Effects of the inhibition of aromatic aminoacids decarboxylase on prolactin secretion in humans. Carbidopa, at the dose of 250 mg. and benserazide at the dose of 125 mg, given orally in a single dose to healthy women aged between 23 - 26 years enhance significantly serum prolactin. The effect is not shared by two other inhibitors of AADC, namely alpha-methyl DOPA (500 mg) and fentiazac (400 mg). The effect of benserazide is suppressed by bromocriptine (2.5 mg) and blunted by 1-DOPA (400 mg) given orally simultaneusly.


Dose and sex related effects of benserazide on prolactin secretion. Benserazide, given orally at various doses ranging from 10 to 125 mg. to healthy women aged 21 to 33 years induces a dose related increase of prolactin titres in serum. When 125 mg are administered the percent increase of the hormone is larger in women than in men.


Ultrastructural aspects of Sertoli cells in infancy. In the present study some aspects of Sertoli cells of testicular-biopsy specimens of children from 0 to 8 years old are examined. We can distinguish two main morphological situations. In the first one, Sertoli cells with monomorphic aspect can be seen; in the second can be shown Sertoli cells with various aspects. In this polimorphic situation we can distinguish three Sertoli cell types differing in cellular shape, cytoplasme electron-density and amount of RER and Golgi complex.


Effect of elaboration of a local motor-food conditioned reflex and reconditioning its effector component on the protein content in neurons of the motor cortex of rats. Elaboration in rats of a local motor-food conditioned reflex in the form of pressing a lever by a preferred foot was accompanied by an increase of the protein content in interneurons in the absence of a change of this index in large and medium pyramidal neurons in the V layer of the motor cortex in the projection of the preferred foot in comparison with the symmetric point of the opposite hemisphere. Reconditioning of the conditioned reflex, i.e., its accomplishment by the nonpreferred foot, was accompanied by a decrease of the protein content in large pyramidal neurons of the V layer of the motor cortex in the absence of changes in the dry mass of interneurons in the projection of the nonpreferred foot in comparison with the projection of the preferred foot. Pyramidal neurons of the III layer reacted by an insignificant change in the protein content both in the case of elaborating the conditioned reflex and reconditioning of its effector component. It is suggested that the pyramidal neurons of the III layer, large pyramidal neurons and interneurons of the V layer of the motor cortex are involved in metabolic provision of elaboration of the local motor-food conditioned reflex and in the formation of new motor coordination at different stages of these processes.


Criteria for selection of physiologically active substances (pharmacometry under screening conditions). The problem of quantitative evaluation of the pharmacological influence of physiologically active substances with receptor action on the organism under conditions of screening is discussed. A vector-significant criterion, based on a functional multiparameter method (FMM), is suggested as the basic characteristic of effectiveness of action. This criterion permits an evaluation of the latitude of the permissible physiological effect, the threshold of subtoxicity, and the selectivity of the action of the substance according to the dominant activity.


Disposition of 5-fluorouracil during chronic hepatic arterial infusion to patients with carcinoma in the liver and effect on circulating platelets. 5-Fluorouracil was administered by continuous hepatic intra-arterial infusion to eight patients with the diagnosis of cancer of the gastrointestinal tract and hepatic metastases. Its elimination characteristics were investigated to see if they correlated with therapeutic effect or reduced clinical toxicity when the drug was given by this route. Urinary excretion of drug and metabolites was similar to findings after intravenous bolus doses. Disposition changes could not be correlated with therapeutic effect or clinical toxicity. A dose-related biphasic effect of 5-fluorouracil was found on circulating platelets. Doses greater than 6 mg kg-1 d-1 decreased the number of circulating platelets, while doses less than that resulted in an increase in circulating platelets. Further studies are required to determine the mechanism of the effect of 5-fluorouracil on platelets.


Simultaneous determination of methenamine and formaldehyde in the urine of humans after methenamine administration. Methenamine (hexamethylenetetramine) and its hydrolysis product formaldehyde are determined in the presence of each other in urine by a spectrophotometric method. Formaldehyde is assayed by a colour reaction with tryptophan, sulphuric acid and ferric chloride after precipitating methenamine by three treatments with mercuric chloride. Methenamine is indirectly analysed by hydrolysis to formaldehyde with dilute hydrochloric acid. Formaldehyde levels as low as 5.0 micrograms ml-1 in the presence of methenamine concentrations as high as 2.5 mg ml-1 can be assayed. Of practical significance is the feature that urine may be stored up to 1 weeks for analysis, by appropriate dilution and freezing, without excessive loss of methenamine or formaldehyde. The method was applied to the dtermination of the bioavailability of methenamine hippurate in ten human volunteers.


Comparison of two dissolution apparatuses with correlation of in vitro-in vivo data for prednisone and prednisolone tablets. Dissolution profiles in 0.1N hydrochloric acid using both the paddle stirrer apparatus and the spin filter apparatus were obtained for prednisone tablets made by seven different manufacturers and prednisolone tablets made by eight different manufacturers. Dissolution parameters were correlated with results obtained in three human bioavailability trials which were previously reported. Also, results obtained in one apparatus were correlated with those obtained in the other apparatus. Such correlations may be useful in the setting of in vitro dissolution rate specifications for commerical prednisone and prednisolone tablets.


Plasma concentrations and pharmacokinetics of dihydralazine after single oral doses to human subjects. After single oral doses of 20 mg of a suspension of dihydralazine sulphate to human subjects, the peak of mean plasma concentrations of dihydralazine of 47.0 ng ml-1 +/- 11.0 standard deviation (S.D.) (n = 7) was reached at 1 h. Mean concentrations declined biphasically with apparent half-lives of 0.57 and 4.96 h respectively. Dihydralazine was partly converted to hydralazine. The peak of mean plasma concentrations of the latter drug of 3.9 ng ml-1 +/- 1.7 S.D. (n = 7) occurred at 1-2 h after dosing with dihydralazine sulphate and declined to 1.5 ng ml-1 +/- 1.5 S.D. at 6 h. Of the seven subjects studied, three were classified as fast and four as slow acetylators. Mean clearances appeared to be slightly more rapid in fast acetylators (1.63 l min-1 +/- 0.32 S.D.) when compared to slow acetylators (1.31 l min-1 +/- 0.31 S.D.) but this difference and differences in plasma concentrations and in areas under the plasma drug concentration-time curves were not significant (p > 0.1).


The renal clearance of disopyramide after bolus intravenous injection. Following bolus intravenous injection of disopyramide in eight normal volunteers the renal clearance of the drug appeared to fall with time. In the first two hours after injection renal clearance had a mean value of 89.0 ml min-1 and fell to 29.4 ml min-1 between 48 and 72 h. In a separate study disopyramide was given by continuous intravenous (i.v.) infusion for 8 h following a loading dose of the drug. Renal clearance of disopyramide was thus estimated hourly over three narrow serum concentration ranges in a single volunteer. The estimate of renal clearance of the drug over the first hour following the start of these infusions was considerably in excess of values obtained later in the experiments. The change in disopyramide renal clearance following bolus injection is partially time-dependent. There are, however, fallacies in calculating short-term clearance values after bolus drug injection from the venous concentration-time curve and these may partially explain the change in renal clearance of disopyramide with time.


Animal model for investigation of fluphenazine kinetics after administration of long-acting esters. A model was developed for studying fluphenazine availability and disposition. Rats were given doses of radioactively labelled esters of fluphenazine by intramuscular injection. Radioactivity excreted in urine, faeces, and expired air was assessed for fluphenazine esters, fluphenazine, and CO2 content. Levels of fluphenazine and its esters were measured in plasma, brain, and muscle (injected and non-injected samples). The data mimicked those obtained in other studies involving the same material given to human subjects, and posed new questions concerning the factors controlling fluphenazine availability when given as 'long-acting' intramuscular injections.


No neoplastic alteration of metabolically competent rat liver cells in vitro by chemical carcinogens: 3-methylcholanthrene, dimethylnitrosamine and Natulan. Epithelial rat liver cell line RL-19 was checked for aryl hydrocarbon hydroxylase and dimethylnitrosamine demethylase activity. Aryl hydrocarbon hydroxylase activity was found at the rate of about 14.5 pmoles 3-hydroxy-benzopyrene per min per mg protein. This activity was not inducible by 3-methylcholanthrene or by phenobarbital and was independent of the subculture level. From the 45th up to the 59th subculture the mean demethylase activity was about 1.08 nmoles HCHO per min per mg protein, but was decreased to 0.64 nmoles HCHO per min per mg protein at the 131st subculture. RL-19 cells were treated with 3-methylcholanthrene (0.5-1.0 microgram/ml), dimethylnitrosamine (100-400 micrograms/ml), or Natulan (50 micrograms/ml), respectively, for 7 to 10 days. During a 6 months subsequent cultivation no neoplastic changes were observed as revealed by morphological investigation, soft agar assay, and transplantation. It is suggested that metabolic competence for carcinogen activation is only one prerequisite for neoplastic alteration in vitro, and that RL-19 cells are refractory to the action of carcinogens in spite of their metabolic capacity.


Evidence of epoxide hydrase activity in human intestinal microflora. Cholesterol-5 alpha, 6 alpha-epoxide has been implicated as an etiologic agent in  human colon cancer. The epoxide is metabolized by human intestinal microflora to a product which was characterized by thin-layer and gas-liquid chromatography as well as combined gas-liquid chromatography-mass spectrometry. Chromatographic properties are identical with authentic cholestan-3 beta, 5 alpha, 6 beta-triol, and these results suggest that microbial epoxide hydrase activity is present in the human colon.


Metabolism of N-nitroso-2-oxopropylpropylamine by rat liver: formation of products resulting from both oxidation and reduction. Metabolism of N-nitroso-2-oxopropylpropylamine (NOPPA) with either a microsomal preparation or the soluble enzyme fraction from rat liver yielded N-nitroso-2-hydroxypropylpropylamine (NHPPA). We have also identified and quantified propionaldehyde, n-propanol and isopropanol following incubation of NOPPA with the microsomal fraction.


Potentiation by clofibrate of in-vivo tumor inhibition by hydrazine sulfate and cytotoxic agents, in Walker 256 carcinosarcoma. Clofibrate as a sole agent was found to have statistically perceptible antitumor effects against the in vivo growth of Walker 256 intramuscular carcinosarcoma in rats. Clofibrate was also found to potentiate the antitumor effect of hydrazine sulfate, cytotoxic drugs and the combination of hydrazine sulfate + cytotoxic drug. The results suggest that substances which might directly or indirectly interfere with host lipogenesis and/or lipolysis, may also have adjunctal antitumor potential.


Immunoelectrophoresis of ligandin.

Immunoelectrophoresis of ligandin. Procedures are described that facilitate the immunoelectrophoretic analysis of the carcinogen-binding protein ligandin. Rocket immunoelectrophoresis is performed at pH 4.9 in agarose gel containing carbamylated antiserum thereby promoting more rapid migration of ligandin, pI 9.0, into the gel. This method is used as a basis for quantitative crossed immunoelectrophoresis using either electrophoresis or isoelectrofocusing of ligandin in the first dimension.


Polypeptides that inhibit human breast cancer cell division. Medium sized (10-15 amino acids) polypeptides isolated from normal human urine inhibit the growth of five established cell lines of human mammary cancer. Cytostatic and cytotoxic effects are dose dependent and reversible at lower doses. Evidence suggests a block to cell division in S phase.


Binding of the Cain quinolinium, NSC 113089, to rat tissue lipid extracts. The binding characteristics of the cancer chemotherapeutic Cain's quinolinium 6-amino-1-ethyl-4-[p-[[p-[(1-ethylpyridinium-4-yl) amino] phenyl] carbamoyl]-anilino]-quinolinium dibromide (NSC 113089) to lipid extracts from rat kidney, liver, heart and skeletal muscle has been studied. Such binding is saturable with an apparent KD congruent to 1.6 microM. Drug binding to the lipid extracts is displaceable by spermine, spermidine, calcium ions and protons. Spermine is the best displacing agent, achieving half drug displacement from the lipid extracts at approximately 6.3 microM regardless of tissue. The inability of the displacing agents to displace all the NSC 113089 bound to the lipid extracts as well as differences in the amount of agent bound to as compared to amount of drug displaced from the lipid extracts indicate that a number of drug binding sites may be present in the lipid extracts. The similarities of drug binding by rat tissue lipids to similar lipids extracted from normal animal and tumor tissues is discussed.


Differential sensitivity of tumor cells to externally generated hydrogen peroxide. Role of glutathione and related enzymes. (1) Oxygen uptake and lactate production of different strains of ascites tumor cells were assayed after exposure to an extracellular photochemical system known to produce reactive oxygen derivatives. The various cells tested showed differential sensitivity to the treatment, ranging from nearly full inactivation of Ehrlich cells to nearly full resistance of Yoshida cells. (2) Glucose plus succinate added after the treatment reestablished basal oxygen uptake capacity suggesting that the cell membrane was the primary site of damage. This was confirmed by dye-permeabilization and protein leakage in sensitive cells. (3) H2O2 was shown to be the only relevant oxygen derivative in the production of cell damage: catalase was the only externally added agent that protected sensitive cells, and H2O2 (congruent to 10(-3) M) had the same effects as the photochemical treatment. (4) While the absence of catalase is a feature common to all tumors tested, sensitivity to H2O2 appears to be related to cellular levels of glutathione peroxidase and of its subsidiary enzymes glucose-6-phosphate dehydrogenase, glutathione reductase and glutathione synthetase.


A theory of cancer induction by parametric excitation. The theory of cancer induction of ultimate carcinogens by parametric excitation is presented. Attention is drawn to the requirement of an energy transfer in perturbing DNA. The concept of energy transfer by resonance is rejected in favor of energy transfer by parametric excitation of which resonance is a special case. The result, reported here, is a remarkable agreement between the Raman vibrational bands of these ultimate carcinogens, various hypochromic bands of DNA and the predictions of parametric excitation theory. This result suggests that the peculiar relation of an ultimate carcinogen and DNA results in parametrically induced energy transfer in the vibrational mode. The problem, then, of cancer induction becomes one of analytical mechanics.


Neutral lipids in DNA, histone and nonhistone fractions of Ehrlich ascites tumor cell chromatin. Lipid content and composition of DNA, histone and nonhistone proteins of Ehrlich ascites tumor cell chromatin were investigated. All fractions contained varying amounts of lipids, mostly neutral lipids, with different quantitative distribution. The DNA fraction was characterized by elevated total cholesterol level (37%); the histone fraction by high glycerol ester content (62%); and the nonhistone protein fraction by high percentage of glycerol ethers (22%). The results suggest that neutral lipids are integral parts of tumor cell nucleoproteins.


Abnormal protein synthesis in malignant melanoma cells. Abnormal proteins in neoplastic cells are present in a variety of animal tumor systems. Our laboratory has isolated several of these abnormal proteins from murine malignant melanoma by preparative gel electrophoresis; these proteins are similar in many respects to analogous proteins found in normal tissues. Examination of these proteins by polyacrylamide gel electrophoresis, amino acid analysis, carboxy and amino terminal analysis and peptide mapping after cyanogen bromide cleavage, supports the theory that these abnormal proteins are the result of deleted sequences in the peptide chain during the attempted synthesis of normal proteins in neoplastic tissue.


Bioassay for thymic extracts: guinea pig spleen lymphocytes-rabbit red blood cells rosette method. An assay is described for assessing the potency of thymic extracts by the capacity of guinea pig spleen lymphocytes to form rosettes with rabbit red blood cells. Its sensitivity and reproducibility have been evaluated by statistical analysis of the data obtained testing different batches of the calf thymus extract TP-1.


Free radical activation of N-hydroxy-2-acetylaminofluorene by methemoglobin and hydrogen peroxide. We have shown that N-hydroxy-2-acetylaminofluorene, a metabolite of 2-acetylaminofluorene, is converted via a nitroxide free radical into N-acetylaminofluorene and 2-nitrosofluorene by H2O2 in the presence of methemoglobin. Utilizing optical methods, we have demonstrated that the rate of 2-nitrosofluorene production parallels that of N-hydroxy-2-acetylaminofluorene oxidation. This evidence is consistent with a model whereby two molecules of N-hydroxy-2-acetylaminofluorene yield two nitroxide free radicals which then dismutate to form one molecule of N-acetoxy-2-acetylaminofluorene and one molecule of 2-nitrosofluorene. The Km of N-hydroxy-2-acetylaminofluorene for this reaction is 114 microM with a Vmax of 50 microM/min.


Correlation of mixed-function oxidase activity with ultrastructural changes in the liver of a marine fish. Specimens of mullet (Mugil cephalus), a marine fish, were given single doses of 3-methylcholanthrene intraperitoneally and the activity of the microsomal mixed-function oxygenase system in the liver was measured by the metabolism of benzo(a)pyrene. The enzyme system was found to be inducible with concomitant ultrastructural changes in the hepatocytes. The specific activity and the metabolic profile approximate those of the rat.


Regional chemotherapy by isolation-perfusion. For 20 years, regional chemotherapy by isolation-perfusion has been employed for limb and selected pelvic lesions using high doses of drugs without systemic side effects. When used prophylactically, it is combined with local excision of the lesion and primary closure reducing the number of skin grafts and recurrence rate for local or intransit disease. Overall survival rate is better than for patients treated by surgery, and perfusion patients also do better with secondary therapy. For advanced melanoma patients with intransit metastasis, a 50% five-year survival may be less than expected. For patients with soft tissue sarcomas < 5 cm in diameter, the five-year survival is just under 80% and just over 40% for those > 5 cm. Complications may occur in 10% of patients treated by prophylactic perfusion, and the rate increases as the dosage and number of drugs are increased, up to a 37% complication rate for patients with advanced disease in a limb.


Evaluation of ten-year survival after operation for upper- and mid-thoracic esophageal cancer. From 1946 to 1976, we studied 1,329 cases of radical resection of upper and mid-thoracic esophageal cancer, a cancer whose prognosis is especially poor. Of these, 7 patients lived longer than 20 years, and 58 longer than 10 years. There were 137 patients who lived for more than 5 years. We particularly examined the ones who lived longer than 10 years, and from the findings of histological and pathological specimens we judged the malignancy grade according to the classification of histological malignancy which we had proposed earlier (cellular atypism, structural atypism, and infiltration). Malignancy grade was demonstrated to be closely associated with the prognosis and survival time.


Characteristics of malignant phenotypes in familial polyposis. Numerous clinical syndromes associated with multiple polypoid lesions of the gastrointestinal tract have been described. These syndromes generally have two striking characteristics: 1) Most of them are familial with the disease being inherited as a mendelian autosomal dominant trait, and 2) most of the affected patients have moderate to marked propensity to develop gastrointestinal carcinoma, usually of the large bowel. Whereas previously many of these syndromes were thought to be well-defined entities, it now appears that there is overlap between certain of them such that they appear more similar than different. The clinical and pathologic characteristics of the various gastrointestinal polyposis syndromes and the methods of diagnosis and treatment are reviewed in this manuscript.


Melanocytoma of the optic nerve head: a review. The melanocytoma of the optic disc is a deeply-pigmented tumor located on the optic nerve head. In contrast to malignant melanoma, it appears to occur in equal frequency in whites and non-whites. Histologically, it consists of deeply-pigmented plump nervus cells with benign characteristics. No treatment is usually necessary and the prognosis is excellent.


On the effects of different laser energy sources upon the iris of the pigmented and the albino rabbit. The irides of pigmented and albino rabbits have been irradiated by a) a CW argon laser beam (exposure duration up to 1 s), b) a 1 ms pulses Nd:YAG laser and c) a 30 ns pulses Q-switched ruby laser. The immediate and long-term pathologies were analysed by scanning and transmission electron microscopy over a period of 13 months. At both the gross and ultrastructural levels, damage configuration may differ considerably, depending on the three modes of irradiation. For each source there are both thermal and mechanical damage components and the significance of mechanical effects increases with decreasing pulse duration for a constant pulse energy. In the argon experiments, tissue destruction is predominantly a consequence of heat, resulting from conduction and convection. The subsequent regeneration of tissue after such heat-induced trauma is fast. The effects of the Nd:YAG laser, at the irradiance levels used in the present study, are again predominantly of a thermal nature and are caused by heating and local evaporation. The pigmented and the nonpigmented iris epithelium are destroyed and widespread decay of the stroma occurs over some months. Such damage never results in full repair. The most prominent feature of Q-switched ruby laser irradiations is their independence of the iris pigment content. In contrast, at the energy levels studied, the argon laser is entirely ineffective, whilst the effect of the Nd:YAG laser is much reduced in the absence of pigment. The consequences of these findings for the clinical applications of such lasers are discussed.


Gyrate atrophy of the choroid and retina with reticular pigmentary dystrophy and ornithine-ketoacid-transaminase deficiency. A 10 year old white girl is presented with gyrate atrophy of the choroid and retina (atrofia gyrata). She also showed reticular pigmentations at the level of the retinal pigment epithelium temporal to both maculas. A generalized hyperornithinaemia was demonstrated in this patient and cultured fibroblasts established the underlying ornithine-keto-acid-transaminase (OKT) deficiency for the first time. Pharmacologic doses of vitamin B6 nor restriction of dietary protein resulted in a significant decrease of the serum ornithine concentration. It is probable that hyperornithinaemia in itself is not the cause of the gyrate atrophy.


Results of pars plana vitrectomy in penetrating ocular trauma. Thirty-four severely injured eyes were operated with pars plana vitrectomy. The nine cases with involvement exclusively of the anterior segment alone were operated with success in all cases. However, the injuries of the posterior segment still reflect significant problems in that only 50 percent obtained successful visual results. This reflects, in great part, the degree of severity of the initial damage. The theoretical rationale for pars plana vitrectomy in penetrating ocular trauma is discussed. Because of the many variables from patient to patient and injury to injury, conflicting clinical impressions as to appropriate management prevail. In the abscence of a definitive clinical trial or suitable experimental model, our guidelines for the role and proper timing of pars plana vitrectomy for penetrating ocular trauma are presented.


Further evidence for the fusional nature of the compensation (or 'eating up') of prisms in concomitant strabismus. The fusional nature of the phenomenon of prism compensation in strabismus was studied. At first a general survey was performed on the characteristics of anomalous fusional movements (a.f.m.). The influence of different kinds of stimuli (foveal and peripheral fusionable targets, non-fusionable targets) on a.f.m. was considered, and finally the effect of a sensorial obstacle to fusion was investiaged. It is concluded that 'eating up' the prisms is definitely a phenomenon of fusional nature, although it has special features which are interpreted as a consequence of the initial pathological condition. In this way the puzzling prism compensation also in subjects with normal retinal correspondence may be explained.


'Rebound-saccade' in the prism cover test. If the fixing eye of a squinting patient is covered, a saccade to take up fixation follows which corresponds to the eccentricity of the image on the retina of the squinting eye. However, in some strabismus patients one finds a saccade even though the image on the retina of the squinting eye has already been deflected onto the fovea centrailis with the aid of prisms. This saccade brings the eye into the primary postion and displaces the image of the fixation target to a peripheral retinal point, so that the image must be recentred onto the fovea by a second saccade. We propose to call this movement to and fro a 'rebound-saccade'. This phenomenon indicates that, in patients with alternating strabismus, extraretinal information determined by the angle of squint influences rapid alternation of fixation between the right and left eyes. The rebound-saccade cannot be explained by anomalous retinal correspondence.


Ischemic optic neuropathy.

Ischemic optic neuropathy. Ischemic optic neuropathy (ION), based on vascular anatomy of the optic nerve, pathogenesis and clinical picture, consists of two distinct entities: anterior (AION) and posterior (PION) ischemic optic neuropathies. AION is due to interference with posterior ciliary artery supply to the optic nerve head and retrolaminar part of the optic nerve; it initially presents with visual loss and optic disc edema which progresses to optic atrophy in a month or two. PION is due to occlusion of nutrient arteries to the posterior part of the optic nerve; in this condition during the initial stages the optic disc is normal in spite of marked visual loss, but the atrophy develops later on. Their pathogeneses, causes, clinical pictures, diagnosis and management are discussed briefly.


Guidelines in the management of penetrating ocular trauma with emphasis on the role and timing of pars plana vitrectomy. The principles and guidelines in the management of penetrating ocular injury are detailed. In the absence of definitive clinical trial or an experimental model, the rationale for pars plana vitrectomy has been presented. In addition, our recommendations as to the appropriate role and timing of pars plana vitrectomy are included.


New observations concerning choroidal osteomas. The clinical and laboratory findings in fifteen patients with nineteen eyes containing choroidal osteomas are summarized. The first case of the disease in a male patient is reported as well as the development of a second tumor in the previously uninvolved eye of an adult patient and the marked enlargement of the tumor in another. The possible etiology of the choroidal osteomas is discussed.


Measurement of visual resolution at high luminance levels in patients with possible demyelinating disease. An interferometric acuity device (Takata) has been used to study visual resolution in individuals with possible demyelinating disease. The instrument employed provides a large field with a continuous range of grid or fringe frequencies and a relatively intense (10(5) mean photopic trolands) stimulus. After a brief period of time with eyes closed, resolution thresholds of patient are repeatedly determined during a five minute period. In all individuals suspected of having a demyelinating disease tested to date, a fall off in resolution capability has been found in time when using this intense stimulus display. This occurs whether eye signs have been present, are present or have not yet been observed. Normal observers do not exhibit comparable decrements. The fall off in resolution capability may or may not occur at lower stimulus levels, and is often not revealed when testing routine Snellen acuity. Outer and inner retinal pathology (division based on vascular support) do not cause a comparable fall off in resolution in time. The interferometric acuity test is a non-invasive, easily applied test.


Four year follow-up of a glaucoma operation. Prospective study of the double flap Scheie. This paper presents the four-year follow-up results of a prospective study on the results of the Double Flap Scheie. The study was started in 1971 and the pre- and post-operative evaluation was carried out according to carefully selected criteria. Admitted were only open angle glaucoma patients. Diurnal IOP-curves, static perimetry, evaluation of lens and optic disc in mydriasis were included in the complete pre- and post-operative examination. In the Douible Flap Scheie a conjunctival and scleral flap are made followed by a cornea-scleral cauterization and incision after which a peripheral iridectomy is made. 51 eyes of 48 patients were operated. After 4 years 42 eyes of 37 patients could still be examined. The mean IOP was reduced from 33.0 to 17.3 mm without additional therapy. This is a mean percentage reduction of 48.5%. 75% of the mean IOP was under 21 mm; with additional therapie 91% was under 21 mm. Diurnal variation decreased from 7 to 4 mm. 48% of the eyes showed a decreased visual acuity of which 38% was caused by cataract. 52% showed visual field deterioration of which one third was attributed to cataract. In 24% the visual field deterioration was considered clinically important. There was no clear relation between IOP level and visual field deterioration.


Intraocular pressure in retinal detachment. Relative hypotony in the affected eye was present in 40% of patients with uncomplicated unilateral retinal detachments. The average pressure asymmetry was only 1.3 mm Hg, but in one out of every four patients the difference was 3 mm Hg or more. In a control group, such a difference occured in only one out of every twenty patients. Relative hypotony persisted for longer than six months after scleral buckling operation, occuring even in patients that did not exhibit hypotony preoperatively.


Double optic pit with wedge-shaped choroidal dystrophy. A case of double optic pit is presented with minimal macular involvement but with an extensive wedge-shaped area of choroidal dystrophy in the nasal fundus. This wedge-shaped area of dystrophy is ophthalmoscopically and fluoroangiographically similar to the lesions of choroidal infarction. As however, it is situated near the nasal pit it might be the result of an unnoticed serous detachement related to the presence of the pit.


The psychopathology of feeling and thinking in a schizophrenic. This paper describes the process and technique of brief analytic psychotherapy with a 22-year-old schizophrenic man who was treated twice weekly for ten months and then followed up for two years. During therapy, re-integration occurred in his affective and cognitive processes. Despite his subjective experience of loss of the capacity for thought and for verbal and non-verbal communication, he had an unusual ability for conveying the stages by which he moved from total confusion and thought disorder to normal intellectual functioning, and for understanding the connections between his various experiences. Four phases of therapy are defined: a phase of disintegration and undifferentiation lasting six weeks, a phase of depression lasting for five weeks, a phase of multiple feelings lasting for fourt thought disorder to normal intellectual functioning, and for understanding the connections between his various experiences. Four phases of therapy are defined: a phase of disintegration and undifferentiation lasting six weeks, a phase of depression lasting for five weeks, a phase of multiple feelings lasting for fourt thought disorder to normal intellectual functioning, and for understanding the connections between his various experiences. Four phases of therapy are defined: a phase of disintegration and undifferentiation lasting six weeks, a phase of depression lasting for five weeks, a phase of multiple feelings lasting for fourteen weeks, and a phase of self-sustained development, starting in the twenty-fifth week and continuing beyond the end of therapy. The patient identified two major types of divisions between thinking, feeling and acting parts of himself and between masculine and feminine parts. Insight into these divisions helped him to understand disorders in his perception of time, and in thinking, remembering and using words and other symbols. His descriptions are presented here in the hope that they may throw light on the difficulties of similar, but less articulate, patients.


Oedipal conflicts in narcissistic personality disorders. A premise of this paper is that a number of male patients we refer to as 'narcissistic characters' suffer intense guilt. This derives from the fact that their oedipal experiences come closer to actualizing what Freud (1916) characterized as 'the two great criminal intentions of killing the father and having sexual relations with the mother' (p.333). Case material is presented to delineate these disturbances. Process material is examined to highlight problems of technique common to these patients.


Defensive and arrested developmental aspects of death anxiety, hypochondriasis and depersonalization. The theoretical distinction between psychopathology based on intrapsychic conflict and psychopathology rooted in a developmental arrest is applied to an analysis of death anxiety, hypochondriasis and depersonalization. The defensive functions of these states are contrasted with instances in which they are symptomatic of interferences with the consolidation of a structurally cohesive and temporally stable self representation. Clinical material is presented to demonstrate that, in their arrested developmental aspects, death anxiety, hypochondriasis and depersonalization are closely related to one another along a continuum of narcissistic decompensation and signal varying degrees or stages of self-fragmentation.


Dimensions of a single word-association in the analyst's reverie. The reverie, an apparently random series of events occurring in the analyst's consciousness when his attention is evenly suspended, is examined through the expansion of one of its elements, a single word-association. When this expansion is compared with other data in the analysis, the reverie appears to be both continuous and self similar.


On the pathology of the separation-individuation process as manifested in later clinical work: an attempt at delineation. In this paper, through clinical example, I have attempted to illustrate and to delineate aspects of the pathology of the separation-individuation process as they are manifested in later clinical work. I have distinguished between pathology of the relation to the differentiated other and the undifferentiated other, the latter being the primary phenomena with roots in the separation-individuation process; and I have attempted to show that the confusion between these two rests on a focus on surface presentations rather than in-depth understanding. A further distinction was drawn within the pathology of the relation to the differentiated other; some clinical phenomena there can be seen as tied to the differentiation process itself, and are thus also linked to separation-individuation. Finally, the relevance of the concepts of separation-individuation to depersonalization/derealization, to 'as if' character, and to folie à deux was discussed.


The development of time sense--from birth to object constancy. This paper represents an attempt to delineate the developmental line of time sense from birth to object constancy, concentrating on those maturational and environmental factors which determine psychotemporal adaptation in infancy and early childhood. Observational data and clinical vignettes are used to support theoretical formulations. Time sense is understood as a subjective, dynamic emergence which evolves throughout the life cycle. Psychoanalysis has paid little attention to the theory of time, and much needs to be accomplished to formulate the developmental line of time for the remainder of the life cycle.


The analysis of a male patient by a female analyst: the problem of the negative Oedipal transference. The clinical work in this paper is focused on the analysis of the negative oedipal phase of a male patient with a female analyst. Determinants of this phase are discussed. Theoretical questions are raised and propositions advanced. Transference phenomena are differentiated from the transference neurosis and the types of transferences formed according to the sex of the analyst are discussed. It is proposed that patients develop maternal transferences to analysts of both sexes, but that such transferences are limited to pre-oedipal phases for patients with male analysts. During the analysis of the oedipal phase, both positive and negative, the patient's transference is to the analyst according to the analyst's sex. A true paternal transference neurosis to a female analyst ordinarily does not occur.


Rehabilitation of the disabled: the role of social networks in the recovery process. This study examines the role of formal and informal intervention systems utilized by the chronically disabled in the process of rehabilitation and recovery. In addition to formal community resources (agents and agencies), the disabled tend to rely on informal social networks (family and peers) as sources of support in the recovery process. The findings presented in this paper focus on the extent to which formal interventions and informal resources are supportive for the disabled and the effect of these support systems on outcome. The analysis is based on empirical data derived from a survey of 950 chronically disabled adults interviewed in a metropolitan community in the U.S.A. Among other findings, the evidence suggests that informal social networks play an important role in the rehabilitation of the disabled. Reliance on informal resources is enhanced in the absence of formal rehabilitation intervention, suggesting alternative modes of social support are actively sought and utilized by the disabled. Furthermore, lay-initiative may constitute another effective resource in the process of recovery. These findings suggest that informal resources are effectively utilized by the disabled, but are not usually identified as part of the formal intervention system in the community.


Patterns of work--rheumatoid arthritis.

Patterns of work--rheumatoid arthritis. Fifty rheumatoid adults successfully competing in full time competitive work were interviewed to determine the factors which distinguish this group and enable their continuing work, which included physical and social barriers and aids to working full time. The data indicate that as a whole they had significant disease, most falling in functional class 2 and 3 (ARA). As a group they were well educated with occupations mirroring their educational attainments. Almost all had inside jobs and most had worked for long times in their occupations. The majority did not change occupations after disease onset and many had been in their jobs for years, often in the same firm. Promotions were few. They had stable marriage patterns. Patients were motivated for work and did what was necessary to get to work despite their disease. These workers had a low level of absenteeism, enjoyed their jobs and felt that personal desire was the most important factor in keeping at work. From consideration of the disease itself, in addition to upper and lower extremity problems, morning stiffness, fatigue and public transport difficulties were highlighted and focus attention on the need to better control these features of the disease and environment.


Early diagnosis and long term management of obstetric paralysis. The muscles of the arms of 45 infants with obstetric injury of the brachial plexus were studied electromyographically. Classical clinical examiniation and routine electromyography were unsatisfactory, but studies of temporary unconditioned motor reflexes with kinesiological electromyography proved more helpful in establishing the site and extent of the lesion. In addition to their diagnostic value, these reflexes rhythmically repeated appear to play a useful therapeutic role in 96 children followed up on a long term basis.


A case of melanodermia in a patient with Cushing's syndrome. The authors describe a case of melanodermia in a patient with Cushing's Syndrome. Examination of the etiopathogenetic factors lead to a diagnosis of probable ACTH secreting extra-hypophyseal neoplasia.


A case of multiple sensitization to three halogeno-substituted mono-nitrobenzenes. A case of occupational contact dermatitis in a female chemical pharmaceutical laboratory researcher is described. The allergological investigation revealed a state of sensitization to three mono-nitrobenzenes with halogen substitutions in the nucleus or a side chain. Problems related to sensitization to these substances and to possible cross-allergy with DNCB are discussed.


Immunologic cross-reaction between enterobacterial common antigen and rat tissue. Livers, sera, and erythrocytes of MAXX, BN, and Wistar rats were examined for an antigen (CRA) that cross-reacts with enterobacterial common antigen (ECA). Extracts of these tissues were tested for their capacity to reduce anti-ECA titers. By this parameter, CRA was present in certain, although not all, extracts of rat tissue. None of the extracts modified red blood cells (RBC) for agglutination by anti-ECA antisera, nor did MAXX liver extracts engender anti-ECA activity in rabbits. It was speculated that a repressor is present in rat tissue that affects both antigenicity and immunogenicity of CRA. To test this concept, extracts of mixtures of enterobacterial suspensions and liver homogenates were prepared. ECA in the presence of tissue did not modify RBC for anti-ECA activity as did ECA alone, nor did enterobacteria-liver extracts significantly reduce anti-ECA titers. Administration of ethanol-soluble fractions of enterobacteria-liver mixtures to rabbits did not elicit an anti-ECA antibody response as did ECA alone. The finding of CRA in certain rat tissues, sera, and erythrocytes may account, in part, for rats being refractory to immunization with ECA. It is proposed that repressors may mask or abrogate the expression of CRA in animal tissue.


Erosive lichen planus and cirrhotic hepatitis. Five out of seven patients with erosive lichen planus were found to have cirrhotic liver complications. In 2 patients active chronic hepatitis was proven by means of laparoscopy and liver biopsy.


Spectral properties and relative quantum yields of new fluorescent stains. Excitation and emission spectra were obtained for thirty-two new fluorescent stains that resist fading when exposed to light. Quantum yields were determined for the fourteen stains that showed the greatest fluorescent intensity. Optimal microscopic excitatory and barrier filters, determined by the experimental results, were used to examine tissues stained with some of these dyes. Cellular detail was evident and there was no fading after several hours of examination.


Catabolism of ornithine in chicken liver. It is shown that most ornithine in a chicken liver homogenate is decarboxylated in the particulate fraction. This fraction, however, requires the cytosol for complete activity. The dialyzed supernatant does not activate decarboxylation of ornithine, while the supernatant is more effective when previously inactivated at 100 degrees C. The supernatant can be substituted by the intermediates of the citric acid cycle (oxaloacetate, citrate, succinate, malate), by pyruvate, and partially by ADP as well. Rotenone blocks decarboxylation suggesting that this occurs through the pathway ornithine leads to glutamic semialdehyde leads to glutamate leads to alpha-ketoglutarate, which in turn is decarboxylated. The activating metabolites would thus have a role in reoxidizing NADH, and the ketoacids also in supplying the acceptor for transamination of glutamate, and indirectly for ornithine transamination. Pyruvate and oxaloacetate do not transaminate with ornithine. Insulin promotes a marked increase of cytosol ornithine decarboxylase activity, but has little effect on decarboxylation by the particulate cellular fraction.


Effect of niridazole and niridazole immunoregulatory factor (NIF) on cutaneous delayed hypersensitivity in mice. It has been suggested that the suppression of cell-mediated immune phenomena following niridazole administration is most likely due to a niridazole metabolite rather than the parent drug. This hypothesis was tested using two inbred strains of mice that manifest different rates of microsomal niridazole oxidation and reduction. DBA/2J mice were found to metabolize niridazole at a rate approximately 3-fold greater than C57BL/6J mice under both aerobic and anaerobic conditions. Niridazole was found to be more potent with respect to suppression of cutaneous delayed hypersensitivity in the former than in the latter. An immunosuppressive component was isolated from the urine fraction obtained from niridazole-treated rats. This component was found to be chromatographically pure; have a simple UV absorbance spectrum containing no 360 nm absorbing material characteristic of niridazole; to show no strain difference with respect to potency or efficacy in the ear-swelling assay for cutaneous delayed hypersensitivity; and to be 10(7) times more potent than niridazole with respect to the suppression of cutaneous delayed hypersensitivity.


Synthesis and chromatographic properties of Se-carboxymethyl-selenohomocysteamine (2-carboxymethyl, 3-aminopropyl selenide). Details are reported for the synthesis of Se-carboxymethylselenohomocysteamine from selenohomocysteamine and monochloroacetic acid. Data on its behaviour on paper and ion-exchange chromatography are also reported, which allow its identification.


The ratio glycerophospholipids/free cholesterol of human serum: a possible parameter of asymmetric fluidity of lipoprotein molecules. The ratio glycerophospholipids/free cholesterol in serum is proposed as a parameter sufficiently easy to be used in routine clinical work. The possible importance of this ratio in the regulation of blood lipoprotein concentration is discussed and special attention has been paid to the asymmetry of the PC and free cholesterol association in the secretion, interconversion and removal of lipoproteins from blood. Many proposals are offered as a working hypothesis for studying the factors involved in the regulation of blood lipoprotein concentration.


Involvement of CDP-choline in phospholipid metabolism of brain tissue in vitro. The ability of phosphorylcholine and CDP-choline to act as lipid precursors was tested in chick brain microsomes (plus supernatant). CDP-choline was, in every case, a much better precursor of choline glycerophospholipids than phosphorylcholine. The cytidylyltransferase reaction which forms CDP-choline appears, therefore, as the limiting step of the metabolic pathway which introduces phosphorylcholine into lipids. This reaction can be stimulated by the addition of phospholipids to the incubation mixture. Choline lysoglycerophospholipids are the most active in this connection.


Separate medullary pathways mediatiating reflex vagal bradycardia to stimulation of buffer nerves in the cat. In this investigation of medullary pathways mediating reflex vagal bradycardia to stimulation of buffer nerves, four series of experiments were done in 37 cats anesthetized with chloralose, paralyzed and artificially ventilated. In the first series using animals in which the contralateral vagus was sectioned and the spinal cord was transected at C2, simultaneous stimulation of the aortic depressor (ADN) and carotid sinus (CSN) nerves elicited a bradycardia of magnitude not significantly different from the algebraic sum of the responses elicited by stimulation of the two buffer nerves separately, suggesting the existence of two separate central pathways mediating vagal bradycardia. In the second series, in spinal unilaterally vagotomized animals, lesions of the nucleus ambiguus (AMB) selectively attenuated the ADN reflex vagal bradycardia but not the CSN response; on the other hand, lesions of the external cuneate nucleus (ECN) attenuated the reflex vagal bradycardia elicited by stimulation of the CSN, but did not alter the ADN response. In the third series of experiments, 153 spontaneously firing single units in the region of the AMB and 98 in the region of the ECN were tested for responses to ADN and CSN stimulation. In the AMB 42% of the responsive units were excited only by stimulation of the ADN, 25% were activated only by stimulation of the CSN and 33% were activated by stimulation of both buffer nerves. Of the single units in the ECN region 85% were excited only by stimulation of the CSN, 15% during stimulation of both the CSN and ADN and none responded to stimulation of only the ADN. In the final series, electrical stimulation of the ECN evoked antidromic compound action potentials in the CSN but not in the ADN. Electrical stimulation of the AMB did not evoke antidromic activity in either the CSN or ADN. These studies provide evidence for the existence of two separate medullary pathways mediating the vagal reflex bradycardia to stimulation of the ADN and CSN.


Reciprocal and non-reciprocal action of the vagal and sympathetic nerves innervating the heart. Simultaneous recordings were made from vagal and sympathetic fibers innervating the heart in dogs anesthetized with chloralose. Reciprocal relationship between the two autonomic nerves was clearly seen in the baroreceptor reflex. Stimulation of chemoreceptors, however, evoked non-reciprocal responses of the two nerves; at the onset of the chemoreceptor reflex cardiac vagal and sympathetic discharges both increased, then, as baroreceptors became excited due to a pressor response, sympathetic nerve activity suddenly decreased while vagal discharges remained high, indicating the appearance of the reciprocal action typifying the baroreceptor reflex. Decrease in ventilatory volume and a slight increase in end-expired CO2 level augmented greatly both vagal and sympathetic discharges. As the phrenic-locked activity of the two nerves (i.e. the activity in vagus nerve occurs only in the absence of phrenic bursts while sympathetic discharges increase with phrenic bursts) increased, the alternate discharges between the two nerves became more conspicuous and the heart rate fluctuated with the respiratory (phrenic) rhythm. Thus, strong reciprocity between vagus and sympathetic can result in an oscillatory heart rate. When ventilatory volume was increased, both nerve activities decreased below control level. Mild hypoxia had similar effects to hypercapnia though changes in nerve activity were greater. When coactivation of vagal and sympathetic nerve was produced in reflex action, changes in vagal discharges occurred earlier and faster than in the sympathetic fibers. The magnitude of change in vagus activity was also far greater. The elimination of afferents in the vagi, the aortic and sinus nerves reduced cardiac vagal activity greatly. However, discharges were still present and occurred between phrenic bursts, indicating that the vagal "tone" is maintained centrally as well as peripherally by input from receptors in the cardiovascular system. The physiological significance of reciprocal and non-reciprocal control of vagal and sympathetic nerves innervating the heart was discussed.


Experimental autonomic neuropathy: ultrastructure and immunohistochemical study of a disorder of reflex vasomotor function. Vasomotor function in ear vessels of rabbits was tested in animals with experimental autonomic neuropathy (EAUN), experimental allergic neuritis (EAN), and controls. Reflex vasodilatation was impaired in animals with EAUN but not in EAN or control rabbits. Ultrastructural examination of paravertebral sympathetic chain, perivascular nerves, and perivascular tissue showed similar changes in all animals differing in degree only. Occasional lymphocytes were seen in paravertebral chains of controls but large numbers of lymphocytes and macrophages occurred in EAUN and EAN. No active destruction of myelinated or unmyelinated fibers could be seen. Perivascular nerves showed similar cellular infiltrates and basophils were found in perivascular spaces of ear vessels which were most abundant in animals with EAUN. Fibre-size spectra analysis of unmyelinated fibres in the paravertebral sympathetic chain showed a shift to the left suggesting regeneration of unmyelinated axons in both EAN and EAUN. No specific immunofluorescence against neuronal components could be demonstrated in sensitized animals. It is concluded that the functional disturbance of reflex vasomotion in EAUN is not accompanied by specific ultrastructural lesions nor could neuronal components be immunologically implicated in the disorder. Regeneration of unmyelinated axons and recovery of function after some weeks together with abundance of basophils in perivascular tissue of sensitized animals, suggests that a localized inflammation may have occurred, the basophils interfacing between foreign antigens, the serum cascade systems, and other inflammatory cells. The usefulness of EAUN as a model for acute pandysautonomia in man remains to be determined.


Intersegmental connections and interactions of myelinated somatic and visceral afferents with sympathetic preganglionic neurons in the unanesthetized spinal cat. The aim of this study was to obtain a measure of the interactions through exclusively spinal circuits, of myelinated afferents with sympathetic preganglionic neurons. Experiments were performed on 16 unanesthetized cats rendered insensitive by bilateral vertebral and carotid occlusion, whose spinal cords had been transected at C1 6-12 h before recording. The evoked responses of 68 tonically active sympathetic preganglionic neurons were recorded from filaments dissected from the cervical sympathetic trunk. Excitation, inhibition and excitation-inhibition sequences were evoked by electrical stimulation of radial, femoral and pelvic nerve afferents. Inhibition was most often observed during pelvic nerve stimulation. Ninety percent of the sympathetic preganglionic neurons tested responded to radial, 77% to femoral and 85% to pelvic nerve stimulation. These differences in percentage of units responding to the three nerves were statistically insignificant. Thus, in the acute spinal cat, the fraction of tonically active sympathetic preganglionic neurons whose activity can be influenced by myelinated afferents is independent of the length of the intraspinal pathway which conveys the input. A main difference between the long pathway (mediating the responses to femoral or pelvic nerve) and the short pathway (mediating the responses to radial nerve) seems to be the efficacy of their connections. While single shocks reliably evoked responses from the radial nerve, trains (200 Hz, 20 msec) were usually necessary to elicit responses from femoral or pelvic nerve, indicating a requirement for summation in the long pathway.


The orthograde labeling of postganglionic sympathetic cardiac nerves in the dog and cat as demonstrated by autoradiography. Previous functional and anatomical techniques have characterized the cardiac nerves and plexuses. They cannot, however, determine the course of fibers arising from a specific ganglion. This study has found that the intraaxonal orthograde labeling of axons can be used to determine the course of postganglionic sympathetic cardiac fibers in the dog and cat. The canine left caudal cervical ganglion and the feline right stellate ganglion were exposed through appropriate thoracotomies. Each ganglion received multiple injections of tritiated leucine (500 muCi/animal). Following a 3--14-day survival period the anesthetized animals were sacrificed by vascular perfusion. The injected ganglia, extracardiac nerves and selected portions of the heart were processed for autoradiography. Autoradiographs from the dog demonstrated labeled postganglionic sympathetic nerves in the extracardiac plexus, left atrial epicardium and the epicardium beneath the coronary sulcus. Labeled nerves in the cat heart were found within the epicardial layers and associated with blood vessels in the left ventricular myocardium. Neither myelinated fibers traveling through the injection site nor intrinsic cardiac ganglion cells were labeled, although the latter were often closely approximated to heavily labeled fibers.


The effect of long-term castration on the histochemically demonstrable catecholamines in the hypogastric ganglion of the rat. The effect of long-term castration on the hypogastric ganglion of the rat was studied using the formaldehyde-induced fluorescence (FIF) method. After castration the fluorescence intensity was lower and the size of the adrenergic neurons was smaller than in normal or in testosterone-treated castrated rats. The fluorescence profile of the ganglia of castrated rats differed from the profiles of control or testosterone-treated castrated rats. Vacuolated neurons were seen in the hypogastric ganglion of controls but not in the ganglia of castrated animals. After long-term castration the size of the ventral prostate was drastically reduced. The density of adrenergic nerves was similar in castrated, normal and testosterone-treated castrated rats. It is concluded that long-term castration has an effect on adrenergic neurons by decreasing the FIF and by producing other morphological changes. The effect can be reversed by testosterone treatment.


Conduction velocity in spinal descending pathways of baro- and chemoreceptor reflex. Activity in the white rami T3 and L2 or 3 has been recorded and averaged with respect to excitation of the carotid sinus baroreceptor afferents produced by the pulsatile blood pressure (baroreceptor reflex) and with respect to brief trains of electrical stimuli exciting low threshold chemoreceptor afferents in the left carotid sinus nerve (chemoreceptor reflex). Experiments were performed on chloralose anaesthetized cats with both vago-depressor nerves cut. From the latency difference between the onset of the responses at the thoracic and their arrival at the lumbar level the spinal conduction velocity for the pathway of each reflex has been calculated. The baroreceptor reflex pathway has slower spinal conduction velocity 3.3 +/- 0.7 m/sec than the chemoreceptor pathway 5.5 +/- 0.9 m/sec. These results indicate that there are separate descending spinal pathways for the two types of reflexes.


Relative contributions of aortic and carotid sinus baroreceptors to the baroreceptor-heart rate reflex of the conscious rabbit. Conscious rabbits with previously implanted perivascular balloons for altering blood pressure were studied before and 6 days after: (i) sham-operation (n = 6); (ii) section of carotid sinus nerves alone (n = 7); (iii) section of aortic nerves alone (n = 5); and (iv) combined sino-aortic denervation (n = 5). Sigmoid mean arterial pressure (MAP)-heart period (HP) baroreflex curves were derived and were characterized by: (i) the HP range (HPR) between upper and lower plateau levels; (ii) the median blood pressure (BP50); and (iii) the average gain (G). Resting MAP and HP and the 3 baroreflex parameters were not altered significantly 6 days after sham-operation. After section of the carotid sinus nerves alone resting MAP and BP50 rose by 18 +/- 2.6 mm Hg, resting HP fell by 31 +/- 4.2 msec, whilst HPR and G fell to about 45% and 20 % respectively of initial preoperative control. After cutting the aortic nerves alone there was a similar fall in resting HP as after carotid denervation. However, the rises in resting MAP and BP50 were only about half of those observed after carotid denervation (P < 0.05) and the changes in HPR and G to 65% and 58% of control respectively were also less marked (P ¿ 0.01). The aortic baroreceptor zone also exerted smaller effects on the sympathetic efferent component of the baroreflex HP response. Despite the different effects exerted by each zone on the reflex parameters there was little difference in threshold pressure for producing cardiac slowing. After combined sino-aortic denervation there was a similar rise in resting MAP (19 mm Hg) as after carotid sinus denervation alone, but there was more marked tachycardia, with a fall in resting HP of 82 msec (P < 0.001) and both resting and baroreflex-mediated vagal tones were completely abolished. The small residual pressure-determined HP changes of about 8 msec were entirely sympathetic and probably mediated through cardiopulmonary baroreceptors.


Visualization of intrarenal catecholamine-containing elements: fluorescence histochemistry and electron microscopy. Fluorescence histochemistry and electron microscopy were used to study catecholamine-containing elements in rat and cat kidneys. There were fluorescent nerve plexuses associated with the arterial system of the renal cortex from which nerves extended into the medulla forming dense networks in the vascular bundles of the outer part of the medulla. Also, there were small cells found singly and in clusters which emitted the blue fluorescence characteristic of catecholamine-containing cells. These cells were associated with the periarterial nerve plexuses and were frequently encountered in the cat medullary vascular bundles. Electron microscopy of the cat renal medulla revealed processes with the structure of typical adrenergic terminals and other processes that resemble small intensely fluorescent (SIF) cell processes.


Electrophysiological and neuroanatomical studies of hepatic portal osmo- and sodium-receptive afferent projections within the brain. Previous investigations concerning the function of hepatic sodium and osmoreceptors indicated that the activation of these chemoreceptive structures significantly affected physiological and behavioral mechanisms related to water and electrolyte homeostasis. Though anatomical studies predicted that such information should follow the previously described gustatory afferent pathy, until recently, the precise course taken by higher order hepatic afferents was unknown. The studies described herein verify anatomical predictions with regard to the central course of vagal-visceral afferents, as hepatically activated neurons were localized to two areas known to relay gustatory input. Further, horseradish peroxidase histochemical studies verified that a path between the nucleus of the solitary tract, the parabrachial nucleus and the ventrobasal complex certainly exists. In the light of recent findings regarding projections from the ventrobasal complex to the supraoptic nuclei, from the parabrachial nucleus to the supraoptic nuclei and from the nucleus of the solitary tract to the paraventricular and supraoptic nuclei it seems likely that the viscero-gustatory path which carries hepatic afferent information is the pathway responsible for the physiological and perhaps the behavioral consequences of hepatic sodium or osmotic stimulation.


Cells of origin of motor axons in the subdiaphragmatic vagus of the rat. The central cell groups that give rise to the motor axons that travel in the subdiaphragmatic vagus were re-examined in the rat by transecting the dorsal or ventral vagus near the stomach and incubating the nerve stump in crystalline horseradish peroxidase (HRP). An exceedingly large percentage of cells was labeled throughout the dorsal motor nucleus of the vagus (mX), with labeled cells extending even beyond the rostro-caudal limits of the nucleus usually assigned on the basis of cytoarchitecture alone. Different patterns of cell-labeling could be correlated with one or the other of the two vagal branches. Incubation of the ventral branch labeled cells only in the left mX, while incubation of the dorsal branch labeled cells on both sides, although more extensively on the right. HRP-positive somata were also observed bilaterally in the nucleus ambiguus (NA) after incubation of either branch of the subdiaphragmatic vagus; this finding is in contrast to previous accounts in which motor fibers from NA were considered to project only to cervical and thoracic structures. These results suggest that mX and NA are responsible for a substantial component of abdominal innervation in the rat.


Chemotherapeutic alteration of small intestinal morphology and function: a progress report. Nine patients with malignancy requiring chemotherapy were evaluated before, during, and in the recovery phase of their antineoplastic regimen with selected absorptive studies and jejunal biopsies. Depression of the crypt mitoses occurred without change in the indices of absorption. The mitotic indices returned to pretreatment counts on the recovery phase biopsies. Even after prolonged therapy, restudy in three of the patients failed to demonstrate clinical malabsorption. We conclude that chemotherapy-related malabsorption does not contribute to overall malnutrition of cancer patients during the first months of treatment.


The outlook after total colectomy in patients with Crohn's colitis and ulcerative colitis. The postoperative recurrence rates for Crohn's colitis (CC) and ulcerative colitis (UC) have varied markedly in different medical centers. We have reviewed the reasons for this variation and present our own series of patients in a manner which allows comparison with previous studies. In our study: 1) Patients with CC had an overall recurrence rate of 38% after total colectomy. By actuarial statistics, this recurrence rate computes to 48% by 12 years after operation. 2) Patients with ileal disease, even if totally removed at operation, had a recurrence rate of 48% whereas those with no obvious ileal involvement had a recurrence rate of 18%. 3) When nonspecific criteria are used for recurrence, which we call "complication," as has been the case in several previous studies of CC, even patients with UC had a complication rate of 33%. Such complications both in UC and CC represent postoperative occurrence rather than ileal recurrence of the inflammatory process. 4) Patients with CC develop more postoperative complications than patients with UC, but for most of the time they were asymptomatic. In this series there were no patients with disease originally or almost entirely limited to the colon who became "intestinal cripples" as a result of recurrent disease. 5) Patients with short preoperative intervals had the highest recurrence rate, whereas patients with disease of the terminal ileum had the highest postoperative complication rate. 6) Patients with "superficial" CC had a low recurrence rate, probably because of a shorter follow-up than the other patients. There were no true recurrences in patients with UC.


Herpesvirus hominis (type 1) proctitis.

Herpesvirus hominis (type 1) proctitis. Herpes proctitis from Herpesvirus hominis type 1 is probably an underrecognized cause of rectal pain and inflammation. Extreme anal pain and a purulent rectal discharge in a heterosexual man led to the appropriate diagnosis. Clinicians should be more aware of herpes as a cause of proctitis.


Comparison of the Menghini, Klatskin and Tru-Cut needles in diagnosing cirrhosis. The Menghini, Klatskin and Tru-cut needles were used to obtain multiple biopsies from cirrhotic livers at autopsy. Comparison of specimens showed that Tru-Cut biopsies were the longest and least fragmented, produced the greatest diagnostic accuracy and fewest false negative diagnoses of cirrhosis. Pending further evaluation of its safety, the Tru-Cut needle seems the instrument of choice for the biopsy diagnosis of cirrhosis.


Gastrointestinal histoplasmosis.

Gastrointestinal histoplasmosis. Histoplasma capsulatum involves some part of the gastrointestinal tract in 75% of patients with disseminated disease, but clinically obvious gastrointestinal involvement is infrequent. Symptoms include crampy abdominal pain, diarrhea, nasopharyngeal ulcers, and rectal ulcers. Granulomatous constrictive lesions may simulate either carcinoma anywhere in the gut or less commonly Crohn's disease. We describe a patient and discuss gastrointestinal histoplasmosis.


Small intestinal changes in enterocolitis complicating Hirschsprung's disease. Hirschsprung's disease is one of the more common causes of childhood bowel obstruction. The disease can cause enterocolitis which, untreated, may result in considerable mortality. We describe our evaluation of two infants who suffered from intractable diarrhea of infancy secondary to Hirschsprung's disease. We found that mucosal damage to the small bowel and disaccharidase deficiency are among the most important mechanisms producing this complications. Therefore, management of enterocolitis including parenteral alimentation should proceed as soon as the complication is observed.


Nonspecific ulcers of the colon: a case presentation of ulceration of the transverse colon. This paper describes a patient with nonspecific discrete ulcer of the transverse colon. The lesion was responsible for diarrhea which was cured by conservative resection. These uncommon ulcers, which mimic carcinoma radiographically and were previously thought to be uniformly fatal, may occasionally heal spontaneously. The patient has taken several drugs, some of which may have played a role in the pathogenesis of the ulcer, but the etiology of nonspecific colon ulcer remains uncertain.


Radiographically guided needle biopsy of abdominal neoplasms--who, how, where, why? Radiographically guided percutaneous needle biopsy is a safe, accurate, well-tolerated alternative to laparotomy for confirmation of advanced abdominal malignancy. Here we describe the indications and methodology for its performance. Eighty-two percent of 66 patients with proven abdominal neoplasms were successfully biopsied with a fine-caliber needle using a variety of guidance methods. Cross-sectional techniques, such as ultrasound and computed body tomography (CBT), provide the preferred monitoring techniques because of their excellent soft-tissue resolution and the capacity to determine tumor depth accurately. The ability of CBT to define the exact position of the biopsy needle tip in a mass makes it the preferable guide for biopsing of small, solid lesions.


Cytostatic effect of spleen cells of cyclophosphamide-treated mice on tumor cells. Spleen cells of mice receiving an i.p. injection of a sublethal dose of cyclophosphamide (CY) have the ability to inhibit tumor growth in vitro. This effect is dose dependent and is maximal at the peak of the spleen regeneration which follows the phase of atrophy due to CY toxicity. This cytostasis is neither tumor-specific nor strain-restricted and the cells responsible for this inhibition of tumor cell multiplication have the characteristics of macrophages: they lack the Thy 1-2 antigenic marker, appear in CY treated nude mice, stick on plastic vessels, and are retained by adherence columns (nylon wool or Sephadex G10); their activity is greatly reduced when a specific macrohpage toxic reagent such as carrageenan is added to the cultures. The effector cells are similar to those which are able to suppress the response of normal splenocytes to T and B mitogens, and which appear in the same conditions of induction, after CY injection.


The effect of prostaglandin E1 or E2 on the in vitro blastogenic response of lymphocytes from normal and tumor-bearing mice. The in vitro effect of exogenously added prostaglandin (PG) E1 or E2 over concentrations ranges of from 1 X 10(-4) to 1 X 10(-9) M were studied in order to determine their effect on the in vitro lymphocyte proliferation of thymic and splenic T and B cells from normal and tumor-bearing CD2F1 mice. It was found that PGE1 generally caused greater inhibition of blastogenesis than did PGE2 when reacted with splenic lymphocytes from normal mice. Indeed, PGE2 was found to be stimulatory for both Con A- and LPS-sensitive normal splenic lymphocytes. Both PGE1 and PGE2 caused potent inhibition of Con A- and PHA-sensitive splenic lymphocytes from the tumor-bearing mice. Additionally, PGE2 was found to stimulate the LPS-reactive lymphocytes from the tumored mice. PGE1 and PGE2 both inhibited the Con A- and PHA-reactive thymic lymphocytes from normal mice at the lower concentrations studied, i.e., 10(-4) to 10(-6) M. Thereafter, at concentration ranges of from 10(-7) to 10(-9) M both PGE1 and PGE2 were both found to be stimulatory. Finally, both PGE1 and PGE2 at all concentrations studied, strongly inhibited the thymic lymphocytes from tumored mice.


Effect of macrophage activation by immunoadjuvants on serum levels of lysosomal hydrolases in mice. The effect of pyran copolymer, injected into mice bearing the M109 Madison lung carcinoma, on serum concentrations of lysozyme, beta-glucuronidase, and N-acetyl-beta, D-glucosaminidase was studied and compared with that of other immunoadjuvants. Increases in lysozyme levels ranging from 50 to 100% were observed after injection of pyran, BCG and Bru-Pel; increases in the levels of the other enzymes were less consistent. Other immunoadjuvants were less effective in raising serum concentrations of lysosomal enzymes. The findings were correlated with the results of previous studies on macrophage activation and antineoplastic action produced by these immunoadjuvants and suggest that serum levels of lysozyme can serve as indices of these effects.


Action of levamisole on E-rosette forming cells and serum adenosine deaminase in Hodgkin's disease. The interaction of levamisole and/or adenosine in vitro on E-rosette forming cells (RFC) of healthy subjects and on low RFC of patients affected with various diseases was investigated. Levamisole did not enhance normal RFC. The drug enhanced low RFC in some patients (responders) but not in others (non-responders). Adenosine inhibited normal and low RFC and this inhibition could be reversed by levamisole. Further, levamisole 150 mg 2 days a week was given to 12 Hodgkin's disease (HD) responders for 2 weeks, then 150 mg 1 day weekly for 2 1/2 months. After one week of treatment RFC increased and the enhancement could be maintained during the whole treatment period. Lastly levamisole in vitro and in vivo diminished serum adenosine deaminase activity in normal subjects and HD patients.


Immunokinetics of a single dose of levamisole. Ten patients with classical or definite rheumatoid arthritis and a low number of E-rosette forming lymphocytes were given single doses of 50, 100 and 150 mg of levamisole. Levamisole produced a dose-related sustained increase in E-rosette forming cells. A single dose of 150 mg restored the number of E-rosette forming cells to normal within 24 hours and this effect lasted 6 to 7 days. These immunokinetic data provide a rational basis for the once-a-week administration of levamisole.


Effects of cyclophosphamide on hemic precursor cells in mouse bone marrow and spleen. Cyclophosphamide severely inhibits the function of various hemic precursor cells in mice. In these studies we compared the effects of Cy on early B-lymphocytic precursor cells in mouse bone marrow to those effects on bone marrow myeloid precursor cells and splenic lymphoid precursor cells. These studies demonstrated that: 1) Pre-ARC in the bone marrow were extremely sensitive to even low doses of Cy (50 mg/kg) with virtually no renewal of this precursor population 11 days after injection of 200 mg/kg. 2) The sensitivity of pre-ARC to Cy along with the lack of their renewal was exemplified by the virtual absence of functional ARC in the spleen when assessed 11 days after injection of 200 mg/kg of Cy. 3) A rapid multiphasic renewal pattern was observed for myelocytic progenitor cells. 4) In general, LPS responsive cells were suppressed to a greater extent than were Con A responsive cells, especially with lower doses of Cy.


MER-BCG (NSC-143769): immunogenicity and toxicity of single and repeated intradermal injections in dogs. Intradermal injections of MER-BCG 0.1 mg or 0.2 mg at each of 10 multiple sites, led to local granuloma formation. The nodules reached approximately 10 mm in diameter, ulcerated and were accompanied by granulomatous changes in the regional lymph nodes. Six or twelve successive treatments (each including 10 injections) at 4 week intervals produced the same histopathological lesions but no changes in hematological and blood chemical parameters or general morphology and no changes in general condition with exception of occasional weight loss in a few animals. Injection with 0.01 or 0.001 mg/site produced similar, though less severe, skin lesions but no changes in the draining lymph nodes. The immunogenicity of MER-BCG was characterized by granuloma formation, a positive skin response to old tuberculin, and a positive lymphocyte transformation to PPD tuberculin, thus indicating stimulation of cell-mediated immune responses. However, there was a decreased responsiveness to PHA and PPD with continuing treatment with MER-BCG. The decreased responsiveness and accumulation of numerous depots of antigen would suggest an "immunologic paralysis" contraindicating the administration of excessive amounts of MER-BCG during immunotherapy. A specific humoral response to the administration of MER-BCG was not detected, but an MER-BCG dose independent decrease in albumin associated with a non-specific, dose related elevation in serum IgG was observed.


Tissue distribution as a factor in species susceptibility to toxicity and hazard assessment. Example: methylmercury. Data on the tissue distribution and pharmacokinetics of methylmercury(MeHg) in cats and humans were utilized as an example of how such data can assist in extrapolating toxicity data between animal species. These data demonstrate that the whole-body half-time for clearance of MeHg was the same for cats (76.2 +/- 1.6 days) and humans (78 +/- 5 days) and that the concentration of MeHg in the brain at comparable signs of toxicity were the same (10 ppm) in the two species. However, the blood:brain ratio of MeHg concentration was 10 times as high in cats (1:1) as humans (1:10). From these data it was hypothesised that the no-effect level of methylmercury intake in cats should be 10 times that for humans. This hypothesis was verified from data o MeHg toxicity in cats and humans which demonstrated that ataxia developed in cats at a minimum dose of 46 microgram MeHg/kg body wt/day with blood MeHg levels of 6 to 8 ppm; humans developed ataxia with blood MeHg levels of 0.6 to 0.8 ppm and an estimated intake of 4 microgram MeHg/kg body wt/day.


The importance of non-linear (dose-dependent) pharmacokinetics in hazard assessment. The chronic toxicity of chemicals is evaluated most frequently in animal species and these results subsequently applied to assessing exposure hazards to man. Initial studies are designed to elucidate target organ effects and to characterize the type of toxicity; therefore, administration of high doses of the test material has been the accepted practice. Inherent in this approach is the assumption that few chemicals are capable of saturating the various biochemical and/or transport processes which determine their fate in the body. However, more recently it has become apparent that the biotransformation, excretion, and protein binding of many chemicals are capacity-limited processes. Since the approach in toxicity testing has been to administer large doses of a test chemical, the probability of encountering saturable processes in animal toxicity tests is high. Deviation from linear, dose-independent to non-linear, dose-dependent pharmacokinetics precludes extrapolating the same toxicity from high to low doses. Toxicity at high doses may be due to saturated detoxification or excretion mechanisms which when fully operative at lower doses do not result in the same toxic response. Therefore, knowledge of the pharmacokinetics of a chemical is essential in evaluating the results of animal toxicity tests. More important, in a prospective sense, is the use of pharmacokinetic data to assist in dose selection for chronic toxicity studies. In both cases, the maximum information is obtained from a well defined dose-response relationship. Therefore, massive doses which result in non-linear pharmacokinetics should be avoided unless those occur at dose levels approximating those experienced in actual conditions of human exposure. If these principles are followed, better judgment could be exercised in using animal data to assess the hazard of exposure in man.


Metabolism of chlorinated alkenes and alkanes as related to toxicity. The chlorine substitution in aliphatic compounds results, by its electron attracting effect, in a destabilization in alkanes and a stabilization in alkenes. Thus, with alkanes the main pathways of metabolic transformation to reactive intermediates are radical formation by C-C break or dechlorination, or dehydrochlorination. In alkenes, the stability of the molecule increases with the number of chlorine substitutions. In the series of chlorinated ethylenes, the first step of metabolic transformation is the oxidation to electrophilic oxiranes which may be hydrolized enzymatically or non-enzymatically, react with cellular nucleophiles, or rearrange to either chlorinated aldehydes or acyl chlorides. With tetra-, 1,2-cis- and trans-di-, 1,1-di-, and monochloroethylene, the metabolites identified in in vivo experiments are identical with the thermal rearrangement products of the respective oxiranes. An important exception is found with trichloroethylene, where the thermal rearrangement product is dichloroacetyl chloride; the metabolites in vivo, however, are entirely derived from trichloroacetaldehyde (chloral). The reason for this peculiar behavior is most probably a Lewis acid catalysis by the oxidizing enzyme system. Mutagenic and carcinogenic activities in the series of chlorinated ethylenes are determined by the stability of their oxiranes, which is higher in symmetrical than in unsymmetrical chlorine substitution: the relatively unstable and unsymmetric oxiranes of trichloroethylene, 1, 1,-dichloro-, and monochloroethylene are mutagenic in the Ames test; the more stable symmetric oxiranes of tetra-, 1,2-cis- and trans-dichloroethylenes are inactive.


Chronic toxicity and carcinogenicity guidelines. For the foreseeable future toxicologists will continue to rely on animal bioassays as the main predictive tools for safety evaluation. While their predictive value is good, there are serious limitations which must be recognized in applying the test results to assess human risk. These limitations are of especially great concern for chronic toxicity tests. During the past decade numerous protocols and guidelines for chronic toxicity and carcinogenesis tests have been developed by national and international organizations. These have been reviewed with two aspects in mind: the potential for standardization and the assessment of issues of greatest concern. Of the major design aspects, animal models, route of exposure, dose selection, pathology, and reporting requirements are the most controversial. While a degree of standardization of protocols has many advantages, complete standardization is not considered desirable as test objectives may differ, and overly rigid protocols would likely stifle development of improved methodology. One of the greatest dilemmas facing government health agencies is the extent of pathology to require in routine bioassays. A thorough microscopic examination is obviously desirable; however, the increased requirements for testing chemicals using the extensive pathology protocols now in existence has created a demand exceeding available scientific manpower.


Considerations in chronic toxicity testing: the chemical, the dose, the design. Rodent bioassay systems are widely used to detect those environmental substances most likely to be carcinogenic. Experience with these systems has revealed several shortcomings of an operational nature which may complicate evaluation and interpretation of the results. Paramount among these are purity of the test chemical, dose selection, and experimental design. Special attention must be given to potential impurities in test substances which may be responsible wholly or in part for the production of toxic effects. Proposals for handling this problem are discussed. It is recommended that test chemicals be studied carefully in the proposed animal species using pharmacokinetic procedures, so that doses may be selected that will not jeopardize the outcome of the test nor overload metabolic detoxification systems. Whether or not a bigenerational exposure is required to adequately evaluate the carcinogenicity of the test substance will depend upon its use pattern and pharmacokinetic and metabolic behavior in the mother and fetus.


Monitoring animal health during chronic toxicity studies. Adequate and appropriate appraisal of the health of the animals in toxicity studies is required to differentiate between toxic manifestations attributable to the test material and non-treatment-related disease. The appraisal will help to ensure that each animal remains on test for as long as reasonably possible and that useful tissue samples are obtained from each animal. Attainment of this objective requires highly motivated personnel who have undergone a specific and continuous training program. The establishment of protocols and procedures for daily and weekly monitoring of the animals, and an efficient and relevant system for data collection, recording, and storage is also required. Various laboratory and clinical procedures are described which may be used either on a routine basis or as diagnostic tools. By following the described procedures it has been possible to reduce the loss of animal tissues due to autolysis to less than 1% during chronic feeding studies.


The effect of dose on cancer latency period. A number of animal carcinogenesis experiments have demonstrated that the time from initial exposure to first detection of tumors increases with decreasing dose. This observation has led to some speculation that at very low doses tumors would take so long to develop that life would end before tumors appeared. We show that the apparent increase in tumor development time can be easily seen as nothing more than a manifestation of the mathematical fact that decreasing the incidence necessarily increases the first time-to-tumor. No physical increase in tumor growth time need be postulated to explain the observations. Existing methods of low-dose risk extrapolation implicitly account for the increase in time-to-tumor statistics insofar as they account for the decrease in tumor incidence.


Bayesian analysis of a dose-response experiment with serial sacrifices. This paper presents analysis and comments which are believed to be appropriate for certain carcinogenesis studies where sacrifices are performed throughout the experiment. Estimates of the risk probability for each dose level and sacrifice time are found utilizing the sample likelihood as the posterior density. The dose-response relationship is investigated with these estimates as the response. In order to test if the dose is effective and to check the appropriateness of the time-to-incidence model a Bayesian multiple comparisons technique is introduced.


An unbalanced experimental design for dose response studies. Sixty sets of real data for 15 different pesticides from both sexes of Balb/C mice in two different experimental designs were generated at NCTR. The quantal responses for the dose groups in this data ranged from 1% to 90%. It was shown that the data could be represented equally well by a probit or logit transformation. It was further shown that the investment in terms of 7 times as many animals would greatly increase the confidence in estimating the parameters of the model and in predicting the dose at the low end of the dose response. Most important, it was shown that the estimation of a safe dose for a specified risk was greatly influenced by the choice of experimental design and method of extrapolation. It might be worth the investment in better experimental design to both the consumer and to the chemical industry if higher safe doses could be established which would allow the chemical to better accomplish its purpose and yet improve the assurance of the safety of the consumer.


Relationships between laboratory and human studies. The problems encountered in trans-species extrapolation of the results of chemical carcinogenesis experiments to man are considered from the viewpoints of experimental techniques for establishing chemicals as carcinogens and the effect of modifying factors therein. Extrapolations from the effects of high doses of carcinogens in experimental animals to low doses in man present problems which are beyond the reach of present epidemiological and experimental methodology. The author prefers a pragmatic approach to the latter problems rather than the use of largely unsupported mathematical methodology.


Predictive value of cancer statistics.

Predictive value of cancer statistics. The value of routinely collected cancer statistics for hypothesis generation and for risk prediction is examined in relation to age, place, migration, time, anatomical sub-site, morphology, and occupation. Current descriptive epidemiological data of this nature reflect the carcinogenic exposures of the past 40 years, and are thus useful for generating hypotheses. While they do not permit prediction of risk associated with a new substance entering the environment, once etiology for a given cancer is known, the likely course of events unless preventive action is taken can be forecast on the basis of existing statistics.


Axonal-ependymal associations during early regeneration of the transected spinal cord in Xenopus laevis tadpoles. The nature and organization of the cellular substrate supporting axonal outgrowth during early regeneration of the spinal cord following transection and/or segment removal were examined in Xenopus tadpoles. Longitudinal axonal compartments, formed by radial ependymal processes in unoperated spinal cords, were maintained within the rostral and caudal stumps throughout the early post-operative period. The first neuritic sprouts to appear near the cut ends of the cord were frequently associated with these processes. Between 5 and 7 days after transection either single or multiple cellular aggregates, which consisted primarily of ependyma, began occupying the lesion zone and were encompassed by numerous small fibres. Ependymal processes subsequently extended among the neurites within the lesion gap and re-established longitudinal axonal channels and a surrounding glia limitans. A concurrent outgrowth of fibres and ependyma from the rostral and caudal stumps was also initiated by 5-7 days following resection of the cord. Axons were seen further within the ablation gap at 10 and 12 days either coursing along the surfaces of the emerging ependyma or organized into small fascicles by the radial processes of these cells. Intermediate stages of axonal fasciculation by the underlying ependyma were also seen. In contrast with previous reports, axonal elongation beyond the cut ends of the cord did not consistently entail the formation of pre-existing ependymal channels. These observations provide additional evidence emphasizing the importance of the ependymal cell surface during axonal outgrowth in the regenerating spinal cord. Guided neuritic elongation, however, does not appear to be dependent upon the prior establishment of a specific type of cytoarchitecture.


Induction and maintenance of free postsynaptic membrane thickenings in the adult superior cervical ganglion. The superior cervical ganglion (SCG) of adult rats was exposed to GABA, either by long lasting microapplication (implantation of glass bulbs for 1-24 days) or in short term experiments (external application up to 6 h). Autoradiography showed that [3H] GABA accumulated selectively in satellite cells. The GABA produced the following effects: (1) Specialized membrane thickenings--similar in fine structural appearance to those seen as postsynaptic membrane thickenings at Gray type I synapses--were formed at the extrasynaptic dendritic surface of principal ganglion cells. (2) Morphometry revealed that the surface to volume ratio of dendrites increased significantly corresponding to an enlargement of their extrasynaptic surface as a result of the formation of spine-like projections. (3) Electrophysiology confirmed that, at least after short term application, the action potentials induced by preganglionic stimulation were heavily suppressed. These results suggest that, in the course of depressed ganglionic activity, so-called free postsynaptic membrane thickenings are generated and maintained in the SCG of adult rats even in the absence of significant axonal degeneration. The discussion focuses on two points: (1) possible similarities between the conditions of neurons after denervation and under the influence of GABA; (2) a possible role of GABA and other substances with inhibitory action in synaptogenesis.


The septum of the lateral axon of the earthworm: a thin section and freeze-fracture study. Septa occur between the axonal segments in the lateral giant septate axon of the nerve cord of the earthworm. This septum is demonstrated here to be permeable to fluorescein and to exhibit a negligible time delay for impulse transmission. Periodic anastomoses between the two lateral axons of the nerve cord are revealed by fluorescein. The permeability of the septum is correlated with the demonstration that nexuses occur along the septum. In thin sections, the nexuses may appear as long septilaminar or pentalaminar membrane appositions, but most frequently appear as a series of short or punctate membrane appositions. In freeze-fracture replicas, the nexuses appear as particles 10-12 nm in diameter on the PF face and as pits on the EF face. The particles and pits are arranged in plaques, in anastomosing strands, or most frequently in small plaques with strands of particles or pits emerging from the periphery. In addition to the nexuses, a junction characterized by the presence of 31 nm diameter hemispherical densities on the cytoplasmic surfaces of the septal membranes is revealed in thin sections. The densities are paired on the adjacent septal membranes, and most frequently are shown by optical diffraction to be arranged on the membrane surfaces in hexagonal or rhomboidal lattices with a centre-to-centre spacing of 34.8 nm. In freeze-fracture replicas, an array of particles and pits with a similar lattice symmetry and spacing to the arrays of hemispherical densities is demonstrated.


Strength and weaknesses of microbial test results for predicting human response. Concern over the mutagenic activity of environmental chemicals is widespread as a result of exploratory work during the past ten years. Mutagens seem to exist in just about every category of chemicals in our environment, and many of these chemicals have been shown to have widespread human exposure. Probably the best example in recent times is the food additive AF-2, (2-[2-furyl]-3-[5-nitro-2-furyl]acrylamide) which was used as a food preservative in Japan for about ten years starting in the mid-60's. It was used to preserve soybean curd, fish, and meat sausage and many other foods which were considered staples in the diet of every person living in Japan during that period. In 1973, AF-2 was found by Japanese scientists to be mutagenic in newly developed microbial tests for mutagenicity as well as in mammalian cells in culture (de Serres, 1974, 1976). Subsequently, AF-2 was found to be mutagenic in numerous other assay systems by scientists in other parts of the world. There was great concern over potential mutagenic effects of AF-2 on the Japanese population early in 1974 as a result of the test data on mutagenicity from experiments on these laboratory organisms. However, it was not until AF-2 was found to produce cancer in the fore-stomach in mice (Sano et al., 1977) in August of 1974 that the use of AF-2 was finally banned by the Japanese Ministry of Health.