman dye test and IHAT is dependent upon the stage of infection. A very good agreement is obtained with latent toxoplasma infections. On the contrary with some new infections (up to 6 months) the IHAT titer is clearly lower than the dye test titer. This discrepancy opens the possibility of determining the infection stage with a single serum-sample.


Mechanisms of long and short term immunity to plague. Long and short term immunity to plague was produced in normal mice by using, respectively, an antibiotic resistant Yersinia pestis and Yersinia pseudotuberculosis. Both immunogens were used live. Passive serum transfer experiments, together with assays for the bactericidal activity of macrophages and delayed hypersensitivity tests, showed that the short term immunity was of a humoral nature and the long term immunity was cell mediated. The plague virulence markers of the two immunogens were: Y. pestis VW- F1+ P1+ P+; Y. pseudotuberculosis VW+ F1- P1- P-. The challenge organism was Y. pestis VW+ F1+ P1+ P+.


The effects of oral D-penicillamine treatment on experimental arthritis and the associated immune response in rabbits. D-penicillamine given orally to rabbits at a dose of 15 mg/kg body weight, administered daily for long periods commencing prior to and at the time of immunization, reduced the concentration of specific IgG antibodies directed against ovalbumin. This effect was not observed when treatment with the drug commenced after immunization and the onset of a mono-articular arthritis. The concentration of serum IgA rose abruptly after antigen was injected intra-articularly to induce the arthritis. This increase was not affected by treatment with D-penicillamine. The concentration of serum IgA decreased markedly during the chronic phase of the mono-articular arthritis, falling below the lower limit of the normal range. Treatment with D-penicillamine for at least 50 days restored the serum IgA concentration to the middle of the normal range. D-penicillamine treatment had no significant effect on the concentration of IgG, or IgM in serum either before or after the onset of mono-articular arthritis.


Cyclophosphamide-like cellular immunostimulation induced by 6-thioguanine (Lanvis). The possible immunostimulating effect of 6-thioguanine was studied in the mouse. It caused a dose-dependent suppression of the cellular and humoral immune response if administered 1 day before immunization. If, however, the interval between 6-thioguanine administration and immunization was extended to 5 days, a significant enhancement of delayed hypersensitivity was observed. The The enhancement occurred only after immunization with 10(6) and 10(7) sheep red cells. The analogy between the immunostimulating effects of 6-thioguanine and cyclophosphamide is discussed.


[3H] thymidine labelling kinetics of peripheral blood lymphocytes in adult thymectomized mice. The appearance of labelled lymphocytes in the blood of adult thymectomized mice was followed for 21 days after a single injection of [3H] thymidine. The results showed that the expected changes in their life-span resulting from thymic deprivation were not reflected in the kinetics of labelling of these cells with this radioactively-labelled precursor for DNA synthesis. Turnover of DNA and exchange of label between cells must be considered in relation to the results, as had been previously concluded from similar studies of intact mice (Harris, 1975a).


The binding of human and guinea-pig IgG subclasses to homologous macrophage and monocyte Fc receptors. Guinea-pig IgG2 and IgT1 bind to contiguous Fc receptors on homologous peritoneal macrophages. Equilibrium association constants determined for the binding of human IgG subclasses to homologous peripheral blood monocytes show that the order of binding is IgG1 greater than IgG3 greater than IgG4 greater than IgG2. Direct binding and rosette assay techniques independently established that both guinea-pig IgG2 and human IgG bind to homologous macrophage-monocyte Fc receptors through a site present in whole Fc (CH2. CH3)2, but absent in pFc' subfragments (CH3)2.


Modulation of the immune response by passive antibodies. IV. Effects of IgG1 and IgG2 anti-hapten antibodies. The effects of IgG1 and IgG2 anti-hapten antibodies waere studied on celluar and humoral reactions induced by immunization with a hapten-carrier complex. IgG2 was shown to depress delayed hypersensitivity reactions to the carrier and to enhance anaphylactic reactions to both the hapten and the carrier whereas IgG1 appeared to have no activity except a little enhancing effect on antibody synthesis to the carrier. The regulatory role of IgG2 antibodies, which were cytophilic for macrophages, in the immune response to a hapten-carrier conjugate is discussed.


Opsonins in human serum for the phagocytosis of complexes between IgG and protein A of Staphylococcus aureus. The phagocytosis of complexes between staphylococcal protein A and 125I-labelled IgG is enhanced by fresh human serum and to a somewhat lesser extent by heat-inactivated serum. Opsonizing activity is detected in two distinct peaks by Sephadex G-200 column chromatography. One peak corresponds to the excluded material and the other to the ascending limb of the second protein peak. The active material in serum is retained on a protein A-Sepharose but not on an IgG-Sepharose column. Active material eluted from a protein A-Sepharose column and run on a Sephadex G-200 column again shows two activity peaks corresponding to those obtained on chromatography of whole serum. The first peak contains mainly IgA nd IgM but very little total protein material. The second peak contains mainly IgG but also IgA. Purified normal IgA, but not one myeloma IgA preparation tested, has the capacity to enhance phagocytosis of protein A-IgG complexes. Possible examinations for the opsonin activity are discussed.


The effect of chemotactic factors and agents which influence neutrophil movement on anaerobic glycolysis and hexose monophosphate shunt activity. The effects of two chemotactic factors, endotoxin activated serm (EAS) and casein and a number of drugs known to affect intracellular cyclic nucleotide levels and various froms of neutrophil movement, on neutrophil anaerobic glycolysis and hexose monophosphate shunt (HMPS) activity were assessed. EAS caused stimulation of glycolysis. HMPS activity and NBT reduction, but casein was without effect on glycolysis and NBT reduction and inhibited HMPS activity. Drug known to increase intracellular cAMP levels caused a depression of HMPS activity whereas those reported to elevate cGMP had a variety of effects. Glycolysis was not affected by any of these agents. These results indicate a lack of relationship between cyclic nucleotide effect on cell motility and neutrophil glycolysis and HMPS activity.


The effects of oral D-penicillamine treatment on experimental arthritis and the associated immune response in rabbits. II. The effects on cellular parameters. Prolonged oral treatment (up to 410 days) of rabbits with D-penicillamine at a dose of 15 mg/kg body weight commencing either before or after immunization and the onset of arthritis, diminished and eventually abolished the delayed hypersensitivity response to intradermally administered tuberculin PPD. The 48 h cutaneous hypersensitivity response to the immunizing antigen (ovalbumin) was also significantly reduced, as was the inhibition of leucotye migration by ovalbumin. Cutaneous Arthus reactivity to ovalbumin was unaffected by D-penicillamine treatment. D-penicillamine treatment of normal rabbits was also found to increase the phagocytic index of the reticuloendothelial system as measured by carbon clearance.


In vitro macrophage chemotactic generation from serum immunoglobulin G by neutrophil neutral seryl protease. A neutral protease with a molecular weight of about 14,00 was separated at acid pH from rabbit neutrophils and then partially purified by elution on DEAE-Sephadex, CM-Sephadex and Sephadex G-75 in that order. This enzyme was inactivated by diisopropyl fluorophosphate (DFP), phenylmethyl sulphonylfluoride (PMSF), soybean trypsin inhibitor (SBTI), or elastatinal, suggesting a seryl protease resembling elastase, but it failed to digest elastin-orcein. The enzyme seemed different from histonase of rabbit neutrophils because of its haemoglobin (3HHb)-degrading ability and of inactivation by heparin. The protease generated in vitro macrophage chemotactic activity from guineapig serum IgG. This chemotactic factor had a molecular weight similar to that of IgG and its chemotacic generation was accompanied by release of dialysable peptide(s). No generation of macrophage chemotactic activity from IgG was induced in vitro by elastase from pig pancreas or by neutral thiol protease from rabbit neutrophils.


Dependence of phagocytosis on strength of phagocyte-particle interaction. Sheep erythrocytes were pretreated with concanavalin A (Con-A-SRC), or glutaraldehyde (G-SRC), or specific rabbit immunoglobulin G (IgG-SRC), or specific rabbit immunoglobulin M and complement (C-SRC). Each erythrocyte type was made to adhere to rat peritoneal cells and adhesion was measured; binding decreased as follow: conA-SRC greater than IgG-SRC  greater than less than G-SRC greater than C-SRC Peritoneal cell-erythrocyte complexes were then submitted to a laminar shear flow, and resistance of binding was assayed. Binging strength decreased in the following order: G-SRC greater than C-SRC greater than IgG-SRC greater than ConA-SRC Cell suspensions were incubated at 37 degrees, and phagocytosis was measured. Ingestion decreased in the following order: G-SRC greater than IgG-SRC greater than C-SRC greater than ConA-SRC It is concluded that: Binding strength may be of importance in triggering phagocytosis; when immunocytoadherence is studied, two independent parameters should be considered: binding and binding strength. This report describes a new method that may allow discrimination between different cell subpopulations of similar binding specificities.


The effect of thiol compounds on lymphocytes stimulated in culture. The effect was studied of D-penicillamine (D-PAm) and other thiol compounds (concentration range, approximately 10(-4)-3.4 X 10(-3) M) on mouse spleen cells, stimulated in culture by concanavalin A or by mixed lymphocyte interaction. Thiols initially enhanced the rate of incorporation of [3H] thymidine into DNA of these cells. The enhanecment was typically followed by a sharp decline in activity to a level often below that of thiol-free cultures. The time which elapsed between adding the thiol and the decline in activity depended on the concentration of the particular thiol used. Exceptional among thiols studied was L-cysteine, which lacked inhibitory properties. Variation of the L-cystine content of the medium used here influenced the effect of thiols such as D-PAm on the cells, an increase in cystine content favouring the retention of high activity. It was found that D-PAm reacted slowly with a constituent of the culture medium, causing the latter eventually to lose its capacity to maintain cells. The effects of this reaction could be counteracted by adding L-cystine, L-cysteine, and certain other thiol compounds. It was concluded that DPAm combined with L-cystine in the medium to form the mixed disulphide, which evidently could not be utilized by the cells as a source of L-cystine. Deprivation of this essential nutrient accounted for the eventual inhibition of [3H] thymidine incorporation in cultures exposed to thiols. The initial, enhancing effect of thiols on stimulated lymphocytes represented a modulation of the response to the primary stimulant: there was no evidence that thiols were themselves mitogenic.


Polyadenylic acid-polyuridylic acid (poly A : U) and experimental murine brucellosis. I. Effect of single and double-stranded polynucleotides on Brucella abortus in vivo and in vitro. The double stranded polynucleotide, poly A : U, when administered intraperitoneally at the same time as intravenous infection with Brucella abortus, suppressed the growth of that organism in the spleen and liver of mice. Single stranded poly A or poly U were not effective. On the other hand both the single and double stranded forms enhanced the growth of Br. abortus in broth culture. Poly A : U did not enhance the blood clearance of intravenously administered Br. abortus. Indeed its suppressive effect was not apparent until 2 days after administration. When mice given Br. abortus and poly A : U were given a second infection 2 days later, with either Br. abortus or Listeria monocytogens, the second infection was exacerbated, indicating a biphasic effect of poly A : U and antigen.


Some metabolic effects of adrenergic drugs in Bubalus bubalis. The effects of intravenous administration of equimolar doses of adrenaline (20.00 microgram/kg), noradrenaline (18.47 microgram/kg) and isoprenaline (23.06 microgram/kg) on blood glucose, serum total protein, serum total cholesterol and serum urea were investigated in buffalo calves. There was significant increase in blood glucose level with all the sympathomimetic amines 5 min after their administration (P less than 0.05). Adrenaline and noradrenaline were almost equipotent in inducing hyperglycaemic response whereas the effect of isoprenaline was relatively less and short-lived. The increased glucose levels returned to pre-administration levels within 5 hr. These sympathomimetic amines produced no significant changes in other metabolic parameters viz. serum levels of total cholesterol, total protein and urea.


Effect of glucocorticoids on insulin sensitivity in newborn dogs. A 3-day treatment with 4 mg/kg Betnesol in anesthetized mongrel pups, 4-55 days of age effectively raised fasting plasma glucose concentration by 23 +/- 2.9%, which was higher than that observed in adult dogs similarly treated. Possibly this was due to the lack of effectiveness of insulin in the pups which is normally produced in response to hyperglycemia. The relative lack of effectiveness of insulin induced hypoglycemia in stimulating hepatic glucose production in the newborn pups was further demonstrated by the fact that insulin administration produced a hypoglycemia which lasted much longer than in adult dogs. On the other hand Betnesol treatment was found to be effective in restoring normoglycemia following administration of insulin in these pups presumably due to its gluconeogenic effect through the liver. In general this investigation points towards the lack of development of appropriate feedback mechanisms for glucose homeostasis in the newborn pups, and that it takes a period of about 3-4 weeks after birth to develop such mechanisms.


Study of heart rate and blood pressure changes under distension of right and left atrial appendages in dogs. Fifteen healthy stray dogs of both sexes were employed in the present study. The effect of distension of right and left atrial appendages with normal saline was observed on heart rate and blood pressure under different situations. It has been found that distension of either appendages separately or simultaneously invariably evoked tachycardia without any appreciable change in blood pressure. Increase in heart rate was found to be of a same magnitude with 5 ml normal saline in both the atrial appendages. However, a higher response was obtained with 10 ml normal saline distension in case of right atrial appendage as compared to left one. Increase in the extent of distension causes more significant response, the receptors of which are stimulated and may be allied to stretch receptors. It is contended that tachycardia could be a reflex effect which is abolished by vagotomy. It is further contended that either afferent, efferent or both pathways exist in the vagi.


Effect of papaya (Carica papaya linn) on pregnancy and estrous cycle in albino rats of Wistar strain. The antifertility effects of Carica papaya were investigated by feeding adult cycling and pregnant rats with different components of its fruits. No attempt was made to force-feed the animals. The results indicate that unripe fruits of papaya interrupt estrous cycle and induce abortions. The abortifacient property seems to decrease as the fruit becomes stale or ripe. Exogenous progesterone counteracts partially the adverse effects on pregnancy and the surviving foeti are without any distinct malformations.


A new sensitive method for detecting human endogenous (leukocyte) pyrogen. Endogenous, or leukocyte pyrogen (EP), the mediator of fever, is currently detected by injection of pyrogen-containing supernatants into rabbits. This assay has been of little value in the study of human fever because it required injection of relatively large amounts of pyrogen. We now report that injection of medium containing human EP produces fever in mice. Supernatant from 1 c 10(5) granulocytes, stimulated by phagocytosis of staphylococci and incubated overnight, or 1 x 10(4) monocytes similarly treated, produce clear pyrogenic responses. This method for detecting EP is about 100-fold more sensitive than the rabbit assay, and it appears to be specific for EP. Preliminary studies of EP released by small samples of needle liver biopsies from febrile and afebrile patients suggests that this sensitive assay may be useful for investigations into the mechanisms of clinical fever.


Effects of cyproterone acetate on the testicular function of bat (Rhinopoma kinneari Wroughton). 1-Cyproterone acetate administration (0.2 mg/day/animal for 25 days) caused widespread testicular necrosis. The lumen of the epididymides were devoid of spermatozoa. The RNA, protein, sialic acid and phosphatase enzyme activity of the testes were reduced. Serum transaminase enzyme activity was slightly changed. Haemoglobin, hematocrit, blood sugar, and blood urea levels were in the normal range. Regressed Leydig cell tissue and decreased production of RNA and sialic acid in the testes could be due to the antiandrogenic action produced by cyproterone acetate.


Role of vagus in thermal panting.

Role of vagus in thermal panting. In dogs anaesthetised with pentobarbitone sodium, raising the body temperature from 37 degrees C to 42 degrees C increased the rate of respiration and pulmonary ventilation but decreased the tidal volume. A similar change though of a lower magnitude, was observed in these parameters after cold blocking the vagi. At 40 degrees C body temperature, however, the vagal block was not effective in reducing the rate. The significance of hyperthermic panting mechanism dominating the Hering-Breuer mechanism at 40 degrees C has been discussed. It has been postulated that the vagi carry temperature dependent afferents that have effect opposite to the Hering-Breuer reflex. At 42 degrees C when respiratory failure usually sets in the temperature regulating function of respiration is the last to be lost.


Restoration of methotrexate-suppressed oxazolone-induced contact sensitivity with levamisole. The effect of levamisole upon cell-mediated immunity was investigated using the oxazolone-induced contact sensitivity response in immunosuppressed and nonimmunosuppressed C57Bl male mice. Mice were sensitized to oxazolone on day 0, and where appropriate, methotrexate (1 mg/kg, p.o.) was administered on days 1 and 2. On day 3, levamisole (5--50 mg/kg, p.o., base) was administered. One hour later, the animals were challenged with oxazolone on the left hindpaw. Twenty-four hours after challenge, the resulting edema was read plethysmographically. Levamisole, in the absence of immunosuppression, had no significant effect upon the oxazolone response whereas, in the face of immunosuppression, restoration of oxazolone responsiveness was observed. These results were suggested to be due to (1) the ability of levamisole to stimulate opposing suppressor and effector components of the oxazolone response coupled with (2) an apparent alteration of suppressor influence by methotrexate allowing levamisole to enhance an unencumbered effector cell population.


Effect of diethylcarbamazine on Setaria cervi in vitro. Diethylcarbamazine (DEC) produced an initial stimulation followed by depression of the movements of the intact worm and nerve-muscle preparation of Setaria cervi. The effective concentration of DEC was reduced to one hundredth in the nerve-muscle preparation as compared to the whole worm, suggesting that the cuticular barrier is highly effective in preventing the penetration of the drugs. The depressant effect of DEC was concentration dependent and was not reversed even after repeated changes of the bath fluid. The worms consumed 7.7 mg +/- 0.2 glucose/g wet weight/hr. The consumption of glucose was directly proportional to its motor activity; it increased during the stimulant phase with low doses of DEC and decreased during the depressant phase.


Pathogenesis of papain-induced emphysema in the hamster. In an effort to determine the mechanism of papain action in causing an emphysema-like lesion in hamsters, the number and types of cells and the activities of two lysosomal enzymes in the lung were determined after papain exposure. Three and four weeks after a 3-h exposure to an aerosol of 3% papain the following alterations in lung structure and function were observed: (1) the mean linear intercept, or average distance between adjacent alveoli, was increased; (2) the internal surface area declined; (3) the dynamic compliance was elevated at low breathing frequencies. The numbers of cells present free in the lung increased from a control value of 2.0 +/- 0.2 x 10 (6)  to 6.6 +/- 0.5 x 10 (6) 5 days after exposure. The free beta-glucuronidase, alysosomal enzyme, likewise increased over threefold during the first 3 days after exposure. These results are consistent with the hypothesis that papain induces an inflammatory-type responses, and this may be in part responsible for inducing the lesion.


The influence of chemotactic factors on neutrophil adhesiveness. The ability of several chemotactic factors to alter polymorphonuclear neutrophil (PMN) adhesiveness to nylon fibers was studied. Partly purified bacterial chemotactic factor, the isolated chemotactic fragment of human C5, and the chemotactic synthetic tripeptide, formyl-methionyl-leucyl-phenylalanine, transiently enhanced the nylon fiber adhesiveness of rabbit peritoneal PMSs. The capacity of these chemotactic factors to augment PMN adherence closely paralleled their ability to aggregate PMNs in suspension and to induce neutropenia when infused into rabbits. However, at least a portion of the adhreence-augmenting capacity of these agents was independent of their ability to induce PMN aggregation. Thus, chemotactic factors appear to transiently enhance PMN adhesiveness to a variety of surfaces. This hyper-adhesiveness may underlie the augmented nylon fiber adherence, aggregation, and neutropenia induced by these factors.


Modification of the toxicity of acetylcholine by prior atropinization in mice. The potentiation of acetylcholine (Ach) toxicity in mice with prior atropinization was tested. The experiments were carried out with three doses of 200 mg, 300 mg, and 400 mg/kg of Ach administered ip. Prior atropinization was observed to potentiate the Ach toxicity at all dose levels of atropine except the highest in the group that received Ach 200 mg/kg and the results were variable in the other two groups.


Two distinct mechanisms for the initiation of mast cell degranulation. II. A specific inhibition of amine release by serum proteins. Our experiments have provided additional data in support of the concept that different mast cell activators follow distinct biochemical path-ways in the initiation of secretion and degranulation. To do this we have taken advantage of the observation that some serum proteins, and albumins in particular, have the capacity to inhibit selectively the release of amines from rat peritoneal mast cells initiated by some, but not all, stimuli. We show that the relative inhibition of release obtained is independent of the concentration of activator but dependent upon the concentration of albumin, indicating that the inhibitory process does not involve a direct activator--inhibitor interaction. Finally, our data demonstrate that the inhibition does not interfere with the ability of the acitivator to interact with the mast cell. Thus, cells incubated with activator in the presence of inhibitor become increasingly unresponsive, or desensitized, to subsequent challenge with activator in the absence of inhibitor. These combined data therefore provide evidence, that, in addition to a selectivity in the activation/desensitization process initiated by different mast cell stimuli, at least one of the biochemical steps subsequent to the activation step is also not shared by all mast cell stimuli.


Pulmonary functions and their correlation with anthropomorphic parameters in young adults of Haryana (India). Pulmonary functions in 169 young males of Haryana were studied with the help of a water seal spirometer and Wright's peak flow meter. Different parameters analysed were FVC, FEV1%, P.F.R., MVV, and expiratory flow rates between 25-50%, 25-75% and 50-75% of FVC. Our mean values are well comparable with those of Indian workers but less than those reported by Western workers. Pulmonary functions correlate better with physical parameters, height arm span and upper segment than with age. Correlation coefficient (r) values of FVC and anthropomorphic parameters are +0.7953, +0.3835, +0.3566 and +0.0992 with arm span, upper segment, height and age respectively. These values of pulmonary functions in healthy adults when compared with those obtained from patients suffering from chronic obstructive lung disease, it was observed that expiratory flow rates may be more useful in the detection of pulmonary changes in obstructive lung diseases at an early and reversible stage.


Sympathetic or reflex footpad swelling due to crystal-induced inflammation in the opposite foot. Sympathetic or reflex footpad swelling occurred in rats when several crystals known to be pathogenic in human joints or soft tissues were injected into the opposite footpad. Monosodium urate (MSU), calcium pyrophosphate dihydrate (CaPPD), hydroxyapatite, calcium oxalate (CaOx), and xanthine (X) suspension induced varying degrees of such reflex of sympathetic swelling. In the second cycle of crystal-induced swelling, the foot that had been the initial or primary site of inflammation reacted with greater reflex swelling, when compared to the first cycle. Similarly, reflex increases in temperature occurred when CaPPD was injected. These reflex increases in swelling and temperature may relate to signs and symptoms of patients with reflex neurovascular dystrophy or shoulder--hand syndrome.


Neutrophilic leukocyte membrane proteins. I. Isolation. Rabbit exudate-derived PMN were homogenized and the cell membranes isolated on a two-phase aqueous system. Glycoproteins were extracted from cell membranes with lithium diiodosalicylate. SDS polyacrylamide gel electrophoretic analysis showed a consistent pattern of three major glycoprotein entities. Cells radioiodinated supravitally showed most of the radioactivity associated with larger glycoprotein entities whereas PMN membranes radiolabeled after isolation yielded a single major peak of radioactivity associated with a much smaller protein entity. Heterologous antisera against rabbit PMN, PMN membranes, and membrane glycoproteins were all cytotoxic for PMN in the presence of complement, and all bound to the PMN surface as demonstrated with immunocolloidal gold on electron microscopy. The data suggest that one or more glycoprotein entities are membrane-associated ectoglycoproteins which can be radiolabeled supravitally.


Effect of three coccidiostatics against toxoplasmosis in mice. Duocoxin, nicrazine and amprol plus showed no therapeutic effect in 50 mice each of which was infected with 25,000 organisms of a virulent Toxoplasma strain.


Sex hormones and the immune response. II. Perturbation of antibody production by estradiol 17beta. The administration of 75 microgram/kg of estradiol 17beta at successively later stages in the immune response of female guinea pigs to penicilloyl-coupled cavian globulins showed that this steroid reduces the rate of attainment of the maximum titer, the magnitude of the titer achieved, and the rate of titer decay. Control titers maximized at the third experimental week and diminished to one third the peak value by the 6th week. When steroid treatment was begun coincidentally with inoculation (week 0), the peak titer was delayed by 3 weeks, and by 2 weeks when hormone priming was begun at week 1 or 2. The highest antibody titers achieved in the presence of estrogen were 25-30% lower than those of sesame oil controls. The greatest immunosuppressive effect was observed when estradiol was given at the peak of the immune response, the titer dropping by 50% and remaining at that level for the next 4 weeks in spite of continued antigen inoculation and steroid treatment. Titer decay after the end of the inoculation course was prevented by estradiol but not by progesterone, CHP, or these same oil vehicle.


Delayed hypersensitivity to hapten-skin protein conjugates in guinea pigs sensitized to benzo(a)pyrene. Guinea pigs were sensitized to 3,4-benzo(a)pyrene, by epicutaneous application or by footbad injection in Freund's complete adjuvant. Conjugates of benzo(a)pyrene and guinea pig skin protein formed by ultraviolet radiation could elicit cutaneous delayed hypersensitivity and could inhibit the migration of macrophages obtained from guinea pigs sensitized to the carcinogen. Extracts of benzo(a)pyrene-treated guinea pig skin and conjugates formed in vitro with benzo(a)pyrene isocyanate were unable to consistently elicit delayed hypersensitivity reactions in vivo or in vitro. The results indicate a high degree of hapten-carrier specificity to contact sensitivity to benzo(a)pyrene.


Activation of neutrophilic granulocytes by products of human lymphocytes. Materials produced by stimulated primary cultures of human lymphocytes and by a continuous human lymphoid cell line, RPMI 1788, were tested for granulocyte phagocytosis promoting activity. Blood lymphocytes of healthy donors were stimulated with tuberculin (PPD) or concanavalin A (con A) and the culture fluids collected after 3 days of in vitro incubation. Fluids of the lymphoid cell line were collected from 2-day-old cultures. All three kinds of preparations were found to induce a significant increase in neutrophilic granulocyte phagocytic activity. Studies on the kinetics of granulocyte activation revealed that it is a relatively rapid process, being maximal within 60-120 min. This is in contrast to the considerably slower activation of monocytes in a comparable system. Intracutaneous inoculation of the active materials in human volunteers resulted in reactions that grossly and histologically resembled accelerated delayed type hypersensitivity reactions.


Cross-reactivity between grass and corn pollen antigens. Analogous reactions of grass and corn pollen extracts in skin tests on patients suffering from pollinosis might suggest an antigenic relationship between grass and corn pollens. This problem was studied using the RAST inhibition test. Tests were performed with cellulose discs labelled with commercial skin test extracts containing grass, rye, wheat, barley, oat and maize pollens. Different mutual inhibitions were measured showing various grades of antigenic relationship. Only grass pollen antigens could strongly inhibit all other antigen-antibody reactions. Thus, we suppose that the investigated grass pollen extract also contains all antigens typical of corn pollen. Therefore, exclusive use of this extract seems to be possible in diagnosis and perhaps therapy of combined grass and corn pollen allergy.


Delayed hypersensitivity to soluble antigens in mice. I. Analysis in vivo. Delayed hypersensitivity to a soluble protein has been analyzed in mice. Ear swelling, 24 h after injection of a test dose of antigen, has been used to monitor the response to a subcutaneous tail injection of egg albumin in complete Freund's adjuvant. Maximal 24 h ear swelling was observed 8 days after sensitization with either 50 or 100 microgram of antigen. These delayed reactions, which were characterized by mononuclear infiltrates, were relatively uncomplicated by Arthus reactions. The latter, antibody-mediated reactions were apparent at later times after immunization. More intense 24 hr reactions were elicited in C57BL/6 than BALB/c mice. Passive transfer of sensitivity has been accomplished with lymph node cells.


A porous metal system for joint replacement surgery. A porous coated chrome cobalt system has been developed to provide long term stabilization in joint replacement surgery. The pore sizes are 50 to 100 microns, thus ensuring sufficient fatigue strength for use in high load bearing situations. Extensive in vitro and in vivo studies have been performed, and a five year follow-up of porous coated total shoulder prostheses has failed to reveal any evidence of loosening. The early results of porous coated hip implants is encouraging.


Studies on sorbents for use in a hepatic support system. A range of adsorbent and ion exchange materials has been tested for the sorption of fatty acids (hexanoic, octanoic and oleic), bilirubin and bromosulphthalein from human plasma. The importance of sorbent particle size for the kinetics of removal of strongly protein bound substances is shown. A system allowing the use of small particle size bioincompatible sorbents for detoxification is presented.


Antithrombogenicity of immobilized urokinase--clinical application. A plasminogen activator, urokinase (UK) was immobilized on four different polymer surfaces: nylon, silicone rubber, poly (vinyl chloride) and a polyester, using our newly devised technique. Each material proved to have plasminogen activating activity. In vitro the thrombus formation time (TFT) of the UK-immobilized nylon tubes was over 45 minutes and the TFT of UK-immobilized silicone rubber tubes varied. When applied clinically, the UK-immobilized nylon tubes showed excellent antithrombogenicity.


Attempts at simulating evolution by a computer: I. evolution of proteins under prebiotic conditions. The effect of random mutations of five identical pentapeptides that have been inserted arbitrarily along a 100 amino acid-long protein chain has been studied by computer simulation. The method used was the application of mutation probability matrix for 2 PAMs of Dayhoff (1972) repeatedly to obtain the desired length of time. The results indicated that, given sufficient length of time, even the identical peptides could become drastically altered and in order to recognise them as stemming from the same origin one has to use reasonable statistical significance thresholds.


A hierarchically-structured model of information processing in neural networks. In order to describe the information processing mechanisms of a neural system a basic building block (sub-network), consisting of a group of interacting neural elements, is introduced. By interconnecting such units to give an integrated structure, a hierarchically-organised processing chain is formed. The properties of such a system are shown to provide a logical description of information processing which links high level events with underlying neural mechanisms.


Computer analog simulation of a model for the regulation of ago-antagonistic couples. A system of quadratic differential equations is proposed within the framework of 'non-linear mechanics', but also outside this framework in respect of certain features, and it is used with a view to formalising a feedback control system. The model helps to simulate states of balance or imbalance within an ago-antagonistic couple and to suggest methods for correcting the imbalances, which do not require modification of the parameter space. Its possibilities of synchronic or diachronic functioning are emphasised. The model may apparently be used for the construction of similar models which include several ago-antagonistic couples. Finally, the aims of such a model, which could be considered as an 'action' model, are defined; its place would be assigned midway between a black-box system and 'knowledge' models.


Robustness of life table methods in large populations--a study by computer simulation. The robustness of the product life table estimator of the survival function was studied for large populations under perturbations in the age distribution, changing levels of mortality and changing patterns of fertility. A macrosimulation system, based on a class of stochastic population models called generalised age-dependent branching processes, was used to carry out the numerical investigations. Aside from drastic perturbations in the age distribution and changes in levels of mortality, the product life table estimator of the survival function was found to be robust in large populations, under a variety of conditions.


Rapidly progressing breast cancer (poussée évolutive) in Tunisia: studies on delayed hypersensitivity. Delayed hypersensitivity reactions to a battery of antigens were measured in 145 Tunisian breast cancer patients to determine whether an immunologic mechanism could be detected which might explain the high frequency (60%) of the rapidly progressing form in Tunisian breast cancer patients. Although a greater proportion (30%) of patients with rapily progressing breast cancer reacted to extracts of a breast tumor antigen (2937) than patients without PEV (9%), no significnat difference between PEV and non-PEV patients could be found in reactivity to DNCB, standard microbial antigens, or extracts from tissue culture cell lines. Rapidly progressing breast cancer in Tunisia is not associated with an impairment of delayed hypersensitivity.


Infectious mononucleosis and Hodgkin's disease. A cohort of 9,454 patients with infectious mononucleosis, serologically confirmed, was followed up to determine their risk of developing lymphoproliferative diseases. A total of 1,759 patients was identified in Scotland from 1959 to 1971 and 7,695 in Sweden from 1952 to 1970. The cancer cases were identified by matching the list of patients with infectious mononucleosis against a list of patients with lymphoma, nasopharyngeal and colon carcinomas registered through 1972 in Sweden and through 1973 in Scotland. A four-fold increase in risk was found for Hodgkin's disease based on 7 cases observed against 1.8 expected. Most of the excess cases of Hodgkin's disease occurred within three years of the diagnosis of infectious moonucleosis and among females. These results are similar to those of four other cohort studies and it is concluded that a positive association exists between infectious mononucleosis and Hodgkin's disease. Several explanations of this association were evaluated. Firstly, it may be that a very small proportion of persons who are in the course of developing Hodgkin's disease are temporarily misdiagnosed as having infectious mononucleosis. Secondly, infectious mononucleosis may increase the susceptibility to a factor which causes or promotes the development of Hodgkin's disease. Thirdly, infectious mononucleosis and Hodgkin's disease may share a common aetiology. Arguments in favour of, or against, each of these explanations are presented.


Substrate activation of cell adhesion factor as a prerequisite for cell attachment. Cell Adhesion Factor, complexed to insoluble collagen-coated tissue culture dishes, is required for the attachment of fibroblasts to this substrate. In solution, the factor has no demonstrable affinity for cells in suspension following trypsin-EDTA removal of cells from monolayer. Cell surface receptors for the factor are present during the assay period since cells allowed to recover for 1 h at 37 degrees C, 4 degrees C or in the presence of 10(-6) M cycloheximide show exactly the same kinetics of adhesion as control cells. It is demonstrated that Cell Adhesion Factor acquires affinity for the cell surface only following its binding to collagen.


Immunological characteristics of leukemia and lymphoma in allogeneic cell immunity: growth of syngeneic tumors in rats immunized with allogeneic cells. The growth of transplanted tumors was strongly inhibited in syngeneic Wistar King Aptekman (WKA) rats immunized with allogeneic tumor cells from Donryu rats. This phenomenon of non-specific immunity against tumors is referred to as "allogeneic cell immunity". However, an exception to the "allogeneic cell immunity" was observed in leukemias and lymphomas. Four transplanted leukemia or lymphoma lines were not inhibited in syngeneic rats immunized with allogenic tumor cells. Furthermore, immunization with allogeneic leukemic cells had only a relatively weak inhibitory effect upon a syngeneic fibrosarcoma and no inhibitory effect upon leukemias. In WKA rats immunized with allogeneic lymphoid cells from Donryu rats, the growth of fibrosarcoma, but not of lymphoma, was inhibited. Using transplantation experiments, both fibrosarcoma and lymphoma were defined as antigenic tumors in WKA rats. Transplantation of mixtures of syngeneic tumor cells and allogeneic tumor cells in WKA rats confirmed the above findings. These results revealed that leukemia and lymphoma differ from non-leukemic tumors in regard to "allogeneic cell immunity".


Work and general psychological and physical well-being. This article describes a study of the influence of job factors (e.g. job control, pay, etc.) on job attitudes (satisfaction, alienation, stress) as well as the joint influence of job factors and job attitudes on general psychological and physical well-being. Satisfaction/alienation and felt stress were found to be two different modes of response to work. Prestige, control, variety, and opportunity for promotion were powerful predictors of satisfaction/alienation. Number of deadlines and job overlap with family life were important predictors of stress. The job factors and job attitudes showed substantively important relationships to general well-being. The testing of various alternate hypotheses supported the inference of a causal work-health link. Implications of the findings are that work must be viewed in a wider context than simply as a form of economic activity if the well-being of the population is to be improved and that a focus on individual "life-styles" as causes of lowered well-being leads to neglect of the underlying social structural bases of disease.


Social relations of production and consumption in the human service occupations. This paper presents a Marxist analysis of human service occupations. As the forces of monopoly capitalism increased the need for human services and destroyed the social institutions which previously satisfied those needs, employment in the human service industries grew rapidly, and may now exceed that in manufacturing. The nature of human services is discussed: production and consumption occur simultaneously; the social relations of consumption and production are closely related; and service workers play a direct social control role. These characteristics generate contradictions between service and control in service work, and between service workers' roles as both oppressed workers and oppressors. Discussions of the ideologies impacting on the relationships between workers and "clients," the dynamics of these relationships, and the struggles to which they give rise conclude the paper.


The magnitude of malnutrition in Latin America. Malnutrition, an illness which can easily be prevented and cured with existing resources and technology, is perhaps the most widespread disease in Latin America. However, it is unrecognized as such, and those population groups that suffer most from it are most prone to have their sufferings unrecorded. Two factors contribute to this: (a) the inaccuracy and incomplete coverage of vital statistics, as reflected by underregistration of deaths, insufficient medical certification of registered deaths, and biases both among certifying physicians and in the International Classification of Diseases; and (b) low population coverage by the health care systems and thus by the statistics which they generate. These factors are related to the ideological bias of those statistical systems and to the concepts of causality which they use. Through a review and analysis of "ad hoc" studies on the frequency of malnutrition in Latin America and its incidence in relation to morbidity and mortality, an estimation is made of malnutrition-caused deaths, which would amount to almost one-fifth of deaths from all causes. As overall availability of food in Latin America is adequate, it is held that this continent ultimately has the level of malnutrition that it wishes to have.


Health policy in France: a major issue in the 1978 legislative elections. For the 1978 legislative elections, all French political parties have, for the first time, a relatively detailed health policy. The right-wing parties of the present government concentrate on the reduction of medical expenditure and the maintenance of the free enterprise tradition of French medicine. The left-wing parties concentrate more on the development of public health institutions and suggest nationalization of the pharmaceutical industry. Within the Left, there is, however, a difference of emphasis: the Socialists propose the setting up of medicosocial centers and abolition of the fee-for-service system; the Communists concentrate rather on industrial health and believe that an improved health service can only come from changes in overall social economic policy. None of these policies is particularly adventurous but their mere existence shows that health is now a major political preoccupation in France. Some of these policies are mainly concerned with individual and public welfare and others with the necessity of maintaining a certain social order. The debate surrounding health policy usually turns around these two issues.


The search for medical care: an exploration of urban black behavior. Results are presented of a study of the medical care-seeking behavior of black adult residents of lower and middle socioeconomic status in two predominantly black, yet geographically and socioeconomically distinct communities within the District of Columbia. Against a varied distribution of primary medical care opportunities within the District, substantial differences are demonstrated in their use by lower- and middle-status residents of a lower-class community. These differences are not, however, manifested among lower- and middle-status residents of an essentially middle-class neighborhood. The patterns of medical care-seeking behavior are observed within a framework of an almost total avoidance of the available medical care personnel and facilities in the proximate suburbs.


Health in Argentina under the Military Junta. The socioeconomic policies of Argentina's Military Junta, in power since March 1976, have led to a sharp impoverishment of the vast majority of the population. In the health sector, facilities which previously were public are being transferred to the private sector, and public hospitals formerly providing free services to the population now charge patients for the care received. As a necessary counterpart to these unpopular measures, a regime of terror has been waged against members of the health team--both those politically active and those considered potentially subversive, particularly the psychiatrists and workers in community health. Differences between the Argentinian situation and previous European fascist patterns are noted, and the possibility of use of the "Argentinian model" in other capitalist countries in crisis is discussed.


The foreign medical graduate and public policy: a discussion of the issues and options. This paper analyzes four basic reasons for curtailing the number of foreign medical graduates (FMGs) entering the United States: the loss to less-developed countries, the possible lower quality of medical care delivered by FMGs, the inability of all U.S. citizens who desire to receive a medical education to do so, and the fear of a possible surplus of physicians in the U.S. For each of these concerns, alternatives are presented and analyzed according to how well they would achieve their objectives. Based on the options proposed for reducing the number of FMGs, the conclusion is reached that the primary concern at present is an oversupply of U.S. physicians.


Ascitic cirrhosis in relation to alcohol consumption. The average daily alcohol consumption of 184 male patients with ascitic cirrhosis and a random population sample of 778 males was ascertained by interview. Relative risks of ascitic cirrhosis are calculated for different levels of daily alcohol consumption: the logarithm of risk is shown to be a linear function of consumption. The proportion of cases attributable to alcohol is calculated and shown to be over 90%. The potential saving of ascitic cirrhosis if individual consumption of alcohol does not exceed 40g. per day is estimated at 80%.


Mortality from malignant tumours of bone and Paget's disease in the United States and in England and Wales. Changes in death rates from malignant tumours of bone among successive cohorts in the U S A and in England and Wales are shown to be remarkably similar. Since cohorts born in the 1870's there have been simultaneous and equal declines in both countries and in both sexes. Comparable cohort trends are also shown for Paget's disease, although the death rates in the U S A are only about one-fifth of those in England and Wales.


Blood pressure and rural--urban migration in Iran. To find the possible association between rural-urban migration and elevation of blood pressure a cross-sectional study was carried out with 379 subjects 40--59 years of age in rural areas of East Azarbaijan, northwest Iran. Another cross-sectional study was carried out in Teheran City in which 403 migrants from the same rural areas and also 357 non-migrant urban residents of the same age group from both sexes were examined. Comparison of the three groups showed that, in all age and sex groups, migrants had higher systolic and diastolic blood pressure than did the people in the rural areas of origin. The blood pressure levels of migrants and non-migrants in the city were not much different from each other. The effect of other variables on the levels of blood pressure was investigated. Age, sex and body build (as measured by ponderal index) were also associated with blood pressure. None of these factors however explained the differences in blood pressure levels between rural-urban migrants and people in the rural areas of origin.


Lichen planus actinicus.

Lichen planus actinicus. Two patients with lichen planus actinicus are reported. Lichen planus actinicus is more descriptive than lichen planus tropicus, since the condition appears in more temperate climate, i.e. Italy. The etiology of this condition is obscure, but light may act as a triggering mechanism.


'The analgesic abuse syndrome': an epidemiological perspective. Mild analgesics are freely available, widely used, and generally safe. Nevertheless a proportion of the population takes excessive quantities, of whom some develop chronic renal failure in consequence. A syndrome of analgesic abuse has been proposed, definable by characteristics other than analgesic intake. To examine this concept, a population study of analgesic consumption was carried out; the distribution was clearly unimodal and no association could be found between the quantity of analgesics taken and social class, marital status, working or not working, tea or coffee consumption or the number of cigarettes smoked. The principal determinants appeared to be sex, with females reporting a higher intake, and the presence of painful conditions. It was concluded that analgesics abuse cannot be defined other than by the number of analgesics consumed, and that the concept of an analgesic abuse 'syndrome' is not helpful in the design of preventive programmes.


The St John's randomized trial of the family practice nurse: health outcomes of patients. From June 1975, to May 1976, in a large family practice in St. John's, Newfoundland, a randomized controlled trial was conducted to assess the effectiveness of a family practice nurse. Effectiveness was assessed using standardized health outcome measures of physical, emotional, and social function which could be applied easily and objectively by non-clinicians to the two groups of patients under study: patients receiving conventional care and patients receiving care from the family practice nurse. After establishing the comparability of these two groups of patients at the beginning of the study, these measurements showed similar levels of physical, emotional, and social function in the two groups after 1 year of receiving either family practice nurse or conventional care. These results agree with previous controlled trials of family practice nurses which have indicated that family practice nurses are effective and safe.


Utilization of services for preventable disease: a case study of dental care in a southern rural area of the United States. The use made of dental services, both preventive and symptomatic, was explored in a small rural southern community in North Carolina as part of a case study illustrative of southern rural patterns of utilization of elective health services. The target population of 1689 persons in 545 households was interviewed in a household survey and in each of four follow-up panel visits over a period of one year--1974--75. Though overall utilization of dental services was low and preventive dental services even lower in both blacks and whites, blacks were at a considerable disadvantage. Unlike whites, increasing education did not increase use of services in blacks; also, unlike whites, black mothers' preventive behaviour was not associated with increased dental preventive behaviour in their children. In addition to barriers to care suffered by the poor, blacks in the south still have additional barriers to overcome: Established patterns of practice are slow to change even when legal and financial barriers are lowered.


Calculation of attributable risks from epidemiological data. Attributable risk is an important epidemiological index, and may be more relevant to many health planning situations than other indices such as the relative risk. This paper outlines the requirements of typical epidemiological data in order to estimate attributable risks, and illustrates the calculations for some common types of research study. The examples chosen have no special significance per se, but represent the main findings of several typical investigations reported in the epidemiological literature. The combination of estimates from several studies and extrapolation to other populations are discussed. Finally the concept of attributable risk as the causal effect of a risk factor is presented.


Some epidemiological factors related to smoking among secondary school children of Delhi urban area. The smoking habits of 1284 school children in Delhi Urban Areas (India) were studied. The prevalence of cigarette smoking was 8.7% overall, increasing from 5.4% amongst boys age 14 to 26.7% at age 19. Nearly 80% started smoking between the ages of 11 to 14 years. Smoking habit was associated with family income and presence of smokers in the family.


A comparative study of urban and rural tetanus in adults. An analysis of 240 patients, aged 15+, admitted to the tetanus ward of Irwin Hospital, New Delhi, with clinically diagnosed tetanus is reported. 134 patients (55.8%) came from rural areas and 106 (44.2%) from urban areas. The male--female ratio for both groups was approximately 2:1. Rural patients were younger, showed a longer incubation period and experienced a lower crude case fatality rate. Traditional practices like the application of cow dung to wounds, ear piercing and tatooing, and chronic ear infections were important factors in developing tetanus, demonstrating a need for health education in rural communities.


Human somatotropin. 55. Synthesis and growth-promoting activity of peptide analogs of the carboxyl terminal plasmin fragment. Three analogs of the carboxyl terminal plasmin fragment of human somatotropin, [Nle 170, Ala165, 182, 189]-human somatotropin-(145-191), [Nle170, Ala165, 182, 189]-human somatotropin-(140-191), and [Lys135,136, 138, Glu137, 139, Nle170, Ala165, 182, 189]-human somatotropin-(135-191) have been synthesized by the solid-phase method. The synthetic peptides were assayed for growth-promoting activity and their potency was found to be comparable to that of [S-carbamideomethylcysteine165,182, 189]-human somatotropin-(141-191) which was derived from the native hormone.


The synthesis and opiate activity of human beta-endorphin analogs. Substituted at residue positions 27 and 31. Four analogs of human beta-endorphin have been synthesized and their opiate activities have been determined. One of the analogs, [27-phenylalanine, 31-glycine]-betah-endorphin, was shown to possess an analgesic potency greater than that of the natural peptide.


Catalytic hydrogenolysis in liquid ammonia. Cleavage of Nalpha-benzyloxycarbonyl groups from cysteine-containing peptides with tert-butyl side chain protection. Application to a stepwise synthesis of somatostatin. To exemplify the extension to synthesis of sulfur-containing peptides of the Nalpha-benzyloxycarbonyl and side chain tert-butyl protective group combination, somatostatin has been synthesized via incremental chain elongation starting from the COOH-terminal cysteine. Cleavage of the Nalpha-benzyloxycarbonyl groups was achieved in high yield, at each stage, by palladium-catalyzed hydrogenation in liquid ammonia. All side chain functionalities including the cysteine thiol groups were blocked by tert-butyl-derived groups. Each gave rise to individual n.m.r. signals which permitted sensitive characterization of all intermediate protected peptides. Mild conditions were used for the removal of all protecting groups from the completed somatostatin tetradecapeptide. The tert-butyl thiol protective groups were readily and completely cleaved by mercuric acetate at pH 4. Oxidation of dihydrosomatostatin with potassium ferricyanide provided somatostatin in good yield. The results indicate that the absolute selectivity between alpha-amine and side chain protective group cleavage afforded by Nalpha-benzyloxycarbonyl hydrogenolysis in the presence of omega-tert-butyl groups may now be extended to synthesis of cysteine- and methionine-containing peptides.


Purification of milk-clotting protease from Bacillus mesentericus strain 76. A two-step procedure for the isolation of pure enzyme from Bacillus mesentericus strain 76 is developed. Ion-exchange chromatography on CM-Sephadex-C50 is used as a second step after precipitation from ethanol. The pure enzyme preparation, obtained after gel filtration on Sephadex-G25 of the ion-exchange chromatographically separated product, possess the highest specific activity achieved. The homogeneity of the final preparation is proved by determination of the N-terminal amino acid (Arg) and by SDS-PAGDE (single disc).


Reaction of ovine prolactin with 2-(2-nitrophenylsulfenyl)-3-methyl-3'-bromoindolemine. The two tryptophan bonds at positions 91 and 150 in ovine prolactin have been cleaved by the use of 2-(2-nitrophenylsulfenyl)-3-methyl-3'-bromoindolemine. The reaction yielded three products: a small fragment containing residues 92-150, a large fragment consisting of residues 1-91 and 151-199 joined by a disulfide bond, and a derivative containing uncleaved but oxidized prolactin. The yield of the two fragments was 38% and 26%, respectively, indicating a cleavage of approximately 55% for each tryptophan residue. The products were characterized by exclusion chromotography, amino acid analysis, isoelectric focusing on polyacrylamide, circular dichroism spectra, two-dimensional chromatography/electrophoresis on tryptic digests, and ultraviolet absorption spectra. The oxidized but uncleaved product had immunological activity, whereas the two fragments had none. None of these derivatives was active as assayed by the pigeon crop-sac test.


Synthesis and circular dichroism studies of two polypeptides H-[Gly-(Pro)3]n-OH and H-[Gly-(Pro)4]n-OH. Recently Gly-(Pro)3 a proline-rich protein (PRP) containing repetitive Gly-(Pro)3 or Gly-(Pro)4 sequences was isolated from human parotid saliva. The synthesis of two polypeptides containing these sequences is described. Their circular dichroism spectra have been recorded and are compared with the circular dichroism spectrum of the natural protein.


Synthesis of an open-chain asymmmetrical cystine peptide corresponding to the sequence A18-21--B19-26 of bovine insulin by solid phase fragment condensation. An insulin fragment containing residues A 18-21 and B 19-26 linked by the disulfide bond between residues A 20 and B 19 was synthesized. The sequence B 21-26 was assembled on a solid support by the Merrifield technique. The protected fragments A 18-21 and B 19-20 were prepared by conventional methods. After forming the disulfide bridge through cleavage of the S-thiocarbonate derivative of A 18-21 by the thiol peptide B 19-20, the resulting assymmetrical cystine peptide A 18-21--B 19-20 was coupled via the carboxyl group of residue B 20 to the free NH 2-terminal amino group of the protected B 21-26 resin. The product was deprotected, cleaved from the resin, and purified to give the homogenous dodecapeptide A 18-21--B 19-26.


Tight packing of protein cores and interfaces. Relation to conservative amino acid sequences and stability of protein-protein interaction. The tightly packed protein interiors and interfaces are taken to be essentially solids. The tight packing, and the r -6 dependence of the energy of van der Waals' interactions may account for the highly conservative core regions of homologous proteins. The hydrophobic free energies used to calculate confirmational stability and the association constants for protein-protein interactions are not adequate, since the free energies are obtained from liquid-liquid transfer of model compounds. An additional term is required, the enthalpy of fusion. This provides an additional approximately 7 kcal mol -1 for the stabilization of the trypsin-trypsin inhibitor complex.


Synthesis and opiate activity of human beta-endorphin analogs with various chain lengths. The synthesis of beta h-endorphin -(1--15), -(1--21), -(1--26), -(1--28) and -(1--29) have been accomplished by the solid-phase method. The opiate activities of the peptides were measured in the guinea pig ileum assay. Their relative potencies were beta h-endorphin (beta h-EP), 1.00; Met-enkephalin, 0.25: beta h-EP-(1--15), 0.17; beta H-EP-(1--21), 0.46; beta H-EP-(1-26), 0.48; beta h-EP-(1--28), 0.89; beta h-EP-(1--29), 1.04.


A survey of atom packing in globular proteins. This survey of the atom packing in the high resolution X-ray crystal structures of 21 proteins indicates that the atom density around a given central atom is determined primarily by its covalently bonded neighbors and proximity to the surface of the protein. Long-range hydrophobic, hydrogen bonding, and electrostatic interactions are strictly of secondary importance. Both radial and angular atom densities were calculated about various central atoms of several residue types, averaged over all occurrences of the chosen residue type in all 21 proteins. Polar interactions, such as hydrogen bonding, involve on the average shorter distances than hydrophobic interactions do, and are more directional. Spatial segregation of polar and non-polar atoms is never complete in long-range interactions since the types of atoms are linked together covalently.


Cyclic peptides. V. Synthesis of AM-toxin II and its analog. A cyclic tetradepsipeptide with a sequence corresponding to AM-toxin II (a phytotoxic peptide) was synthesized in order to confirm the proposed structure by a conventional method. This was mediated through a dehydration reaction of cyclodepsipeptide containing a D-Ser residue, by methanesulfonyl chloride containing sulfur dioxide. The synthetic peptide and natural AM-toxin II were identical as regards t.l.c., crystal form, several kinds of spectra measurements and biological activity in causing necrosis on apple leaves. An analog, [L-Phe1]-AM-toxin, containing the lower homolog (L-phenylalanine) instead of L-2-amino-5-phenylpentanoic acid in position 1 of natural toxin II, was synthesized simultaneously. [L-Phe1]-AM-toxin showed extremely weak activity; the relationship between the bulkiness of an aromatic side chain and the biological activity of AM-toxin II is discussed.


Visual acuity: the influence of refraction and diffraction and the use of interference fringes. In summary, interference acuity provides an exceedingly useful technique for separating optical from retinal causes for poor vision. Opacities can cause gross disturbances of the fringe pattern, so failure in this test may or may not be caused by poor macular function. For patients who would be operated on only if indications of existing potential for vision could be obtained, this test is invaluable. We had several patients who would have been excluded from consideration for a cataract extraction but who were not because we were able to show good potential for acuity; postoperatively, they achieved acuities as predicted. The test succeeded in evaluating macular function in instances when the usual methods of testing for vision potential, such as two-point discrimination, electroretinography, and ultrasound, provided only crude estimates of retinal function. Although the apparatus required is simple-a small laser, a few optical components, and a patient chair-I am not sure how long it will take before ophthalmologists will have it available for office use. But I am optimistic about the possibilities offered by the widespread use of what I consider to be a promising new technique for evaluating macular function behind opacities of the ocular media.


The relationship between retinal receptor orientation and photoreceptor optics. At this time, based on still-restricted studies, it would seem that a fundamental property of vertebrate receptor optics is anterior pointing by receptors. The anterior pointing locus is most probably a point approximating the center of the exit pupil of the eye. There is evidence for the recovery of orientation when that orientation is disturbed. One or more mechanisms mediate that orientation, and we must seek to define and understand their functional properties. We must better define how disturbance in orientation influences vision. Briefly stated, substantially disturbed receptors have reduced light-guiding capability (and hence reduced sensitivity), reduced contrast sensitivity (caused by increased cross talk and so forth), and reduced resolution capability. These combine to creat a detectable (but not necessarily common) form of amblyopia [30]. In a sense, these cases of poor acuity would seem to represent a failure of the photoreceptor alignment system. An interesting set of theories has evolved in relation to receptor alignment in the neonate. There is considerable mechanical hydraulic stress on the newborn ocular vascular system at the time of delivery. Retinal hemorrhages and transient edema of the optic papilla following intracranial pressure rise and rapid decompression later during delivery of the head commonly occur. These can readily causd disturbances in receptor alignment. In some instances the macula is involved. While hemorrhages are apparently rapidly absorbed, if foveal receptors remain misaligned during the critical period (not yet really defined) for the development of vision, central fine-resolution capability may fail to develop. That is, subsequent elaboration of the visual system is dependent upon the quality of the optically transmitted and neurally transformed retinal image during the critical period for visual development. If the capability for realignment exists and occurs after part or all of the critical period, then signs of a prior receptor disarray may no longer be present in later years, but reduced resolution capability can persist. There is interesting literature on the subject [63-68]. K. Simons is currently reviewing this literature as part of his dissertation. Simons points out that the rupture of vessels may in fact partially serve as a safety valve protective of the infant in the presence of these substantive forces, i.e., fine-vessel rupture may limit the potential for damage to the eye. At this stage of investigation it is dangerous to carry speclation too far. Thus not only must we consider the mechanism for orientation, the nature of a possible error signal, and the mechaniisms for maintaning orientation and relating the retina to its substrate, but we must also analyze the consequences of disturbances in these mechanisms in relation to the individual's visual capability. Of equal importance is the need to understand the mechanisms and processes leading to failure of recovery of proper photoreceptor orientation...


Possible indication of dopaminergic blockade in man by electroretinography. In view of the finding that dopamine is the principle neurotransmitter in the retina, an attempt was made to demonstrate dopaminergic receptor blockade by means of electroretinography. In an open experimental setting, the effect of 50 mg thioridazine was compared with that of placebo in 2 groups of 10 normal volunteers. In the placebo group, the post-drug scotopic electroretinogram (ERG) was not significantly different from the pre-drug ERG, while in the thioridazine group, the post-drug scotopic ERG showed prolongation of 'a' wave latency time, prolongation of 'b' wave evolution time, and diminution of 'b' wave amplitude.


Rhodopsin and visual threshold in retinitis pigmentosa. Rhodopsin kinetics and visual threshold were determined in three subjects with a dominant form of retinitis pigmentosa. The retinal areas studied showed varying loss of sensitivity, which correlated well with the reduction in the measured density of rhodopsin in the test region. Rhodopsin photosensitivity was normal, and there was no evidence that either rhodopsin or the cone pigments regenerated more rapidly than normal. The findings in these cases of retinitis pigmentosa, when compared with the threshold changes induced by vitamin A deficiency or photic bleaching, suggest that the disease produces an imbalance between disc removal and new disc formation, which results in a progressive shortening of the photoreceptor outer segments and, eventually, in their complete disappearance.


Normal and amblyopic contrast sensitivity function in central and peripheral retinas. Contrast sensitivity functions (CSF's) for temporally modulated sine wave gratings were established at a variety of retinal eccentricities in three esotropic amblyopes with acuities in their amblyopic eyes of 20/50, 20/100, and 20/300. CSF's were shown to vary with eccentricity and the degree of amblyopia. In the 20/50 amblyope, reduced CSF's were confined to the higher spatial frequencies and to the central 5 degrees of the retina. Given greater acuity deficits (e.g., 20/100 and 20/300), CSF's were depressed over the entire spatial frequency range tested, with the effects intruding farther into the peripheral retina than for the 20/50 amblyope. In addition, the detection of the temporal as well as the spatial modulation was depressed in the CSF's of the observers with severe amblyopia.


A displaced Stiles-Crawford effect associated with an eccentric pupil. Receptors tend to be oriented toward a point near the center of the pupil in the normal eye. We report psychophysical studies of receptor orientation and directional sensitivity in a subject whose right pupil is displaced nearly 3 mm nasally as a result of injury sustained 25 years ago. The Stiles-Crawford effect was measured for foveal cones and for parafoveal cones and rods. Greatest sensitivity was found in all cases at a point close to the center of the natural pupil, indicating that the receptors in this eye are trained toward the abnormally situated pupil. At large angles of incidence, foveal cones exhibited a clear asymptote of sensitivity 0.83 log units below the sensitivity for axially incident light. Parafoveal cones were more directionally sensitive, with a suggestion of an asymptote for oblique incidence about 1.2 log units below the sensitivity for axial incidence. Rods showed a sensitivity pattern decentered like that of the cones, with a greatest observed sensitivity loss of 0.28 log units. Best acuity for cones was observed for entrance pupils close to the optical axis of the eye, remote from the pupillary region for best sensitivity.


The effects of intravitreally injected prostaglandin E1 on retinal function and their enhancement by a prostaglandin-transporter inhibitor. The effects of intravitreally injected prostaglandins (PG's) E1 and F2alpha were studied on conscious, bromcresol green (BrCG)-pretreated and control rabbits. The electroretinogram (ERG) of both the PG-injected and the contralateral control eyes was recorded with contact lens electrodes; and electrocorticogram and the visually evoked response (VER) were recorded from both hemispheres with previously implanted supradural electrodes. In normal rabbits, intravitreal injection of 0.70 mg of PGE1 resulted in a small reduction in the amplitude of the ERG b-wave and of the slow negative wave (SNW) of the contralateral VER. In BrCG-pretreated rabbits, intravitreal injection of 0.70 mg of PGE1 caused a statistically significant decrease in the amplitude of the ERG b-wave and the SNW. Intravitreal injection of 0.7 mg of PGE1 also caused a significantly prolonged inhibition of the ERG in BrCG-pretreated, but not in normal rabbits, following exposure of the eye to a bright light flash. A smaller dose of PGE1 (0.35 mg/eye) caused more moderate effects on some of these parameters. These effects could not be explained by the PG-induced miosis. PGF2alpha (0.7 mg/eye) caused no significant changes in any of the parameters studied. These results indicate that exogenous PG's can have adverse effects on retinal function and that these effects are enhanced by BrCG, a PG-transport inhibitor. Presumably, this inhibitor blocks the PG-removal mechanisms across the blood-retinal barriers and hence allows the accumulation of PG's in the extracellular fluids of the retina.


Reduction by indomethacin of the degeneration increase in outflow facility after superior cervical ganglionectomy in the rabbit. The effects of indomethacin and aspirin on the increase in facility of aqueous outflow occurring 24 hr after removal of the the superior cervical ganglion from rabbits have been studied. Both drugs were administered in the suppository from 1 hr prior to facility determinations. After pretreatment of rabbits with indomethacin in this  manner, the degeneration increase in outflow facility was significantly reduced but not completely abolished. After pretreatment with aspirin, on the other hand, outflow facility of the denervated eyes, although showing a trend toward reduction from values for ganglionectomized eyes of untreated rabbits, was not changed statistically. The effect of indomethacin may be due to inhibition of porstaglandin or thromboxane synthesis. Because of the results with aspirin, however, a special action of indomethacin in reducing the elevated outflow facility must also be considered.


Abnormal retinogeniculate projections in the congenitally microphthalmic cat. The retinogeniculate projections from the normal eye of a unilaterally microphthalmic cat are abnormal in that optic tract fibers cross laminar borders and end, inappropriately, in geniculate layers that would normally receive input from the microphthalmic eye. This congenitally induced abnormal retinogeniculate projection is quite similar to that seen in cats with one eye surgically removed shortly after birth. Although most cells are shrunken in the laminae normally innervated by the microphathalmic eye, cells in the region of the abnormal projection appear normal. The normal pattern of geniculate lamination is also disrupted in that cell-free interlaminar regions are considerably more difficult to define in the microphthalmic cat.


Inflammatory response of guinea pig to injected limbal tissue. This study examined the possibility that homologous limbal tissue, including trabecular meshwork, serving as an antigen, could elicit inflammatory cells responsible for both aqueous obstruction and inflammation; the possible role of this response in ocular disease was also studied. Four sets of guinea pigs were sensitized with complete Freund's adjuvant. One set received just adjuvant and saline, one set received adjuvant plus uvea, and two sets received adjuvant plus limbal tissue. The animal injected with only adjuvant and saline all showed normal ocular histology. Sensitizing guinea pigs with limbus and adjuvant produced mononuclear infiltration of the uvea, trabeculum, and episclera. Lymphocytes and plasma cells predominated. The response induced by the limbus seemed to consist of two components: a uveal and a specific limbal component. The lymphoid infiltration of the uvea was identical to the response induced by uveal antigen in our uvea control group. The limbal component was characterized by clusters of lymphocytes and plasma cells in the trabecular and episcleral regions. This study showed that limbal tissue antigen induces an inflammatory response in both uvea and limbus, and that the inflammatory response in the trabeculum is greater with limbal than uveal antigen.


Elastin content of the scleral spur, trabecular mesh, and sclera. The scleral spur and trabecular mesh of the human eye contain approximately 5% elastic tissue. Elastic tissue forms less than 2% of the sclera.