The auditory cortical projections onto the medial geniculate body in the cat. An experimental anatomical study with silver and autoradiographic methods. The auditory cortical projections to the medial geniculate body (MGB) were studied in the cat. Lesions carefully restricted to each one of the subdivisions of the auditory and peri-auditory cortex were made and degenerating fibres were mapped in the MGB. In other experiments L-[4-5-3-H]leucine was injected into the cortex of AI, AII and SF and its transport to the MGB was studied by autoradiography. The results show that fibres arise in the deep layers of the cortex of AI, pass through the deep subdivision of the dorsal nucleus of the MGB as well as through the magnocellular MGB. and end in the pars lateralis of the ventral nucleus of the MGB, Arising from AII, axons pass through the magnocellular MGB and end in the superficial and deep subdivisions of the dorsal nucleus extending to the most caudal part of the MGB. The ectosylvian posterior auditory cortex projects diffusely to all subdivisions of the MGB as well as to its magnocellular part. Of the peri-auditory areas, only the suprasylvian fringe projects to the parvicellular MGB, and it sends axons to the dorsal nucleus of the MGB. The SF and the ectosylvian anterior periauditory area send fibres to the magnocellular MGB. The insular cortex does not project to the MGB but sends heavy projections to lower nuclei of the auditory pathway. The complementary use of degeneration and autoradiographic methods shows that each method may be used to eliminate the drawbacks of the other. This strategy appears as being most adequate for the study of reciprocal projections such as those found between the MGB and the three auditory areas AI, AII, and the ectosylvian posterior auditory area.


Spectral analysis of the EEG recorded during stimulation of the human fovea. Computer spectral analysis was performed on the EEGs of 6 subjects recorded during monocular foveal stimulation. Stimulus wavelength and subjective brightness were varied independently to determine their importance to changes in the ongoing EEG. The contribution of oculomotor control to these effects and the retinal area of their origin were also investigated. The major results were as follows. (1) Stimulation of the fovea reduced the amplitude of the EEG and the coherence between hemispheres at all frequencies, but most dramatically in the alpha band. (2) It increased the variance of EEG amplitudes and widths of spectral peaks in the alpha band and shifted these peaks to lower frequencies. (3) Auto-spectral intensities in the alpha band were enhanced slightly at brightness levels near photopic threshold, but were unaffected by changes in stimulus wavelength. (4) The fovea appeared to be the most effective retinal area in which irradiation attenuated ongoing alpha activity.


Responses of muscle spindles in a tortoise. Responses were recorded from muscle spindles in the extensor digitorum longus muscle of the freshwater tortoise Chelodina longicollis. Most spindles showed no resting discharge unless the muscle was stretched up to a millimetre beyond the minimum body length. The firing rate then increased by 2-5 imp./sec/mm extension. All spindles were relatively insensitive to the rate of change of muscle length. The dynamic index was small and increased in direct proportion to the rate of stretch. Stimulation of selected filaments of the nerve produced a response from the spindle that was attributed to intrafusal contraction. A comparison of the response of the spindle to muscle stretch with the response during simultaneous stretch and stimulation of a motor filament revealed two distinct types of behaviour. In the first, a dynamic effect, motor stimulation greatly increased the response of the spindle to the velocity component of stretch. Other filaments had a static action: an increase in firing of the spindle with the muscle at constant length, but little change in the response to the velocity component of stretch. Stimulation of up to 7 different filaments produced an effect on a spindle. When the motor effects for a given spindle could be clearly characterised, they were all static or all dynamic. Both static and dynamic effects on the one spindle were seen only rarely.


Analysis of various factors involved in EEG synchronization during milk drinking in the cat. Electroencephalographic (EEG) and multineuronal activity (MUA) from several brain structures were recorded in 11 adult cats during milk drinking. Milk drinking elicited parietal and hippocampal EEG synchronization and inhibited multiunit discharge in several brain regions. The proportion of EEG synchronization varied considerably between animals, but remained more or less constant for each cat after several testing days. Neither modification of milk concentration nor fasting influenced the proportions of EEG synchronization during milk drinking. Adaptation of the animals to the experimental environment facilitated the appearance of EEG synchronization during milk drinking. Chlorpromazine (3 mg/kg) significantly increased the proportion of EEG synchronization observed during milk drinking. By contrast, displacement of the head, neck or postural body adjustments during milk drinking blocked EEG synchronization. Amphetamine also had a suppressive effect on the EEG parietal and hippocampal synchronic activity observed during milk drinking. Our results suggest that development of parietal EEG synchronization in response to pleasant stimulation is a complex phenomenon requiring a relaxed condition of the animal, including its adaptation to the experimental environment and relative immobility with the concomitant diminution of afferent inflow from some of the muscles involved in locomotion.


The pontine taste area in the rat.

The pontine taste area in the rat. The pontine taste area relays gustatory information from the rostral pole of the solitary nucleus to both the thalamus and ventral forebrain. An electrophysiological investigation of this area was carried out in 3 stages. First, multiunit responses from the dorsal pons were mapped using sapid, thermal, and tactile stimuli applied to the anterior tongue. The gustatory zone lies within and just dorsal and ventral to the brachium conjunctivum as it enters the pons from the cerebellum. Second, gustatory stimuli were applied independently to the anterior and posterior tongue to determine whether receptors in both fields are represented in the pons. Responses with characteristics similar to those obtained from the glossopharyngeal nerve were located on the dorsal edge of the pontine gustatory zone. More ventrally the responses from the posterior tongue mimicked anterior tongue responses, but were of lesser amplitude than the largest anterior responses occurring at the ventral edge of the gustatory zone. Third, 71 single units were isolated in the dorsal pons, and tested for sensitivity to gustatory stimulation of the anterior and posterior tongue separately. More than half the units responded to gustatory stimuli--some from the anterior tongue alone, some from the posterior alone, but most responded to stimuli applied to either field. In the latter instance 7 of 10 units tested continued to respond after anesthetizing the chorda tympani with Xylocaine instilled into the middle ear, thus demonstrating a true glossopharyngeal input. This proves that gustatory information from two distinct receptive fields may converge on the same central neuron.


On the structure of chromosome ends as revealed by trypsin treatment of Locusta migratoria chromosomes. Anaphase chromosomes exhibit two longitudinal structures which are connected at their ends in a U-shaped closed configuration. The U-shaped ends might be part of the chromosome characterized by a relatively dense condensation of chromosomal material or part of the loop-like structure of the chromosome per se.


Heterochromatin and multiple inversions in a Drosophila chromosome. A chromosomal polymorphism is described from a Maui (Hawaii) population of D. disjuncta. The acquisition of an extra heterochromatic segment in a mitotic chromosome is specifically associated with the presence of multiple inversions in the same chromosome. This suggests the possible effect of a chromosomal break-point within the area of centromeric heterochromatin in causing an increase in the amount of repetitive DNA. The possibility exists that the extra heterochromatin may play a role in the suppression of gene recombination in a certain region of the chromosome and/or in strengthening pairing of the inversion-laden chromosome with its normal homologue. This may reduce the changes of sterility due to nondisjunction during meiosis.


Chromosome cytology and polymorphism in the California High Sierra golden trout (Salmo aguabonita). The population variability in chromosome karyotype was examined in six samples of California High Sierra golden trout, Salmo aguabonita. From the analysis of 1,318 cells from anterior kidney tissue of 92 specimens, the modal diploid chromosome number was 2n equals 58 with 104 chromosome arms. Of cells with 2n equals 58 chromosomes, the typical karyotype was one containing 44 chromosomes with median centromeres, 2 chromosomes with submedian centromeres, 2 with subterminal centromeres and 10 with terminal centromeres. In addition, many cells contained a chromosome with a prominent satellite. Variability in chromosome number within the six populations followed a Robertsonian pattern and permitted the identification of two distinct population distributions. One population, made up of two samples, was more variable than the other and supported the hypothesis that this population was of golden trout times rainbow trout hybrid origin. Texamination of metaphase 1 cells from testes showed numerous ring and rod multivalents consistent with the random nature of Robertsonian variability.


Sex differences in gene expression for pupa weight in long term selected lines of Tribolium. Full-sib matings in two populations of Tribolium which had been selected for increased pupa weight for more than 85 generations resulted in a significant inbreeding depression in male progeny but showed no effect in the female progeny. An analysis of variance of a population produced by backcrossing the selected populations to the inbred lines originally used to establish the select populations (Design-III) indicated some genes were still segregating which produce dominance effects in males but not in females. The data support the hypothesis that a class of genes exists, associated with the autosomes, that differ in their dominance effects of pupa weight in the two sexes.


Effects of selection for postweaning gain on testicular function in mice. Changes in testicular and epididymal function and selected endocrine organ size were examined in a line of mice selected for rapid postweaning gain (M16) and in reciprocal crosses with an unselected pedigree control line (ICR). The larger body weight of the M16 line was accompanied by larger testes, epididymides, seminal vesicle, pituitary, thyroid and adrenal weights (P smaller than .01) although the testes, epididymides, seminal vesicle and adrenal weights of M16 mice, expressed per gram body weight, actually decreased (P smaller than .01) relative to the ICR line. Testicular and epididymal sperm reserves were higher in M16 mice but the difference was not significant. However, when adjusted for gland size, testicular and epididymal sperm reserves were lower in the M16 line (P smaller than .01). Absolute and relative weights of testes, epididymides and pituitary were larger (P smaller than .01) in M16 male times ICR female crosses than in ICR male times M16 female crosses. Although testicular and epididymal sperm reserves were higher in M16 male times ICR female males the reciprocal difference was significant only for testicular sperm (P smaller than .05). Heterotic effects were significant for both absolute and relative weights of testes, epididymides (P smaller than.01), pituitary (P smaller than .05) and relative weight of siminal vesicles (P smaller than .05). Although percent heterosis was 8.5 for testicular and epididymal sperm reserves, significant heterotic effects were found only for epididymal sperm (P smaller than .05).


[Reconstructive laryngectomy].

[Reconstructive laryngectomy]. Following a brief historical review of the sporadic attempts to improve the total laryngectomy, the author presents a technique for reconstructive laryngectomy. This technique should be restricted to one part of the cricoid and, according to certain modifications, to the free part of the epiglottis. Using these modifications, this technique allows the neck to be closed completely, thus avoiding a permanent tracheostomy. Relearning phonation and swallowing is spontaneous. Four cases are presented -- two successful. In the two failures, it was noted that one death was due to a hepatic deficiency and one to failure in relearning to swallow, which was attributable to senility.


Identification of the facial nerve in parotid surgery. A short outline of anatomical relations leads to a discussion of the various techniques of facial nerve identification as they present in the literature. Particular attention was given to a relatively unknown technique that has served as a valuable manoeuvre in 14 consecutive cases of superficial parotidectomy.


Management and prevention of primary perilymph fistula in otosclerosis surgery. Management of 10 cases of primary perilymph fistula is described. The modified technique of stapedectomy described in this article, seems to prevent primary perilymph fistula; time will tell if it will prevent secondary fistula. The hearing gain obtained with this technique is slightly inferior to the gain obtained with Gelfoam-wire prosthesis, but most significant is the fact that discrimination score is excellent in all cases. The author is convinced that the extra time and dexterity required to perform this procedure are well justified by the safety provided and the results obtained.


Laryngeal tuberculosis in an age of chemotherapy. Twenty-one cases of laryngeal tuberculosis were found while surveying 1,383 patients with pulmonary tuberculosis, giving an incidence of 1.5 per cent. All had abnormal chest films and tubercle bacilli in their sputum. Symptoms were variable. Patients with pain were relieved within seven days of triple therapy. All but one patient's laryngeal appearance was normal after two months' therapy.


Case report: Chylous fistula following right radical neck dissection. Two unusual cases of chylous fistulae following right radical neck dissection are presented. Treatment in the second case consisted of pressure dressing and replacing the regular blended tube feeding diet with one containing medium chain triglycerides to replace ordinary lipids (long chain triglycerides). Caloric intake was supplemented with parenteral protein and fat infusions. This resulted in prompt cessation of the leak. Other methods of controlling fistulae such as re-operation and oversewing the area or using muscle flaps, or direct packing of the wound often lead to other complications and frequently require considerable time to control the leak.


Case report: Cystic lymphangioma of the vallecula. The incidence of vallecular cysts is low. They deserve full awareness of their existence because clinically they may produce upper airway obstruction. The case of a 20 month old infant in whom the large vallecular cyst was incidentally found on a routine examination is presented with a review of the literature.


Elevated plasma CEA during radiotherapy for glottic carcinoma of the larynx. Carcinoembryonic antigen (CEA) levels in plasma were determined serially during radiotherapy in 10 patients with glottic carcinoma of the larynx. There were moderate high levels initially in three patients, all of clinical stage T1. Elevation during irradiation was noted in seven patients at a tumor dose of around 4000 rad. At this does the tumors were no longer visible and it is possible that the raised CEA represents circulating breakdown products from them. As raised levels were not seen in all patients, it is less likely that irradiation of laryngeal tissue by itself raises CEA plasma levels. After treatment, CEA normalized to the initial levels.


Current advances in radiological diagnosis of laryngeal cancer - "optimum" method, exposure data, projection. An acceptable roentgenologic evaluation of the laryngeal status can only be made at present with the use of contrast medium. Further, a high potential technique should be used, combined, if possible, with a p.a. projection. Lesions of 1-2 mm size should be detectable with this technique. Xeroradiography is not at present superior to conventional roentgenography and involves an increased radiation hazard.


Roentgen examination of laryngeal cancer: a critical evaluation. In the management of laryngeal cancer, roentgen examination is imperative in the evaluation of every lesion. The currently most commonly used roentgen techniques are lateral soft tissue roentgenography of the neck, frontal tomography of the larnyx, and contrast laryngography. Clinical application of these techniques depends upon the character and site of the lesion. Lateral soft tissue roentgenography of the neck can reveal tumor mass located mainly in the sagittal plane of the larynx. In addition, it is often relied upon for the detection of destruction of the thyroid cartilage. Frontal tomography is a static study of the larynx and usually demonstrates tumor mass in profile. Contrast laryngography allows a dynamic study of the larynx and is the most reliable roentgen technique for a precise delineation of the anatomical abnormalities and a clear evaluation of the functional alteration of the involved structures of the larynx. When used in combination, particularly lateral soft tissue roentgenography of the neck and contrast laryngography, these techniques yield invaluable information in the diagnosis of the laryngeal cancer.


The value of tantalum powder as a contrast medium in laryngography. Dionosil and powdered tantalum laryngograms are compared in 18 patients with known laryngeal cancer. Dionosil more reliably defined the epiglottis, valleculae, and pyriform fossae. The glottic and subglottic regions were more clearly visualized with the use of tantalum. Both agents were equally effective in the evaluation of the supraglottis.


Radiologic-pathologic correlations in laryngeal carcinoma. Radiological examinations are a prerequisite for accurate assessment of laryngeal tumors, especially when contemplating partial (voice conservation) surgery. The clinical assessments and preoperative radiographs from five cases have been compared with the histologic findings in whole organ serial sections of the laryngectomy specimens. These studies demonstrated both the accuracies and the deficiencies of the present clinical and radiologic examination methods. The mucosal extension of tumor is accurately assessed by a combination of direct laryngoscopy and radiography. The latter mainly gives information concerning the vertical extent of tumor, especially contrast laryngography. Xeroradiography may give additional information. Deep invasion of tumor with cartilage destruction and spread outside the larynx is often not assessable preoperatively. Circumferential and symmetrical lesions may be missed radiologically as much of the interpretation is based on asymmetry. New methods must be developed to assess the deep invasion of tumor. The necessity of a close liaison between the laryngologist, radiologist, and clinical pathologist is stressed.


Appearances of the larynx after radiation therapy. Laryngeal tomography and lateral Xerox radiographs from 21 cases of carcinoma of the larynx previously treated by irradiation were analyzed. Although false negatives and false positives did occur, radiology made a useful contribution to the diagnosis or exclusion of recurrence in a number of cases. The most relevant positive findings were: 1. Ulceration, 2. Asymmetrical swelling, 3. Failure of tumor mass to shrink.


Relative prognostic significance of vasospasm following subarachnoid hemorrhage. A retrospective analysis of 274 patients with intracranial aneurysms, diagnosed either angiographically or at autopsy between 1968 and 1973 at the University of Alberta, was carried out. One hundred and forty-six patients had intracranial clipping of the aneurysm. Clinical and radiologic data were abstracted from the chart and the angiographic studies. Probability of survival curves were constructed. Associations between various clinical factors and survival at two months were demonstrated. The most important prognostic factors were the clinical grade at angiography or surgery, followed by the presence of preoperative spasm, hematoma or focal edema, elevated blood pressure on admission, time of interval from hemorrhage to surgery and age. The data lends some support to the policy of operating on patients in good neurological condition, even if their pre-operative angiogram shows spasm.


The Chiari malformation in adults.

The Chiari malformation in adults. The clinical features of the Chiari Malformation in seven adult patients are presented. It is suggested that the clinical syndromes associated with this malformation, in adults, can be classified as (a) compression of structures at the level of foramen magnum (with or without radiologically demonstrable associated bony anomaly at the cranio-vertebral junction (b) increased intracranial pressure or obstructive hydrocephalus and (c) intramedullary cervical cord syndrome. The usefulness of tomography, and demonstration of the vertebro-basilar circulation in the neuro-radiologic investigation of these patients is emphasized. The surgical procedures performed in the management of these patients are outlined.


Meningo-encephalomyelitis due to the saprophagous nematode, Micronema deletrix. A five-year-old boy succumbed 24 days following an unusual farm accident in which considerable manure was deposited in multiple lacerations. Death was due to an extensive meningo-encephalomyelitis caused by a nematode that is ordinarily saprophagous.


Giant intracranial dermoid cyst: Case report and review of the literature on intracranial dermoids and epidermoids. A 45-year old man was referred to the Johns Hopkins Hospital with a seven-year history of repeated episodes of light-headedness, increasing irriability and forgetfulness. Examinations revealed a right superior, incongruous quadrantanopsia. EEG showed an abnormality in the left temporal lobe, and a cerebral angiogram outlined an avascular mass in the left cerebral hemisphere. At operation, the patient was found to have a giant dermoid cyst involving the left frontal, temporal and parietal lobes. Over the last 30 years we have encountered only 6 cases of intracranial epidermoids and 3 cases of intracranial dermoids. These cases are cited, and a discussion of the embryology, histology, clinical characteristics, and treatment of these lesions with a review of the literature is undertaken.


Compression of the cauda equina due to a necrobiotic granuloma of ligamentum flavum. A 56 year old woman developed symptoms of lumbar nerve root compression caused by a granuloma arising in the ligamentum flavum. The histological features of the lesion are discussed and the clinical and radiological findings of the patient are described.


Fetal cerebellar tissue associated with a primitive neuro-epithelial tumor in an ovarian teratoma. This is a single case report of an ovarian teratoma. It is a unique case of a primitive neuroepithelial tumor with many similarities to a medullo-blastoma arising in a ovarian teratoma, and the second report of fetal cerebellum occurring in a teratoma of the ovary.


Isolated spinal cord arteritis.

Isolated spinal cord arteritis. This patient presented as a subacute progressive cervical myelopathy and the differential diagnosis included cervical spondylotic myelopathy and intramedullary mass. Microscopically, vascular lesions plus a patchy myelomalacia indicated a vasculitis. However, there was no suggestion of a generalized vasculitis at autopsy and the only supporting laboratory study was a raised erythrocyte sedimentation rate. It would seem that a vasculitis similar to polyarteritis nodosa or other collagen disease may be confined to the spinal cord.


Plasma progesterone and aldosterone in pregnancy. Plasma progesterone, aldosterone and renin activity were measured simultaneously in seven women during normal pregnancy. Beginning at the 2nd trimester and until approximately 4 weeks before delivery there was a constant increase in plasma progesterone concentration. There was a significant correlation between weight gain and duration of pregnancy and between weight gain and plasma progesterone concentration. There was also an increase in plasma aldosterone concentration although this was less consistent than that of progesterone. And there was a significant correlation between plasma progesterone and aldosterone concentrations and between the progesterone/aldosterone ratio and duration of pregnancy and weight gain.


Sensorimotor and physiological effects of various alcoholic beverages. Effects of a standard dose of alcohol (1.3 g/kg) in the form of Canadian rye whisky, Canadian beer and a sparkling table wine were compared with those of a nonalcoholic carbonated control beverage. Sixteen young male and eight female subjects, all moderate drinkers, were tested in a Latin square design. Measurements were made on the pursuit rotor and quantitative Romberg tests, and of skin temperature, heart rate, malar flush and blood alcohol concentration during the prealcohol baseline period and at regular intervals over the 4-hour drinking period. The three alcoholic beverages produced blood alcohol curves that did not differ significantly. All three alcoholic beverages produced increasing sensorimotor impairment over time, which corresponded in degree to the increasing blood alcohol concentration. There were no significant differences between the three beverages on either the sensorimotor or physiological measures at any blood alcohol value. The results of this study indicate that the degree of impairment after alcohol ingestion in a socially relevant manner is not dependent on the type of beverage consumed, but only on the resulting blood alcohol concentration.


Emergency department use at two Hamilton hospitals. This report compares emergency department use at two urban Hamilton hospitals. One mainly serves lower socioeconomic and industrial groups and the other predominantly suburban residents. Although the groups served are different, the patterns of use at both hospitals were found to be similar. Over one third of visits at both are classified as nonurgent. The urban industrial hospital has higher proportions of visits that are nonurgent, by men and due to trauma. However, other parameters such as arrival time, use of ambulance, proportion admitted, percentage of emergencies, percentage of repeat visits, use of radiology and laboratory facilities and proportions of visits in different categories of presenting complaint were similar at the two hospitals. Similarities in use patterns may be due to universal health insurance, for 90% of users have medical insurance and have family doctors.


Mitral stenosis with posterior diastolic movement of posterior leaflet. The echocardiographic diagnosis of mitral stenosis depends in part on the demonstration of abnormal posterior leaflet movement to distinguish it from other conditions that similarly affect anterior leaflet motion. In mitral stenosis the posterior leaflet has been shown to move anteriorly in diastole rather than in the normal posterior direction. A patient presented with clinical evidence of moderate mitral stenosis. The anterior leaflet echo was typical but the posterior leaflet showed posterior diastolic movement. At catheterization moderate mitral stenosis was confirmed. To our knowledge this is the first report of the echocardiographic demonstration of posterior diastolic movement of the posterior mitral leaflet in documented mitral stenosis.


Adenocarcinoma of the endometrium in a teenager. Endometrial carcinoma developed in a teenager with obesity, hypertension, hyperestrinism and lack of diurnal variation of plasma cortisol concentration. She underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy and is receiving estrogen therapy. Her six obese sisters and her mother, who are at risk for endometrial carcinoma, are being managed conservatively.


Disaggregation of prostates and purification of epithelial cells from normal and cancerous prostates using sedimentation in an isokinetic density gradient of Ficoll in tissue culture medium. A brief summary of our work on the separation of epithelial cells from prostates and prostatic carcinomas is presented. Epithelial cells have been obtained from hamster prostates, human prostates, and human prostatic carcinomas in greater than 95 percent purity.


Specificity of cell membrane antigens in prostatic cancer. Mice bearing a 3-methylcholanthrene-induced fibrosarcoma (MCAM-7) transplant in the right leg underwent surgical excision of the tumor and showed specific resistance to subsequent challenges with that identical tumor line. An in vivo response to tumor-specific antigens (MCAM-7 antigen) solubilized by hypertonic potassium chloride was measured by 24-hour footpad swelling response in mice immunized to the tumor from which the antigens were extracted. These observations suggested that the transplantable MCAM-7 fibrosarcoma could produce immunity toward the solubilized MCAM-7 tumor antigens and that this tumor immunity could be measured by footpad swelling response to injection of the solubilized antigens, an indication of cell-mediated immunity. The footpad swelling response was also minotored in relation to the extent of tumor growth. Mice received MCAM-7 tumor transplants by injection of 5 times 10-6 tumor cells and were tested for footpad swelling response at intervals following tumor transfer. A significant footpad response to injected MCAM-7 antigens was present 10 days following tumor transfer; at this time signs of tumor growth were only minimally detectable. The footpad swelling response to injected antigens disappeared by 28 days following initial tumor transfer; at this time the tumor diameters were in excess of 1.0 cm. Surgical removal of tumor at this point promptly restored footpad responses within 24 hours. Similar techniques have been applied to patients bearing adenocarcinoma of the prostate, where skin testing was substituted for the measurement of footpad swelling in animals. Seven patients with known prostatic carcinoma were given intradermal injections of soluble tumor antigens extracted from their own tumors. Three of the seven patients exhibited a cutaneous delayed type hypersensitivity response to the injected autologous tumor extracts. No positivereactions were observed in response to solubilized components of control tissues, including benign prostatic hyperplasia. The significance of the demonstrated concomitant immunity in these patients has not been resolved. However, these observations suggest that some patients bearing adenocarcinoma of the prostate can exhibit an immunologic response to specific antigens present in their own neoplasms.


Initial chemotherapeutic trials in patients with inoperable or recurrent cancer of the prostate. This paper describes a random study being conducted to compare the value of 5-fluorouracil plus diethylstilbestrol vs diethylstilbestrol alone and the value of 5-fluorouracil vs CCNU in the treatment of stage D adenocarcinoma of the prostate. We have established that similar normal values of acid phosphatase are encountered in serum and bone marrow of patients with nonmalignant and malignant diseases without osseous metastasis.


Potential test systems for drugs against prostatic cancer. A number of chemotherapeutic agents have been tested in two systems which could be useful as models in the search for effective drugs for cancer of the prostate. One system involved the effects of the administered drugs on rat prostatic 5 alpha-reductase and arginase activities. Since both enzymic systems are androgen dependent and essential for prostatic function and anatomy, the effectiveness of a drug in these systems could be indicative of its value in the treatment of prostatic cancer. Michaelis constants were obtained with Lineweaver-Burk plots and the conclusions are based on a comparison of these plots with those of the controls. Thus, the following results were obtained: (a) isophosphamide, bleomycin, and procarbazine produced definite inhibition of 5 alpha-reductase in either or both the ventral and dorsolateral glands of the rat; (b) 5-fluorouracil, vincristine, bleomycin, procarbazine, adriamycin, and hexamethyl-melamine inhibited arginase activity significantly in both glands; (c) streptozotocin and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388) produced inhibition of arginase in the ventral gland only; (d) in contrast to the noncompetitive or uncompetitive inhibition of most of the drugs, particularly in the ventral gland, procarbazine, hexamethylmelamine, bleomycin, adriamycin, and NSC-45388 produced competitive inhibition of arginase in the dorsolateral gland; and (e) seven of the drugs led to an activation of 5 alpha-reductase (5-fluorouracil, vincristine, NSC-45388, hexamethylmelamine, CCNU, streptozotocin, and diglycolaldehyde). The second model system utilized the deposition of labeled estriol and testosterone in the dog prostate and the effects of drug therapy as a possible index of effectiveness in prostatic cancer. Streptozotocin and procarbazine definitely interfered with the deposition of both estriol and testosterone. On the basis of the data obtained, the model systems investigated by us could potentially serve as reliable indicators for the clinical use of drugs against cancer of the prostate.


Estimating "safe" levels, a hazardous undertaking. Various problems beset the question of identifying chemical carcinogens in the environment or setting permissible levels for potential carcinogens. Issues arising are cost-benefit questions, existence of thresholds, appropriate experimental designs, how to extrapolate to man, results from tests on laboratory animals, etc. Certain approaches implicitly involve use of a double standard, with much more stringent measures taken when clearer evidence of carcinogenicity is found. Such double standards may discourage careful testing of carcinogens as this could more probably lead to imposition of the stricter measure. Even-handed application of devices like that recommended by Mantel and Bryan for setting "safe" levels could avoid this difficulty and would encourage more adequate testing. Why laboratory testing should be at high or moderately high levels is explained and the futility of "mega-mouse" experiments at very low dose levels is indicated. A surface-area rule for extrapolating dose levels from laboratory animal to man is suggested, but this is indicated to lead approximately to direct equivalence when dose levels are expressed as dietary concentrations.


In vitro evaluation of in vivo brain tumor chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea. An in vitro colony formation assay was used to determine the efficacy of in vitro therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on a rat brain tumor. The fraction of clonogenic cells surviving in vivo therapy was determined by a comparison between the in vitro colony-forming capacity of cells derived from previously treated and untreated tumors. With this intracerebral solid tumor a direct correlation was found between the surviving fraction of cells and animal survival, implying that the in vitro assay system is a reliable test of therapeutic effect. The BCNU dose-response curve was exponential up to a dose of 0.75 times the LD10 dose with little additional cell kill noted at higher drug levels. This plateau does not appear to represent a resistant subpopulation of cells, since retreatment of tumors derived from cells surviving an LD10 dose were as sensitive to BCNU as those with no prior drug exposure. Instead, it may represent, at least in part, failure of the drug to reach and/or enter cells in all parts of solid tumors. On the average BCNU doses of 0.75 times the LD10 dose or greater resulted in slightly more than a 3-log cell kill and doubled the life-span for our tumor-bearing animals. The finding that an increase in animal life-span requires at least a 1-log tumor cell kill indicates that survival studies with intracranial tumor models may be insensitive to single courses of many chemotherapeutic agents with modest but significant antitumor activity.


Nonspecific inhibition of DNA repair synthesis by tumor promoters in human diploid fibroblasts damaged with N-acetoxy-2-acetylaminofluorene. The effects of selected tumor-promoting agents and their nonpromoting analogs on DNA repair synthesis were examined in human diploid fibroblasts (WI-38) damaged with N-acetoxy-2-acetylaminofluorene. Over a range of doses, three promoters (croton oil, 12-O-tetradecanoylphorbol-13-acetate, and anthralin) were found to inhibit DNA repair synthesis while their nonpromoting analogs (phorbol and 1,8-dihydroxyanthraquinone) had little effect. Another tumor promoter, phenol, inhibited DNA repair synthesis only at very high concentrations while an analog, 4-nitrophenol, produced inhibition of DNA repair synthesis at molar concentrations at which phenol had no effect. To investigate the specificity of this phenomenon, the effects of these agents on DNA-replicative synthesis, RNA synthesis, protein synthesis, and cell morphology were evaluated. At equimolar concentrations, tumor promoters were found to inhibit DNA-replicative synthesis as effectively as repair synthesis. RNA and protein synthesis were similarly inhibited over the same range of concentrations. Extensive morphological changes, interpreted as evidence of toxicity, were seen at concentrations of promoters that inhibited the macromolecular syntheses studied. The nonpromoting analogs, with the exception of nitrophenol, had little effect on these processes and showed only slight morphological damage. Thus tumor-promoting agents appeared to inhibit a number of macromolecular synthetic events, including DNA repair synthesis. It is suggested that the effect of tumor promoters on DNA repair synthesis is part of a general response to cellular injury rather than a selective response involving a single metabolic pathway. Furthermore, it is unlikely that the inhibition of repair synthesis represents the major mode of action of promoting agents in the carcinogenic process.


Effects of cis-diamminedichloroplatinum (NSC 119875) on murine and human hemopoietic precursor cells. The effects of cis-diamminedichloroplatinum (NSC 119875) on murine and human hemopoietic precursor cells were studied in culture. When murine cells from normal and actively regenerating marrows were exposed to cis-diamminedichloroplatinum in culture, washed free of the agent, and assayed for the surviving hemopoietic precursor cells, similar sensitivity curves were obtained. This result indicates the absence of cell-cycle dependency of cis-diaminedichloroplatinum. When marrow cells were exposed to cis-diamminedichloroplatinum in culture at various temperatures, only minimal reduction of cytotoxicity was noted at 4 degrees. This observation, unlike that from the experiment with nitrogen mustard, suggests that the transport of this agent is by passive diffusion. Finally, when the sensitivity of human hemopoietic precursor cells to this agent was assessed using similar conditions and compared to that of murine hemopoietic precursor cells, a significant species difference was observed.


Human prostatic tumors in conditioned animals and culture. A nude mouse colony has been established with a capacity of over 1000 mice. These mice have been injected with human prostatic tumors. A spleen injection method has been developed which enables us to follow the growth of tumor cells in the animal for short periods of time and to assess the effects of hormones on this growth. We have also studied the behavior of several animal cell lines in culture and in nude mice as possible models for a hormone-dependent human prostatic tumor. By using nude mice, we have been able to show that apparent "normal" revertants of cancer cells are actually antigenic variants which can be used to immunize animals against the original tumor cells. A melanoma cell line has been developed whose growth appears to be markedly enhanced by androgens. Rat ovarian cell lines have been developed whose growth and viability are hormone dependent in vivo and in vitro.


Characterization of prostatic carcinoma among blacks: a preliminary report. This study was designed to compare United States (Washington, DC) black prostatic carcinoma patients (high-risk group) with Nigerian (Ibadan) black prostatic carcinoma patients (low-risk group). Although the material is meager, preliminary analyses suggest that carcinoma of the prostate is a common disease in both US black men (196 of 1000 autopsies) and in Nigerian black men (67 of 1000 autopsies). The tumor tends to be of a higher histologic grade (less well differentiated) and the carcinomatous foci are more numerous in the Nigerian patients. Fifty-three percent of US patients are in stages I and II when the disease is first discovered. Plasma testosterone, estrone, and estradiol concentrations did not differ significantly between US patients and controls. A statistically significant positive association is indicated between carcinoma of the prostate and the following epidemiologic variables: racial admixture, age of puberty, and age of first coitus. The median age of necropsy cases with carcinoma was 50.0 years in Nigeria and 68.3 years in the US.


Serum inhibition of in vitro 67Ga binding by L1210 leukemic cells. The influence of human serum on in vitro 67Ga uptake by L1210 leukemic lymphoblasts has been investigated. Both high- and low-molecular-weight serum components inhibit cellular uptake of the isotope. Inhibition by the high-molecular-weight serum fraction correlates closely with the extent of binding of the radionuclide. Although transferring participates in high-molecular-weight inhibition, it accounts for 10 percent or less of the inhibitory and binding capacity. Similarly, various low-molecular-weight serum components, including citrate, phosphate, glutamate, and others, contribute to inhibition. This inhibition of 67Ca uptake by serum results from the presence of several, perhaps many, inhibitory components.


Identification of phosphorodiamidic acid mustard as a human metabolite of cyclop  hosphamide. An active metabolite of cyclophosphamide, N,N-bis(2-chloroethyl)phosphorodiamidic acid, has been confirmed as a circulating and excreted metabolite in patients receiving the drug in therapy, by selected ion monitoring on a gas chromatograph mass spectrometer.


The aqueous solution conformation of tubercidin and tubercidin 5'-phosphate. The backbone of tubercidin and tubercidin 5'-phosphate in aqueous solution has a flexible molecular framework with preference for 2E-gg and 2E-gg-g'g' conformations, respectively. The glycosyl bond is unusually flexible and no definite preference for either anti or syn conformation could be detected. It is proposed that the incorporation of tubercidin 5'-phosphate into nucleic acids will disrupt the polymeric structure because of the high accessibility of syn conformation, and this might be related to the reported inhibition of nucleic acid and protein synthesis.


Vitamin A and benzo(a)pyrene carcinogenesis in the respiratory tract of hamsters fed a semisynthetic diet. Male Syrian golden hamsters were fed a semisynthetic diet, given 12 weekly intratracheal instillation of 3 mg benzo(a)pyrene adherent to 3 mg Fe2O3, and then given either 100, 1600, or 2400 mu-g retinyl acetate (RA) per week intragastrically in 2 divided doses. One-half of the animals in each group were housed conventionally; the other half were housed in laminar flow units. Hepatic and serum vitamin A levels were markedly increased in hamsters given 1600 or 2400 mu-g RA per week compared to controls given 100 mu-g, which is adequate for growth and maintenance. In hamsters housed conventionally, increased RA intake was associated with an increased incidence of benign respiratory tract tumors. In all groups of hamster housed in laminar flow units there was a longer period to death with respiratory tract tumor than in conventionally housed hamsters; increased RA intake was associated with a somewhat lower incidence of respiratory tract tumors. Laminar flow housing significantly reduced the incidence of respiratory tract infection in non-tumor-bearing hamsters. Squamous papillomas of the forestomach were significantly reduced in all groups of hamsters given high levels of RA, regardless of housing.


Isolation of an immunosuppressive peptide fraction from the serum of cancer patients. An immunosuppressive peptide fraction was isolated by means of gel filtration, membrane partition, and ion-exchange chromatography from the sera of patients hospitalized for cancer. The resulting peptide fraction, which was heterogeneous as judged by high-voltage electrophoresis, was found to suppress both phytohemagglutinin-induced proliferation of lymphocytes in vitro and the in vivo induction of splenic plaque-forming cells in mice. The specific activity of the peptide fraction, which was isolated from the sera of cancer patients, was significantly increased over that of the unfractionated starting material. Moreover, in control experiments, when the sera of normals or non-cancer-bearing hospitalized individuals were subjected to the same chromatographic techniques, no active peptide fraction could be obtained.


Enzyme activities at the surface of intact Ehrlich tumor cells with albumin in the isotonic assay medium. Glyceraldehyde 3-phosphate dehydrogenase and 3-phosphoglycerate kinase are, together with some other enzymes, present on the surface of intact Ehrlich tumor cells. Aldolase, on the contrary, represents cytoplasmic enzymes not present at all on the external surface, provided 2.5 percent of bovine albumin is included in the isotonic assay medium. A flux of aldolase from the cell interior to the cell exterior could be demonstrated in the absence of albumin. Therefore, any enzymatic activity monitored when keeping the Ehrlich tumor cells in the isotonic assay medium containing 2.5 percent albumin was considered to be primarily related to the outside of the plasma membrane. Of the total glyceraldehyde 3-phosphate dehydrogenase, 0.7 percent was located on the outer surface of the tumor cell, while the corresponding figure for 3-phospoglycerate kinase was 2.7 percent. Eighty percent of this surface-located 3-phosphoglycerate kinase was released into the assay medium during incubation, while the release of glyceraldehyde 3-phosphate dehydrogenase, at the same time, was minimal. A plasma membrane preparation of Ehrlich cells, mainly consisting of vesicles, showed the presence of 3-phosphoglycerate kinase but the absence of glyceraldehyde 3-phosphate dehydrogenase. Because of the vesicular nature of the membrane preparation, it was assumed that only one side of the membrane was exposed during assay. The specific binding properties of the two enzymes to the plasma membrane, as well as possible differences in their intramembranous location, are discussed.


The enhanced cytotoxicity of combinations of 1-beta-D-arabinofuranosylcytosine and methotrexate. Although both 1-beta-D-arabinofuranosylcytosine (ara-C) and methotrexate are presumed to be toxic as a result of their interference with DNA synthesis, results obtained with L1210 cells in vivo suggest that the combination of ara-C and methotrexate is capable of killing cells by a mechanism not related simply to DNA synthesis inhibition. Simultaneous administration of ara-C and methotrexate, or administration of these two agents within a 10-hr interval, independent of order, produces a synergistic cell kill of L1210 cells but a less than additive effect on normal hematopoietic stem cells. The extent of synergy seems dependent upon the dose of ara-C.


Localization of polycyclic hydrocarbon carcinogens in the lung following intratracheal instillation in gelatin solution. The deposition and localization of benzo(a)pyrene (BP) suspended in a gelatin-0.9 percent NaCl solution was studied in hamster lungs by ultraviolet fluorescence microscopy. BP was deposited primarily in the alveolar region of the lung. Although large numbers of BP-filled macrophages were seen in the upper airways by 24 hr after an instillation, little BP appeared to penetrate into the bronchial epithelium. The intratracheal instillation of polycyclic hydrocarbons in a gelatin-0.9 percent NaCl solution appears to be a useful model when it is desired to deliver the carcinogen dose to the peripheral lung.


Cyclophosphamide-adriamycin combination chemotherapy of transplantable murine tumors. The two-drug combination of cyclophosphamide plus adriamycin was found to be therapeutically potentiating against four different C3H mammary tumor lines, the B16 melanoma, the Ridgway osteogenic sarcoma, and the P388 leukemia. The potentiation was not schedule dependent.


Carcinogenesis from polyurethans.

Carcinogenesis from polyurethans. Seventeen polyurethans, containing various substituent groups, and a polyethylene were implanted i.p. in groups of male black Bethesda rats and were evaluated for carcinogenesis over a 2-year period. Thirteen of the polyurethans and the polyethylene were similarly studied in females. Tumor development in these animals was expressed in terms of the incidence in the at-risk population, and the tumorigenic latent period was approximated for each sample. Twenty months after implantation, the relative tumorigenicity (area under the corrected cumulative tumor mortality versus time curve) in the males ranged from 0 (for the unimplanted controls) to 6.18 (for Y-238); for female rats this range was 0.29 (for unimplanted controls) to 5.72 (for Y-238). Estimated latent periods in the males ranged from 5 months (for Y-304) to 16 months (for Y-303), and 22.5 months for the unimplanted controls; for the females, the range was from 9 months (for Y-290) to 13.5 months (for Y-217), and 14 months for the unimplanted controls. The relative tumorigenicity of each sample was also compared to its in vitro activation energy for thermal decomposition. These data are discussed in terms of solid-state versus chemical carcinogenesis.


Species differences in the effect of benzo(alpha)pyrene-ferric oxide on the respiratory tract of rats and hamsters. When given intratracheal injections of a suspension of benzo(alpha)pyrene-ferric oxide, rats and hamsters showed striking species differences in the response of their respiratory tracts to the carcinogen. Hamsters produced squamous metaplasia of the trachea and large bronchi; in contrast, squamous cell nodules of bronchioloalveolar origin developed in rats within a few weeks after carcinogen application. The different sites of the early proliferative and metaplastic responses correlated in their location with the sites of later tumor development. There were no obvious differences between the two species in retention of benzo(alpha)pyrene in the lungs or tracheas. A species difference was observed, however, in the localization of the benzo(alpha)pyrene in the tracheal tissues using ultraviolet fluorescence microscopy. Carcinogen was found to be present in the epithelium of hamsters but not in the epithelium of rats, suggesting a species difference in penetration of carcinogen from the lumen into the tracheal tissues.


Effects of allopurinol on the therapeutic efficacy of methotrexate. The antitumor effects of methotrexate against early leukemia L1210 were partially reversed by the coadministration of allopurinol in vivo, even though allopurinol did not alter the growth-inhibitory effects of methotrexate against L1210 cells in culture. These data suggest that this alteration in antitumor activity results from a decreased catabolism of preformed systemic purines by allopurinol, a potent inhibitor of xanthine oxidase. On the other hand, the therapeutic effect of methotrexate against the P288 leukemia was not significantly altered by allopurinol did not significantly alter the toxicity of methotrexate that, in the mouse, the antileukemic effects of methotrexate are more related to a purineless rather than a thymineless death.


Cell-surface antigens induced by Friend and Rauscher virus complexes and their associated lymphatic leukemia viruses in the rat. The WKA/Mk rat tumors induced by Friend virus complex, Rauscher virus complex, and their associated lymphatic leukemia viruses were investigated for their antigenic relationhips with transplantation experiments and cytotoxicity tests. It was found that Friend lymphatic leukemia virus-induced tumors lacked part of the tumor-associated transplantation antigens (TATA's) on Friend virus complex-induced tumors, and the former did not express the type-specific (Friend) TATA for the latter not shared by Rauscher virus complex-induced tumors, which was previously reported by the authors. In contrast, the antigenic differences between TATA's of Rauscher virus complex-induced tumors and those of Rauscher lymphatic leukemia virus-induced tumors were not clearly demonstrated. Furthermore, these studies indicated that Rauscher lymphatic leukemia virus-induced tumors had a weak type-specific TATA not shared by the tumors induced by Friend lymphatic leukemia virus. These results of transplantation studies were also serologically supported by cytotoxicity tests.


Acute, chronic and terminal toxicity to 4'-demethylepipodophyllotoxin thenylidene glucoside (VM26) in mice. The development of toxicity to 4'-demethylepipodophyllotoxin-9-(4,6,-O-thenylidene-beta-glucopyranoside) an epipodophyllotoxin with oncolytic activity, was characterized in mice treated three times at 3-day intervals with 10 mg of drug i.p. per kg of body weight. Changes in organ function and general metabolism were determined by measuring 18 constituents of blood for up to 10 weeks after drug administration. The results indicate three distinct phases of toxicity to 4'-demethylepipodophyllotoxin 9-(4,6-O-2-thenylidene-beta-glucopyranoside). Acute toxicity developed within the first 10 days and was expressed by a depressed hematocrit and elevated plasma levels of glutamate-pyruvate transaminase, glutamate-oxaloacetate transaminase, lactic dehydrogenase, amylase, lipase, and uric acid. By 4 weeks, levels ahd returned to normal. The acute phase was followed by a chronic phase, which was characterized by progressive decreases in plasma levels of glucose, cholesterol, albumin, and total protein. Finally, about 7 weeks after treatment, a terminal phase indicated by correlated increases in glutamate-pyruvate transaminase, glutamate-oxaloacetate transaminase, lactic dehydrogenase, and blood urea nitrogen became apparent. Plasma levels of creatine phosphokinase, calcium, inorganic phosphate, total bilirubin, ketones, and alkaline phosphatase did not change. Although the pancreas liver and marrow were all affected during acute toxicity, boserved changes in blood components during the chronic and terminal phases correlate best with continued hepatotoxicity. The present evidence on delayed toxicity to 4'-demethylepipodophyllotoxin 9-(4,6-o-2-thenylidene-beta-D-glucopyranoside) is most compatible with irreversible hepatotoxocity which leads to metabolic deficiencies and terminates in death of mice.


Pharmacological and therapeutic efficacy of daunomycin:DNA complex in mice. The pharmacological and therapeutic effects of the daunomycin (DNM):DNA complex were compared with those of free DNM in mice. A complex formation between dnm and DNA (1:11.7, w/w) resulted in a 79% decrease in DNM complex was dialyzable. The DNM fluorescence was completely recovered from the complex in 0.3 N HCl and 50% ethanol solution, and a short contact with biological tissues studied did not quench DNM fluorescence after extraction. The plasma fluorescence (DNM equivalent) 5 min after the i.v. injection of DNM:DNA complex at a dose of 20 mg/kg was 60-fold higher than that of an equivalent amount of free DNM. The complex was cleared for plasma with an initial half-life of 20 min. In spite of an initally higher blood generally similar except in liver and spleen, where DNM equivalent were significantly higher than those of free DNM. The uptake of DNM:DNA into L1210 cells in vitro was low and, at 1 hr, was about one-twentieth of that from DNM. Treatment of DBA/2 mice bearing i.p. L1210 leukemia transplant (initial cell number, 10-3) with DNM:DNA complex resulted in identical increases in life-span as occurred with free DNM. When routes of cell transplant and treatment were different, no therapeutic advantage of DNM:DNA over DNM was seen.


Damage and repair of DNA in various tissues of the rat induced 4-nitroquinoline 1-oxide. 4-Nitroquinoline 1-oxide induces pulmonary tumors when given by a s.c. route or skin cancer by repeated local applications. This carcinogen is absorbed by the lung more readily than other tissues. Therefore, we have compared the ability of 4-nitroquinoline 1-oxide to damage DNA of the liver, lung, and kidney in the intact animal. A differential effect of DNA damage was detected in all three organs, with the lung showing the greatest amount of damage. All three tissues were able to repair the damaged DNA. The preferential damage of rat lung DNA by 4-nitroquinoline 1-oxide correlates with the specificity of this carcinogen to induce pulmonary tumors.


The surface of the pecten oculi in the pigeon. A scanning electron microscopic study of the pecten reveals the rib-like character of the pectinal folds, the nature of their connections with the base and bridge of the pecten as well as the presence of interconnections between the bundles of superficial collagenous fibers. It has been suggested that the pecten may have a mechanical significance, namely protection of the retina from the excessive movements of the vitreous humour. The relationship between the superficial membrane of the folds which is continuous, the intercellular spaces and the process of diffussion has also been discussed.


The projection of ocellar neurons within the brain of the locust, Schistocerca gregaria. Cobalt iontophoresis of the median and lateral ocellar nerves of Schistocerca gregaria, combined with silver impregnated sections of the brain, has demonstrated the projection area of the large and medium-sized ocellar afferent neurons. These neurons terminate within the brain and their cell bodies lie within the protocerebrum. Ocellar neurons project to two discrete areas on each side of the brain, each area receiving input from a different set of fibres. Both postero-dorsal complexes receive an imput from two large ipsilateral and two large median fibres. Their dendritic fields maintain an ordered spatial array relative to one another. The two antero-lateral complexes receive an imput from one large ipsilateral fibre and medium-sized ipsilateral and medium small-field afferent fibres. Each lateral ocellus has two large fibres in common with the median ocellus. These lateromedial fibres receive photoreceptor input from both ocelli but form no major arborisations within the brain. The lateral ocellar tracts appear to form a third ocellar association area since higher-order neurons branch amongst the lateral and latero-medial fibres within the tract. The axons of the higher-order neurons descend to the ventral cord via the circumoesophageal commissures.


Correlated changes in the structure of the anterior pituitary gland, testes and interrenal tissue during sexual maturation of male lizards. The anterior pituitary gland, testes and interrenal glands of a series of young males of the teiid Cnemidophorus l. lemniscatus (L.) have been studied by light microscopy in order to correlate the changes occurring during sexual maturation. In the testes of the smallest animals, spermatogenesis does not progress beyond primary spermatocytes and there is no differentiated interstitial tissue. In medium-sized animals, spermatids and some interstital cells appear, and in the largest lizards, spermatogenesis is completely established and Leydig cells abound. Simultaneously with the development of the testes, interrenal glands undergo great hypertrophy and hyperplasia, especially in the peripheral reactive zone. Starting in animals of intermediate size, the anterior hypophysis exhibits a considerable hypertrophy of two rostral cell types: the chromophobic corticotrophs and the acidophilic PAS-positive cells considered to be interstitiotrophs, These cells show large, vesicular nuclei and prominent nucleoli, signs of enhanced cellular activity. The hypertrophy begins in the dorso-rostral region of the gland close to the median eminence, at the site of entry of the portal vessels. This suggests a hypothalamic influence on the function of these pars distalis cells. The scattered basophilic gonadotrophs or folliculotrophs are scarce, small, and do not vary appreciably among the animals studied. The hyperactivity of corticotrophs may account for enlargement of the interrenal glands. Testicular development is apparently related to an increased activity of interstitiotrophs but to a stable level of activity in folliculotrophs.


Absorption and transport of ferritin and exogenous horseradish peroxidase in the opisthonephric kidney of the sey lamprey II. The tubular nephron. The tubular nephrons in the opisthonephric kidney of the sea lamprey, Petromyzon marinus L., were demonstrated to absorb and transport exogenous protein. The proximal convoluted segment is the major site of protein absorption from the tubular lumen and the process involved is similar to that described for the proximal convoluted segment in the kidneys of other vertebrates. The lateral intercellular spaces are a possible channel for the transport of intact proteins in this segment. The cilated neck segment, the intermediate segment, and the collecting segment demonstrate only limited involvement with protein tracers and likely are not involved in the absorption of protein from the glomerular filtrate. A substantial involvement of the distal segment with the absorption and transport of protein is suggested. Diffusion of tracers from the peritubular capillaries and sinusoids through the basement membrane into the lateral intercellular spaces and smooth vesicles of cells in both the proximal and distal segments indicates that retrograde transport likely occurrs. This also demonstrates that the cytoplasm of these cells contains a complex endomembranous system continuous with the plasma membrane. The significance of these findings is discussed in relation to possible functions of the kidney in osmoregulation of the sea lamprey in both freshwater and saltwater environments.


Diffusion of horseradish peroxidase perfused through the lateral ventricle of the chick telencephalon. Horseradish peroxidase, perfused into the lateral ventricle of chick brain, freely and slowly diffuses through the cerebral extracellular spaces. The layer of astrocytic end-feet surrounding blood capillaries does not consitute a barrier to the tracer which permeates the basal lamina, diffuses between the pericytic cells and finally accumulates in the intercellular space beneath the tight junctions between contiguous endothelial cells. No evidence was found for transport by micropinocytotic vesicles from the cerebral parenchyma to the capillary lumen.


Effects of induced pinocytotic activity and extreme temperatures on the morphology of Golgi bodies in Amoeba proteus. The morphology of the Golgi apparatus of Amoeba proteus can be influenced by substances inducing pinocytotic activity as well as by extreme temperatures. During the ingestion of a solution of 0.5% egg white the number of Golgi bodies decreases from 100% measured in control cells to 82% measured in cells showing induced pinocytosis. Simultaneously the ratio of the surface area  of the cisternae at the proximal face to that of the vesicles at the distal face of single dictyosomes remains constant (1.74-1.72). The decrease and increase of the temperature of the culture medium to 4 degrees C and 30 degrees C respectively, causes the disappearance of most of the dictyosomes. After keeping the cells for 3-10 h at these temperatures the number of Golgi bodies was only 5-10% of the controls. A continued treatment with cold or warm culture medium leads to a partial reorganization of dictyosomes. After 15 h the number of Golgi bodies counted per cell returned to 57% at 4 degrees C and 38% at 30 degrees C. The ratio of the surface area of the Golgi cisternae to the surface area of the Golgi vesicles also alters under the influence of extreme temperatures. The values measured after treating the cells for 3h, 4 h 10 h and 15 h at 4 degrees C and 30 degrees C amounted to 0.75, 0.85, 1.14 1.53 and 0.93, 0.38, 0.88, 1.60, respectively, compared to 1.72 of control amoebae. The different values of the ratio of the surface area of cisternae to that of vesicles indicate that there are strong morphological changes of single dictyosomes.


Brain tissue transplanted to the anterior chanber of the eye: 2. Fluorescence histochemistry of immature catecholamine- and 5-hydroxytryptamine neurons innervating the rat vas deferens. Small pieces of the wall of the rat vas deferens were homologously transplanted to the anterior chamber of the eye together with small pieces of embryonic brain stem containing either developing noradrenaline (NA) cells of the locus coeruleus or 5-hydroxytryptamine (5-HT) neurons of the developing raphe system. The eyes of the recipients were sympathetically denervated. The double transplants became rapidly vascularized from the host iris. After 3 1/2 months the irides, together with their two transplants were analyzed by Falck-Hillarp fluorescent microscopy. Both the NA and the 5-HT neurons had survived and matured in the eye. Fluorescent varicose nerve terminals of the NA and 5-HT type respectively were found in all three potential receptor areas, i.e. within the CNS transplants, in the host irides and in the vas deferens transplants. In the latter, the newly formed monoamine nerve terminals arborized mainly within a well developed smooth muscle layer. The density of such new fibres was higher than or similar to that of the normally present sympathetic plexus in areas of the transplant close to the CNS transplant and lower in areas at a distance from the CNS transplant. It is concluded that immature central NA and 5-HT fibres are able to grow simultaneously into different types of sympathetically denervated smooth muscle tissues to form networks of fibres in the receptor organs resembling the normal sympathetic innervation.


The aminergic innervation of the pituitary gland in the roach Leuciscus rutilus. Fluorescent (aminergic) fibers were demonstrated by the Falck-Hillarp technique in all parts of the neurohypophysis (NH) in the roach (Leuciscus rutilus). The fibers are very thin and few in number in the rostral (RNH) and proximal neurohypophysis (PNH) but slightly more numerous in the NH adjacent to the pars intermedia (PI). The fibers occur in normal fish as well as in specimens pre-treated with gamma-methyl-noradrenaline. It is proposed that all parts of the adenohypophysis have a very sparse aminergic innervation. There is no correlation between the number of type "B' fibers and fluorescent fibers in the roach NH. The technical difficulties in obtaining good and reliable results in teleost material are discussed.


An investigation of the foetal rat spinal cord. I. Ultrastructural observations on the onset of synaptogenesis. Ultrastructural studies on the foetal rat spinal cord show that during synaptogeneis there is difficulty in recognizing true synaptic precursors. Symmetric densities are found at unusual sites forming, for example, somato-dendritic and somato-somatic junctions. They are also found between neurons and possible glial processes. Symmetric densities occur between nerve cells but may be confused with desmosomes. Profiles exhibiting membrane density, cleft material and 50 nm vesicles, which are the most reliable indicators of presumptive synapses, are found between neurones, but also at junctions between neurons and what may be glial processes. The picture is further confused by the presence of degeneration axodendritic synapses at early foetal stages. Caution must be exercised in defining an apparent synapse or precursor in foetal cord as that of a presumptive functional synapse because of the observed degenerating profiles and because of our knowledge, somato-somatic, somato-dendritic, and neurono-glial synapses have not been observed in adult cord. It is not known whether these structures are an unwanted consequence of development or play a role in guiding development.


An investigation of the foetal rat spinal cord. II. An ultrastructural study on the development of synapses with the aid of observations on some electrophysiological properties. Electrophysiological and ultrastructural studies were carried out on foetal rat spinal cord. The electrophysiological observations allowed certain identification of the site of second order sensory neurones, regions of the most functionally mature ventral horn cells and the adequacy of reflex conduction at 18 days. In the ultrastructural studies we made use of these identifications. No definitive synapses were found at 13-14.5 days in dorsal and ventral horn neuropil though some possible precursors were seen. Immature axodendritic synapses are found first in both dorsal and ventral marginal zones at 14.5 days and in both dorsal and ventral neuropil regions at 15-16 days. At 17 days there is an abrupt increase in frequency and maturity of synaptic profiles in all regions; synapses containing pleomorphic populations of vesicles are first seen in the ventral horn neuropil at this age as rare axo-somatic synapses. At 18 days the synapses population increases and multiple contacts involving axons or dendrites commonly occur. Furthermore, axo-somatic synapses are seen for the first time in the dorsal horn. From 20 days onwards mature synapses were commonplace and all earlier stages can be found. In addition axo-dendritic synapses with pleomorphic populations of vesicles were first seen in the dorsal horn. Axo-somatic synapses in the dorsal horn remained immature in appearance at this time. These findings are discussed particularly in relationship to previous studies by others on the development of motility in the rat. It appears that in the rat lumbar cord, onset of formation of different synapse types in specific locations precedes the onset of possible related functions by 1-2 days.


Ultrastructural study of the prothoracic glands of Galleria mellonella L. in the penultimate last larval, and pupal stages. The prothoracic gland (PGL) of Galleria mellonella is a Y-shaped, paired organ, consisting of 45-50 polyploid giant cells. The PGL cells are supplied by neurosecretory axons; release of neurosecretory granules (1000-1300 A in diameter) directly on the surface of PGL cells was frequently observed. Based on ultrastructure, the last two larval instars can be divided into three phases: 1) restitutive phase immediately after moulting; 2) gradual activation in mid-intermoult as indicated by the logarithmic cell growth, decrease of nucleo-cytoplasmic ratio, increase in the number of cell organelles participating in protein synthesis, and the structural changes of these organelles; 3) "release' period preceding moulting, characterized mainly by the extreme dilatation of peripheral invaginations. From the prepupal stage onward cellular activity is asynchronous. Part of the cells already show the signs of involution, while others histolyse only after the activation phase subsequent to moulting. PGL in G. mellonella is one of the larval tissues. In the course of activation its ultrastructure changes as a function of juvenile hormone (JH) cocentration, in the absence of which it histolyses. Accordingly, it has seemed to us to be a suitable model for the cytological study of JH activity.


A human lymphoid cell line secreting immunoglobulin G and retaining immunoglobulin M in the plasma membrane. A selected clone, LA 85.2, of a human lymphoid cell line produces, mu gamma, and light chains. The cells secrete IgG but not IgM. Assembly of mu chains and light chains produces 8S IgM which is retained in the plasma membrane. IgM is produced at a slow rate and in lesser amounts than IgG. LA 85.2 cells produce a plasma membrane protein which can bind to antibody-antigen precipitates. It is suggested that this protein plays a role in holding the surface IgM in the plasma membrane.


Response of type B atrial vagal receptors to changes in wall tension during atrial filling. In anesthetized curarized cats with their chests open, we recorded the activity of type B right atrial vagal stretch receptors, right atrial pressure, and instantaneous dimensional changes of the right atrium. The nervous activity was analyzed during alterations in atrial dynamics produced by acute volume loading of the right atrium under control conditions and during sympathetic and vagal stimulations. Our results demonstrated that the mean frequency of discharge in the burst was dependent on the absolute tension and the rate of change in tension developed in atrial muscles during filling. The responses of different receptors to changes in atrial dynamics were qualitatively similar but characteristic for each receptor studied. In some experiments nervous activity was recorded after the cats had been killed: static and dynamic changes in atrial tension were then produced by injecting blood into the right atrium. Under these conditions dynamic stimuli always activated the receptors at tensions below the threshold for static stimuli. During dynamic stimuli the instantaneous firing rate was always higher than it was during static stimuli applied at the same level of tension. This study indicates that the nervous activity of type B atrial vagal receptors is closely dependent on static and dynamic changes in atrial wall tension.


Depolarization-induced movement of Mn 2 cations across the cell membrane in the guinea pig myocardium. The effects of Mn-2+-containing solutions on the mechanical and electrical responses of myocardial tissue were studied on guinea pig ventricular strips. At a concentration of 10 mM, Mn-2+ abolished the twitch responses and caused the development of a contracture in stimulated preparations but not in resting or in Ca-2+-depleted preparations. The duration of action potentials was shortened, and dV/dt-max was decreased. In Ca-2+-depleted (0.1 mM), Mg-2+-free medium, Mn-2+ also increased the amplitude of the overshoot; the increase was due to a slow phase of depolarization. Measurement of the Mn-2+ uptake showed an increased influx of these ions in stimulated preparations compared with that in quiescent preparations. These results suggest that Mn-2+ (1) generates a transmembrane current in guinea pig myocardial cells and (2) interferes with the excitation-contraction coupling process at two levels: the cell membrane and an intracellular site.


Differentiation of neurogenic and myocardial angiotensin II receptors in isolated rabbit atria. The effect of angiotensin on the action of tyramine was studied in isolated rabbit left atria paced by point and field stimulation to more clearly define the interaction of angiotensin with the sympathetic nervous system. Administration of angiotensin resulted in similar increases in contractility in both point- and field-stimulated atria. In point-stimulated preparations only the muscle is stimulated to contract, whereas in field-stimulated preparations both nerve and muscle are stimulated. 1-Sar-8-Ala-angiotensin II completely blocked the direct inotropic effect of angiotensin in a molar dose ratio of 3:1 in both point- and field-stimulated preparations. However, angiotensin (0.05-10 ng/ml) potentiated the inotropic effect of tyramine in field-stimulated atria only. This facilitatory effect was not inhibited by 1-Sar-8-Ala-angiotensin II at a molar dose ratio of 3:1; indeed, a ratio of 500:1 was necessary for complete blockade of this angiotensin-induced potentiation. This antagonist in odses of 0.1-1000 ng/ml was without contractile effect in any preparation, regardless of whether tyramine was present. The data suggest the presence of (1) a presynaptic angiotensin receptor that, in the presence of sympathetic nerve stimulation, modulates the release of norepinephrine and (2) a second angiotensin receptor in cardiac tissue that directly influences myocardial contractility.


Inotropic effects of different calcium ion concentration on the embryonic chick ventricle. Comparison of single cultured cells and intact muscle strips. The effects of changes in the calcium ion concentration in the medium bathin single beating cultured chick embryo ventricular cells were determined using an electro-optical monitoring technique for measuring the amplitude and velocity of cell wall motion. Although single cells showed significant decreases in the amplitude and velocity of cell wall motion during contraction when the calcium ion concentration was lowered from 1.8 mM to 0.9 mM, there were no significant changes in these parameters when the concentration was increased from 1.8 mM to 3.6 mM, and the magnitude of this response increased with increasing embryonic age. These results suggest that there is a reduced positive inotropic responsiveness in young chick embryo ventricular cells, which is particularly marked in the single cultured cell preparation because of the tendency of culturing techniques to select out immature cell populations.


Pressure drop across artificially induced stenoses in the femoral arteries of dogs. Stenoses were artificially induced in 13 large mongrel dogs by implanting small hollow cylindrical plugs in their femoral arteries. The instantaneous pressure drop across the stenosis and the flow rate were measured for a series of stenoses varying in severity from 52.3 to 92.2%. Mean pressure drops ranged from approximately 2 to 30 mm Hg with peak pressure drops ranging from 9 to 53 mm Hg. The pressure drop could be estimated from a relatively simple equation that was originally developed for flow through model stenoses. With this equation, the effects of several factors that contribute to the pressure drop, including stenosis size and shape, artery lumen diameter, blood density, blood viscosity, and velocity and acceleration of flow, could be clearly delineated. For severe stenoses, unsteady flow effects were small and flow could be treated as quasi-steady. Calculations based on data obtained from the dog experiments revealed that the mean pressure drop across a stenosis increased nonlinearly with percent stenosis and showed quantitatively that the value of critical stenosis decreased with increasing demand for blood flow.


Correlation of the glycoside response, the force staircase, and the action potential configuration in the neonatal rat heart. The rat heart demonstrates marked alterations in its responses to ouabain and increased frequencies of stimulation and in the duration of its action potential during the initial 21 days of life. At an age of 6.2 days 5 times 10- minus 5M ouabain produced a 158.2% increase in dP/dt compared with a 17.2% increase at 21.1 days (P less than 0.001). At 6.2 days dP/dt increased by 53.4% when the heart rate was accelerated from 30 to 90 beats/min compared with an increase of 12.2% at 21.1 days (P less than 0.005). The positive glycoside and staircase responses at the younger age were virtually eliminated when the hearts were perfused with a solution containing 50% [Na+]o and 25% [Ca-2+]o ([Ca-2+]o/[Na+]o-2 maintained constant). The duration of the ventricular action potential progressively decreased from 350-400 msec at birth to 100-150 msec at 21 days of life. This decrease was due to a shortening and a decrease in the potential level of the plateau phase. The prominent plateau typical of the early neonatal period was significantly diminished by perfusion with 50% [Na+]o. The results suggest that Na+ flux through a slow membrane channel plays a significant role in the positive staircase and glycoside responses of the early neonatal rat heart. As the heart matures and becomes functionally anomalous relative to other mammalian species, the slow channel progressively closes.


Inhibition of coronary blood flow by a vascular waterfall mechanism. The mechanism whereby systole inhibits coronary blood flow was examined. A branch of the left coronary artery was maximally dilated with an adenosine infusion, and the pressure-flow relationship was obtained for beating and arrested states. The pressure-flow curve for the arrested state was shifted toward higher pressures and in the range of pressures above peak ventricular pressure was linear and parallel to that for the arrested state. Below this range the curve for the beating state converged toward that for the arrested state and was convex to the pressure axis. These results were compared with a model of the coronary vasculature that consisted of numerous parallel channels, each responding to local intramyocardial pressure by forming vascular waterfalls. When intramyocardial pressure in the model was assigned values from zero at the epicardium to peak ventricular pressure at the endocardium, pressure-flow curves similar to the experimental ones resulted. Thus, we conclude that systole inhibits coronary perfusion by the formation of vascular waterfalls and that the intramyocardial pressures responsible for this inhibition do not significantly exceed peak ventricular pressure.


Reduced myocardial reflow and increased coronary vascular resistance following prolonged myocardial ischemia in the dog. Studies were performed to determine whether an alteration in coronary vascular resistance and a reduction in the reflow phenomenon occurred in the blood-perfused, heparinized canine heart after various periods of myocaridal ischemia. Regional myocardial blood flow was measured with radioactive microspheres. Proximal left anterior descending coronary artery blood flow was measured with a periarterial flow transducer. Reduced reflow to the ischemic portion of the left ventricle and increased resistance in the left anterior descending coronary artery were present after 120 minutes of myocardial ischemia. The reduction in reflow was specific to the subendocardium of the ischemic area. Saline and isosorbide dinitrate (Isordi) did not prevent the increase in coronary vascular resistance or the significant reduction in reflow to the subendocardial portion of the ischemic area. Hypertonic mannitol given so as to increase serum osmolality 40 mosmoles/kg prevented the increase in coronary vascular resistance and modified the reduction in the reflow phenomenon to the subendocardial portion of the ischemic area. Thus, both an increase in coronary vascular resistance and a significant reduction in reflow to the subendocardial portion of the ischemic area occur in the canine heart after 120 minutes of myocardial ischemia. Moreover, the increase in coronary vascular resistance can be prevented and the reduction in reflow to the subendocardial portion of the ischemic area can be modified by the administration of hypertonic mannitol.


Determinants of fast- and slow-pathway conduction in patients with dual atrioventricular nodal pathways. Electrophysiological studies were performed in two patients with documented paroxysmal supraventricular tachycardia and dual atrioventricular (AV) nodal pathways as defined by the atrial extra-stimulus technique. Both patients manifested two ranges of A-H intervals (AV nodal conduction times) at critical cycle lengths, reflecting fast- and slow-pathway conduction. The occurrence of fast- and slow-pathway conduction at the same cycle length depended on a long fast-pathway effective refractory period relative to the spontaneous or driven cycle length. At critical cycle lengths with fast-pathway conduction, a shift to slow-pathway conduction could be induced by a premature atrial impulse falling within the effective refractory period of the fast pathway. Repetitive retrograde concealed conduction to the fast pathway then maintained antegrade slow-pathway conduction. Resumption of fast-pathway conduction was induced with premature atrial impulses falling within the effective refractory periods of both the fast and the slow pathways, allowing recovery of the fast pathway for antegrade conduction. Atrial echoes and AV nodal reentrant paroxysmal supraventricular tachycardia occurred when sufficient slow-pathway delay was achieved to allow recovery of the fast pathway for retrograde conduction.


Mesenteric hemodynamics in early experimental renal hypertension in dogs. To investigate mesenteric hemodynamics in early perinephritic hypertension, we measured blood flows and intravascular pressures in innvervated, collateral-free, naturally perfused loops of ileum in 50 male mongrel dogs anesthetized with sodium pentobarbital. In addition, we studied venous pressure-volume relationships in temporarily occluded segments of mesenteric veins in vivo and in excised segments of mesenteric veins in vitro. In 10 dogs (group H-1), one kidney was wrapped in silk 11 days before study; in 15 other dogs (group H-2), one kidney was wrapped 4 weeks before study and the other was removed 2 weeks before study. Twenty-five additional dogs were prepared as normotensive controls: in 10 one kidney was sham-wrapped (group C-1), and in 15 one kidney was sham-wrapped and the other was removed (group C-2). A significant rise in mean arterial blood pressure occurred in groups H-1 and H-2. Compared to controls, (1) ileal blood flow in the hypertensive dogs (H-1 plus H-2) was increased by 17% (P smaller than 0.05), (2) calculated ileal vascular resistances (total and segmental) were unchanged (P smaller than 0.05), and (3) in vivo and in vitro mesenteric vein pressure-volume curves of H-2 (but not of H-1) hypertensive dogs were shifted in the direction of the pressure axis (P smaller than 0.05). These data suggest that in the early stages of perinephritic hypertension in dogs (1) ileal blood flow is increased. (2) ileal vascular resistance is not elevated, and (3) mesenteric venous compliance is reduced. Analysis of the venous pressure-volume curves suggests that the decreased venous compliance is attributable to factors other than smooth muscle contraction.


Urinary kallikrein excretion in spontaneously hypertensive rats. Urinary kallikrein was similar in 16-week-old Wistar/Kyoto (W/Ky) and spontaneously hypertensive (SH) rats, but at 23 weeks the SH rats excreted significantly less kallikrein. When dietary sodium was restricted, kallikrein excretion increased in the W/Ky but not in the SH rats. On high dietary sodium the opposite occurred: kallidrein excretion increased in the SH but not in the W/Ky rats. The pattern of urinary kallikrein excretion has some similarity to that seen in human hypertensive disease, i.e., the SH rat excretes less kallikrein than the normotensive control at 23 weeks of age and does not show an increased excretion when fed a low sodium diet. However, the rise in kallikrein shown by the SH rat on a high sodium diet is unique for this hypertensive model.


Identification of angiotensinogenic hypertension in man using 1-sar-8-ala-angiotensin II (Saralasin, P-113). Peripheral plasma renin activity (PRA) is not invariably elevated in patients whose ischemic renal lesion is causing hypertension. Infusions of an angiotensin II antagonist, 1-sar-8-ala-angiotensin II (P-113), have been used to determine whether the blood pressure responses might indicate angiotensin dependence in 221 consecutive hypertensive patients. In 32 patients P-113 infusion reversibly reduced blood pressure, and almost all of these "P-113 responders" had elevated renal vein and/or peripheral PRA levels, together with evidence of renal ischemia. Among the 189 "P-113 nonresponders," peripheral PRA was elevated in seven (3.8%), and renal vein PRA ratio was abnormal in two patients, who might represent exceptions to the otherwise successful record of the P-113 response in identifying "angiotensinoginic" hypertensives.


Effect of varying perfusion pressures on the output of sodium and renin and the vascular resistance in kidneys of rats with "post-salt" hypertension and Kyoto spontaneous hypertension. Isolated kidneys from both "post-salt" normotensive and hypertensive rats were perfused with blood from donor rats at varying pressures. At 130 mm Hg inflow pressure 15 "post-salt normotensive" kidneys put out 0.75 muEq Na/min/g kidney while 14 "post-salt hypertensive" kidneys put out 0.28 mu-Eq Na/min/g (P less than 0.001), a 63% reduction. They also put out 55% less water (P less than 0.002). Thus, if "hypertensive" kidneys are perfused at normal pressures, they put out subnormal amounts of Na and H-2-O. Such Na and H-2-O retention maintains the hypertensive state. Normal Na output in these kidneys was only reached at hypertensive (160) inflow pressures. This shift in the "pressure natriuresis" curve explains in part how some "hypertensive" kidneys maintain hypertension. These "hypertensive" kidneys have grossly abnormal autoregulation curves, each increment of pressure actually producing progressively greater increments of blood flow. Isolated kidneys from Kyoto hypertensive and normotensive rats showed no difference in Na and H-2-O excretion at 130 mm Hg inflow pressure. Thus, a tendency to Na retention demonstrable in the isolated kidney is apparently not supporting Kyoto hypertension. Moreover, isolated kidneys form Kyoto hypertensive rats released significantly lower amounts of renin at all levels of inflow pressure, averaging a 70% lower rate than Kyoto normotensive kidneys (P less than 0.01). Hence, Kyoto hypertension is not supported by a supernormal renin release inherent in the kidney. One can speculate that Kyoto hypertensive rats normally have an elevated sympathetic tone which stimulates release of renin. The denervation which occurs in isolating kidneys might therefore produce a proportionally greater percentage loss of sympathetic influence in these kidneys, which could possibly account for some of their reduced renin release. These Kyoto hypertensive kidneys are apparently not "reset" to maintain hypertension with either Na or renin.


Evidence for the existence of an acetone soluble renin inhibiting factor in normal human plasma. After addition of exogenous human renin, the in vitro rate of angiotensin I generation is faster in plasma of patients with chronic renal insufficiency and, to a lesser extent, in plasma of patients with essential hypertension than in plasma from normotensive control subjects. The increased reactivity of renin in hypertensive and uremic plasma is not related to differences of endogenous renin activity, angiotensinase activity, renin substrate concentration, or substrate reactivity. Addition of normal, hypertensive, and uremic plasma to a human renin-sheep renin substrate system inhibited the rate of angiotensin generation, although significantly less inhibition was observed with uremic plasma. The reactivity of renin increased in normal plasma but not in uremic plasma after treatment with 95% acetone. After acetone extraction renin reactivity in normal and plasma inhibited the rate of angiotensin generation in a renin-renin substrate system. Less inhibition occurred with the acetone extract from a pool of uremic plasma. These results provide evidence for the existence of a naturally occurring acetone soluble renin inhibiting factor in normal and uremic plasma. The increased reactivity of renin in uremic plasma may be related to a deficiency of this factor.


Plasma renin and sodium balance during development of moderate and severe renal hypertension in rats. The changes in systolic blood pressure, plasma renin activity (PRA), and sodium balance were studied during the first 3 weeks of the development of renal hypertension in rats with an undisturbed contralateral kidney. Moderate hypertension (160 to 180 mm Hg) was reached after application of a 0.25-mm solid clip; severe hypertension (200 to 230 mm Hg) developed after application of a 0.20-mm solid clip. Basal levels of PRA in peripheral blood increased only in rats with a 0.20-mm clip, when blood pressure had already risen to 160 to 180 mm Hg. Elevated peripheral PRA, however, may have contributed to the initial increase of blood pressure in both groups of hypertensive rats, as indicated by higher late-afternoon PRA values at the peak of the normal diurnal rhythm of PRA. PRA in renal venous blood from the clipped kidney increased during the development of both moderate and severe hypertension at a rate quantitatively related to the rise in blood pressure. During the first 8 to 10 days after application of both sizes of clips, sodium retention per gram gain in body weight was significantly higher than in the sham-operated controls. Subsequently, sodium balance and blood pressure stabilized in animals with a 0.25-mm clip. In the rats with a 0.20-mm clip, sodium balance returned to control levels and became even lower than in the sham-operated group. Despite this negative sodium balance, blood pressure showed a further rise. These results suggest that in rats with an undisturbed contralateral kidney, a positive sodium balance has a role in the early phase of the development of renal hypertension. The enhanced plasma renin activity also probably contributes to the early phase, but appears to make a major contribution to the further development of severe hypertension.


Role of renin in the pathogenesis of renal hypertension. To test the hypothesis that renin is circulating in pressor amounts in renal hypertension, two-kidney Goldblatt hypertension was produced in rats. After hypertension had been present for a variable period of time (4 to 21 days), the ischemic kidney was removed, and an infusion of rat renin was started immediately to replace the endogenous renin that the ischemic kidney had been releasing. Since the amount of renin released by the clipped kidney was not known, the amount infused was regulated by a feedback mechanism set to keep the mean blood pressure at the same level as before ipsilateral nephrectomy. Hypertension remission was therefore prevented by this procedure. The PRA at the end of the renin infusion was similar to that prior to the ipsilateral nephrectomy. This finding indicates that the levels of the PRA circulating in renal hypertension are within the pressor range, thus supporting the hypothesis that renin plays a role in the pathogenesis of the acute or semiacute phase of renal hypertension. However, the participation of other factors cannot be ruled out since no correlation was found between PRA and blood pressure.


Effects of high and low sodium intake on arterial pressure and forearm vasular resistance in borderline hypertension. A preliminary report. The purpose of this study was to evaluate effects of high and low sodium intake on arterial pressure and forearm vascular resistance in subjects with borderline hypertension and to compare responses to sodium excess in these subjects with responses in a recent study in normotensive subjects. Six subjects with borderline hypertension were studied after ten days of high (410 mEq/24hr) and low (10mEq/24hr) sodium intake. Potassium intake was constant. In five of six subjects, high sodium intake decreased forearm blood flow and increased forearm vascular resistance and arterial pressure. During low and high sodium intake forearm blood flow averaged 7.8 plus or minus 1.2 (SE) and 5.9 plus or minus 0.8 ml/min x 100 ml, respectively; forearm vascular resistance averaged 13.5 plus or minus 2.2 and 19.1 plus or minus 3.0 units, respectively; and mean arterial pressure averaged 89 plus or minus 3 and 98 plus or minus 2 mm Hg, respectively. High sodium intake augmented forearm vasoconstrictor responses to lower body negative pressure, a stimulus to neurogenic vasoconstriction. The results contrast with our earlier results in normotensive subjects in whom sodium excess produced forearm vasodilatation and failed to increase arterial pressure significantly. Decreases in renin and aldosterone with high sodium intake were similar in the two groups. The results suggest that excessive sodium intake in subjects with borderline hypertension produces abnormal increases in forearm vascular resistance, neurogenic vasoconstriction, and arterial pressure. The reasons for the contrast between the borderline hypertensives and normotensives are unknown, but they do not seem to be related to the renin-angiotensin-aldosterone system.


Altered cardiac responsiveness and regulation in the normal cardiac output type of borderlind hlpertension. Of 145 patients with borderline hypertension, 30% had increased resting cardiac index (QI), whereas the remainder had normal values. The specific aim of this study was to investigate cardiac regulation in patients who had normal resting QI. Eighty-five control subjects were used for comparison. At rest, patients with normal QI showed evidence of decreased parasympathetic inhibition; the QI after injection of atropine increased less than in control subjects. After complete cardiac autonomic blockade with propranolol and atropine, QI and stroke volume were significantly lower in patients than in control subjects. The mechanism of this low QI was further analyzed. Central blood volume, which strongly correlates with stroke volume, was used as an estimate of the cardiac venous filling. After blockade, stroke volume was decreased in patients, but central blood volume was normal. Patients also showed a decreased heart rate and QI response to infusion of isoproterenol. It is therefore postulated that two components may be responsible for the low QI in the "denervated" heart: patients exhibit a decreased responsiveness to sympathetic stimulation, and they may also be less responsive to venous filling. Behind the facade of cardiac normality in these borderline hypertensive patients with normal cardiac output, there is evidence of altered autonomic control of the heart (decreased vagal inhibition) and of changed cardiac response to sympathetic stimulation and possibly to venous filling.