Coloscopy clinic: an evaluation of 500 new patients. Among the many responsibilities of the gynecologist in modern practice is the detection of neoplasia at the earliest possible opportunity. The advances made in the field of cytology as related to the practice of gynecology are well known and have significantly changed the detection of cervical carcinoma. The resurgence of colposcopy in the evaluation of patients with abnormal cervical cytology has added valuable new dimensions in the understanding of early cervical neoplasia and our ability to diagnose and treat these lesions. The complete acceptance of colposcopy as an essential step in the study of such patients requires a re-education and alteration in the philosophy of management which has been prevalent in American gynecologic practice to date.


Intravenous alcohol -- a single blind study in the prevention of premature delivery: a preliminary report. A single blind study for the evaluation of intravenous ethanol in the prevention of premature delivery is reported. Randomly selected patients admitted to Tripler General Hospital with uncomplicated pregnancies between 24 and 36 weeks' gestation having regular, sustained contractions were evaluated. Therapy consisted of intravenous 5% ethanol in 5% dextrose/water according to a weight-time-dose schedule. Control patients were given conventional treatment. Statistical evaluation of data has shown no significant difference between success and failure between the study and control groups to date.


Leukocyte alkaline phosphate determinations and urinary estriol excretion in normal and pathologic pregnancies. A comparison of the results of two assays for monitoring fetal well-being in normal and pathologic pregnancies is described. Concomitant leukocyte alkaline phosphatase (LAP) score determinations and 24-hour urinary estriol excretion were preformed in the same groups of pregnant women from the 31st week of pregnancy onward. There were 45 women with normal pregnancies, 10 women with antepartum death, 8 women in whom the membranes ruptured at least 30 hours before the determination, 40 women with moderate or severe preeclampsia and 26 women with postmaturity. Determination of LAP score is an easy, rapid and inexpensive method which can be performed in every laboratory. The results are as reliable as estriol determination. Thus LAP score may serve as a valuable method for evaluation of fetal well-being.


The pill and the breast.

The pill and the breast. Estrogen and progesterone, although of a synthetic type in contraceptive pills, play a major role in the development, growth and function of the breasts. There is no statistically valid evidence to indicate that the widespread use of estrogens for contraceptive purposes and for the menopausal syndrome has increased the incidence of benign, premalignant or malignant breast lesions. However, if a cancer is present in a woman's breast, estrogen can increase its rate of growth. Furthermore, while the effect of exogenous estrogen administration to the population as a whole may be null, there may be a subgroup in which their use may have different effects, with a possible increase in breast cancer incidence in nulliparous or late parous women and a decrease in those with early parity. Patients with a dominant lump, suspicious diagnostic aid changes, serous, serosanguineous, bloody or watery nipple discharge or other adverse breast changes should not receive exogenous estrogens unless the lesion is found to be completely benign on biopsy. Even then, patients with gross cystic disease will continue to have these changes as long as estrogens are administered, and so they should avoid the use of estrogens. Patients in the high rist group for developing breast cancer should be cautioned about the potential dangers of the use of estrogens, whether in birth control pills or in other preparations for the menopause, and if they use them, these patients should be followed carefully by breast self-examinations, periodic examinations by physicians and diagnostic aids. Finally, serious consideration should be given to the inclusion of estriol in all estrogen preparations for its impeding or blocking effect against the potential carcinogenic properties of estradiol and estrone and to the addition of progesterone for its estrogen-antagonistic effect.


The making of a colposcopist. A safe and sensible approach. A program was established to determine the accuracy of colposcopy at our institution. Forty-three patients with cytologic or histologic evidence of severe dysplasia or worse underwent diagnostic conization following satisfactory colposcopy. Thirty patients subsequently had either therapeutic conization or hysterectomy preceded by biopsy only. In all 73 cases, the surgical specimen did not reveal a more advanced lesion. However, when the colposcopy was unsatisfactory, the rate of error was 20.8%. It is our opinion that colposcopy is a safe and valuable technique as long as one recognizes the need for training and understands the indications for further diagnostic studies. The use of the colposcope for the evaluation of abnormal cervical cytology has increased steadily over the last few years, and several excellent courses are now offered throughout the United States. Armed with a certificate from such a course, many gynecologists then become self-proclaimed colposcopists in spite of warnings to the contrary by the instructors. In addition, supervision by experienced personnel is not always available. How, then, does one indeed become an accomplished colposcopist to the point that he or she can safely spare the patient the risk, inconvenience and expense of diagnostic cervical conization? Although several recent publications 2,5,6,9,11 document the diagnostic accuracy of colposcopically directly biopsies, we feel each individual should develop and evaluate his or her own skill before altering or abandoning conventional methods of diagnosis and management. The purpose of this report is to present our experience with colposcopy utilizing a program which can perhaps serve as a model to other clinicians.


The human semen and fertility regulation in the male. International Conference in Andrology. An international conference in andrology was held on April 24, 25 and 26, 1975, at the C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan. Eighty-five papers were presented by 165 contributors from Austria, Argentina, Belgium, Canada, Denmark, Finland, France, Germany, Japan, Netherlands, Norway, South africa, Spain, Sweden, Switzerland, Thailand, the United Kingdom and the U.S.A. Eleven sessions of the conference dealt with testicular and epididymal physiology; functional anatomy of spermatozoa; sperm motility and migration; seminal plasma; seminal proteinases and their inhibitors; endocrine-andrology; immunoandrology; neuro-andrology; clinical andrology (diagnostic, endocrine, therapy and surgical); artificial insemination and male contraception.


Incidence of endometriosis in diagnostic laparoscopy. Endometriosis is a common finding at laparoscopy. In order to make a correct diagnosis and institute appropriate management it is recommended that laparoscopy be performed on all patients with chronic pelvic pain and on most patients with infertility or acute pelvic pain.


Synthesis of a potential water-soluble radiographic contrast medium, 2, 4, 6-triiodo-3-acetamido-5-N-methylcarboxamidophenyl beta-D-glucopyranoside. Starting from 3,5-dinitrobenzoic acid, the infinitely water-soluble compound, 2, 4, 6-triiodo-3-acetamido-5-N-Methylcarboxamidophenyl Beta-D-glucopyranoside (9), was synthesized in nine steps. Glucoside 9, the first example of potentially a new class of water-soluble x-ray contrast media, is rapidly excreted from dog's plasma into the urine, unchanged. It has low intravenous toxicity in mice (LD50 = 24.5 g/kg). Thin-layer chromatography of aqueous solutions of 9 revealed first appearance of aglycon 7 after 1 week at room temperature.


Radiopharmaceuticals. 16. Halogenated dopamine analogs. Synthesis and radiolabeling of 6-iododopamine and tissue distribution studies in animals. A simple halogenated derivative of dopamine, 6-iododopamine (1), has been synthesized using two different methods. These synthetic sequences have been applied to the radiolabeling of 1 with carbon-11, iodine-131, and iodine-123. The tissue distribution of 1 in mice, dogs, and rats was determined. The ratio of radioactivity (%/g) in the adrenal medulla-kidney in dogs increases from 3.45 at 2 h postinjection to 33.3 at 24 h postinjection. Thyroid uptakes in mice, dogs, and rats show that in vivo deiodination of 1 is not significant.


Hypoglycemic alpha-cycloalkylphenylmehtyl, furanalkyl, and thiophenealkyl lactamimides. A series of alpha-cycloalkylphenylmethyl lactamimides and a series of furan- and thiophenealkyl lactamimides were prepared for biological evaluation as an extension of earlier finding of hypoglycemic activity in lactamimides. Compounds 7, 20, 23, 25, 29, and 32 produced pronounced hypoglycemia after oral administration to fasted, glucose-primed rats.


Synthesis and biological activity of camel and bovine beta-melanotropins. Two natural occurring melanotropins, camel betaC2-MSH and bovine beta-MSH, have been synthesized by improved solid-phase procedures. The coupling reaction of tert-butyloxycarbonylamino acids was achieved by using their preformed symmetrical anhydrides. The synthetic hormones were purified by gel filtration on Sephadex G-10 and G-25, chromatography on carboxymehtylcellulose, and partition chromatography on Sephadex G-25 with final yields of 56 and 35% for betac2-MSH and betab-MSH, respectively. They were then shown to be identical with their natural hormones in amino acid analysis, paper electrophoresis, disc electrophoresis, thin-layer chromatography, enzymic digests, and bioassays. Bioassay data of these two synthetic melanotropins indicate that the replacement of Ser by Gly in betab-MSH does not change its melanocyte-stimulating activity.


Sturcture-activity relationship of daunorubicin and its peptide derivatives. The synthesis of potentially specific antitumor peptide derivatives of daunorubicin is presented. The interaction specificites of the drugs with nucleic acids have been examined via stop-flow kinetics as well as the inhibition of DNA template activity. It is found that the biological activity of the daunorubicin derivatives against the mouse P388 tumor is directly proportional to RNA polymerase inhibition and inversely proportional to the rate of dissociation of the DNA complex. It is concluded that the biological efficacy of drugs which act at the replicative and transcriptional level may be estimated by the more rapid in vitro techniques provided that problems of permeability, solubility, stability, etc., in vivo are not encountered.


Physicochemical and pharmacological studies of some 8-substituted decahydroisoquinolines. Several compounds of a diastereoisomeric series of 8-substituted 2-methyldecahydroisoquinolines have been found to be equipotent or more potent than quinidine in prolonging the refractory period of isolated guinea pig atria. The effects of selected compounds on the intracellularly recorded transmembrane action potential of isolated canine Purkinje fibers indicated a mechanism of action similar to quinidine in causing a large decrease in the rising velocity of rapid depolarization. Acid dissociation constants and percentage buccal membrane absorption have been determined, in an attempt to correlate these physiochemical properties and the stereochemistry of the derivatives with the observed antiarrhythmic potency. Compounds with high lipophilicity and the trans ring-juncture stereochemistry generally appear to possess superior potency.


Etodolic acid and related compounds. Chemistry and antiinflammatory actions of some potent di- and trisubstituted 1, 3, 4, 9-tetrahydropyrano[3, 4-b]indole-1-acetic acids. A series of 37 1-ethyl- and 1-n-propyl-1, 3, 4, 9-tetrahydropyrano[3, 4-b]indole-1-acetic acids bearing one, or two, substituents on the benzene ring has been synthesized via the acid-catalyzed condensation of a substituted tryptophol with ethyl propionylacetate or ethyl butyrylacetate. Antiinflammatory and ulcerogenic effects were examined and the results show that 1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano[3, 4-b]indole-1-acetic acid (etodolic acid, USAN) is a potent agent, particularly active against a chronic rat model of inflammation (ED50 0.7 + 1-0.1 mg/kg po in the adjuvant arthritis model) and which has a relatively low acute ulcerogenic potential in the same species.


Aminobenzioc acid diuretics. 8.(2) 3, 4-Disubstituted 5-methylsulfonylbenzioc acids and related compounds. Various 2, 4- and 3, 4-disubstituted 5-methylsulfonylbenzoic acids were synthesized as methylsulfonyl analogues of previously described 5-sulfamoylbenzoic acid diuretics. The results of the diuretic screening in dogs reveal that substitution of the sulfamoyl group by the spatially and sterically similar methylsulfonyl group does not affect the diuretic pattern but leads generally to somewhat decreased potency. For the highly potent 3-benzylamino-4-phenoxy-5-methylsulfonylbenzoic acid the corresponding 5-methylthio and 5-methylsulfinyl analogs were prepared and found still to exhibit diuretic activity. Internal aldol condensation and subsequent dehydration of 3-benzylamino-and 3-n-butylamino-4-benzoyl-5-methylsulfonylbenzoic acid provided the corresponding inactive 4-alkylamino-6-carboxy-2, 3-dihydro-3-hydroxy-3-phenylbenzo[b]thiophene 1, 1-dioxides and 4-alkylamino-6-carboxy-3-phenyl-benzo[b]thiophene 1,1-dioxides.


Conformational influence of a 19-methyl substituent in 19-oxygenated steroid structures. The crystal and molecular structure of (19R)-19-methyl-5-androstene-3beta, 17beta, 19-triol (C20H32O3) has been determined. The crystals are orthorhombic and the space group is P212121. The unit cell parameters are a =11.179 A, b = 21.485 A, and c = 7.328 A. The structure was solved using the direct methods program MULTAN and refined anisotorpically to an R of 7.2% for all data. The methyl substituent on C(19) is located over the B ring and the hydroxyl between the A and C rings. The flexible B ring has a distorted half-chair conformation. The 19R configuration suggests that the reaction mechanism for the formation of this compound proposed by Wicha and Caspi is incorrect. Furthermore, these results indicate that the stereochemical assignment of C(19) by Skinner and Akhtar resulting from a tritiated sodium borohydride reduction is also suspect.


Contraceptive agents from cycloaddition reactions of diarylcyclopropenones and diarylthiirene 1, 1-dioxides. The potential for compounds with antifertility activity from the reactions of diphenylcyclopropernone (1) and 2, 3-diphenylthiirene 1, 1-dioxide (2) with enamines is described. In certain instances, a marked dissociation of antifertility from estrogenic activity was possible. Two series were studied extensively, one was stilbene amides (7) and the other stilbene amino ketones (8). The latter series (8) afforded several materials from which, on further biological work-up, was singled out compound 21 as a potent antifertility agent in rats and hamsters.


Analogs of luteinizing hormone-releasing hormone with increased biological activity produced by D-amino acid substitutions in position 6. The incorporation of simple d-amino acids in place of glycine in position 6 of the LH-RH decapeptide produces analogs which have far greater gonadotropin-releasing activities in vivo and in vitro than the natural hormone. An investigation of the structural features of the d-amino acids responsible for this phenomenon suggests that an increase in the lipophilic character and perhaps the size and aromaticity of the side chain coincides with an increase in biological activity. This is demonstrated by the LH-releasing activities of the following series of peptides which were assayed over a period of 6 h in immature male rats: [d-Glu(6)]-,1.8;[d-Ala(6)]-,7.0;[d-Leu(6)]-,9,0;[d-Phe(6)]-,10;[d-Trp(6)]-LH-RH, 13 times more active than LH-RH itself. In contrast to previous results with [d-Ala(6)]-and [d-Leu(6)]-LH-RH, where the substitution of an ethylamide group for the glycine amide at the C-terminus produces large increases in LH/FSH releasing activity, the ethylamide derivatives of [d-Phe(6)]-and [d-Trp(6)]-LH-RH were actually less potent than their parent peptides. [(N-Me-d-Ala)(6)]-LH-RH was found to be approximately 70 times less active than [d-Ala(6)]-LH-RH which indicates that disruption of a preferred receptor-site binding conformation might be brought about by methylation of the amide linkage in this position.


Synthesis of the antileukemic compound N,N(11)-[5-[bis(2-chloroethyl)amino]-1, 3-phenylene]bisurea. Conversion of 5-nitro-1, 3-benzenedicarboxylic acid (1) to the diamide 2 followed by hypochlorite rearrangement to the idamine 3 and subsequent reaction with acetic anhydride gave the bisacetamide 4. Reduction to the amine 5 followed by treatment with ethylene oxide formed the diol 6. The latter was converted to the bistosylate 7, which undrewent facile displacement with lithium chloride in acetone to give the mustard 8. Removal of the acetyl groups with hydrochloric acid gave 9, which reacted with potassium cyanate to provide the bisurea 10. In an alternative, but less satisfactory synthesis of 10, the compound (5-nitro-1, 3-phenylene) biscarbamic acid diphenyl ester (11), or the corresponding diethyl ester 12, was converted by ammonolysis to 13. The nitrodiurea 13 was next reduced to the amine 14, the hydrochloride of which reacted with ethylene oxide to give the diol 15. Treatment of the latter in dimethylformamide with N-chlorosuccinimide in the presence of triphenylphosphine gave 10 in low yield. The nitrogen mustards 8, 9 and 10 showed significant antitumor activities against P388 lymphocytic leukemia in mice.


Structure and antitumor activity relationship of 2-arylidene-4-cyclopentene-1, 3-diones and 2-arylideneindan-1, 3-diones. A series of 2-arylidene-4-cyclopentene-1,3-diones and 2-arylideneindan-1,3-diones, as well as mono- and bis(arylidene substituted)cycloalkanones, was synthesized and examined for antitumor activity against ascites sarcoma-180. All the 2-arylidene-4-cyclopentene-1,3-diones and one arylideneindan-1,3-dione (where the arylidene group was either a hydroxybenzylidene or substituted hydroxybenzylidene) exhibited a high degree of activity. Among both types of 1,3-diones and 3-methoxy-4-hydroxybenzylidene derivatives were found to possess the greatest potency, while all the mono- and bis(arylidene)cycloalkanones were found to be inactive.


Synthesis and central nervous system depressant activity of some bicyclic amides. A series of aryl bicyclic analogs of succinimide and glutarimide was prepared and evaluated for CNS depressant activity. The 8a-aryl-3,4,6,7,8,8a-hexahydro-2H-pyrrolo[2,1-beta][1,3]oxazin-6-ones possessed the best overall spectrum of activity relative to the standard agents glutethimide and phenobarbital.


Potentiation of the estrogenic activity of stilbestrol by spiro (cyclohexane-1,2'-indan)-1',4-dione. During the investigation of a series of spiro compounds having approximately similar molecular dimensions to naturally occurring estrogens, the novel compound spiro(cyclohexane-1,2'-indan)-1',4-dione was prepared. The pretreatment of mice with this estrogenically inactive compound was found to potentiate the estrogenic activity of stilbestrol.


A senior-year experience similar to an internship. A senior year experience similar to an internship was initiated in community hospitals. It is designed to shorten the overall length of training and to restore a broad-based clinical experience to the period of "intermediate patient care responsibility" in the training of new physicians. The program provides students with an opportunity to observe and practice in a primary care setting and expands the clinical resources of the medical school. Analysis of the performance of students in the class of 1974 indicates that they perform on a level comparable with first-year house officers. This program provides a general clinical experience for those students who have not yet decided on future training plans or who are going into primary care fields.


A follow-up evaluation of a summer health career program for minority students. In an effort to attract minority students to health careers, a special summer education health career experience was developed. A matched comparison group design was utilized to determine the value of this program. Data were collected on both the participants and a matched comparison group three months before and six months after the program. Differences on most of the measures were not significant; however, there was a significant difference on stability of first career choice, indicating that a special summer program can and does have an effect on the participants. The study makes it clear that program effects cannot be assumed unless a follow-up evaluation is undertaken.


Relationships between clinical competence ratings and examination performance. Relationships between faculty ratings and performance on components of the National Board of Medical Examiners Certifying Examination for Primary Care Physician's Assistants were investigated. A factor analysis of the clinical competence rating form yielded three discrete factors. Results of tests of simple relationships between each rating factor and examination component indicated that four of the six examination components correlated significantly though modestly with at least one of the rating scale factors. The results of multiple regression analyses indicated complex relationships between each of two examination components and the set of rating factors. One implication is that faculty members are able to make discrete judgments about students on more than one dimension.


A report on graduates of the Boston University six-year combined liberal-arts--medical program. Graduates of a six-year combined Liberal-Arts-Medicine Program and their medical school classmates (traditional "eight-year" students) are compared as to their medical school performance and their professional postgraduate activities. On standardized examinations (Medical College Admission Test and examinations of the National Board of Medical Examiners) the six-year group was somewhat better than the eight-year group. In other aspects, such as class ranking, honors at graduation, and medicine clerkship grades, the six- and eight-year groups were similar. The two groups were remarkably similar in their postgraduate professional career choices and in achieving board certification. The data for the first three classes indicate that qualified high school students can succeed academically in an accelerated collegiate-degree program, do well in medical school, achieve postgraduate certification, and begin the practice of medicine at a younger age.


The University of Michigan integrated premedical-medical program. The University of Michigan Medical School and the College of Literature Science and the Arts are now conducting a six-year program for recent high school graduates which integrates a liberal education and the work necessary for the M. D. degree. There is a single admission point in the spring for seniors in high school. Personal characteristics are heavily emphasized in the admissions process. A number of innovative course sequences have been developed for the program. A variety of evaluation studies are being conducted and will be available as they are completed.


The Lehigh--Medical College of Pennsylvania six-year B.A.-M.D. program. Lehigh University and the Medical College of Pennsylvania have developed a program in which selected high school students are admitted directly to medical school. The students spend two years at the university completing the premedical basic sciences and the required humanities and social sciences for the bachelor's degree. Students may choose to extend the two-year university phase to three or four years. Science credit is given by the university for medical school courses, and the student graduates with a B.A. degree after four years and an M.D. degree after six years.


Causes of physician migration: responses of Iranian physicians in the United States. Each of the 2,270 Iranian physicians listed by the American Medical Association as residing in the United States in 1973 was sent a questionnaire in which he was asked whether or not he intended to return to Iran, his reasons for not returning if he did not intend to return and other questions concerning his history and present status. A total 760 questionnaires were returned. The results indicated that age, level of training, martial status, and previous practice in Iran were all related to intention to return, although whether or not the physician had returned to Iran on a visit was not an important factor. The most frequently cited reasons for not returning were professional reasons, particularly lack of medical facilities and equipment in Iran.


Evolution of a Family Nurse Practitioner Program to improve primary care distribution. The Family Nurse Practitioner Program of the Univeristy of California, Davis, has effectively improved the distribution of primary health care manpower in medically underserved areas. This has been accomplished by selecting students, preceptors, and faculty from areas of need; decentralizing the clinical and didactic training sites; developing a competency-based, portable curriculum; and coordinating it all with a circuit-riding, institutionally based faculty.


A comparison of the ability of normal liver, a premalignant liver, a solid hepatoma and the Zajdela ascitic hepatoma, to take up amino acids in vitro. The net total uptake of several amino acids at low (0.8-3.1 mumoles/liter) as well as high (800-1200 mumoles/liter) extracellular concentrations, by normal rat liver, a premalignant liver, a solid hepatoma, and the Zajdela ascitic hepatoma cells, has been compared under conditions in which protein synthesis continues. At low amino acid concentrations, the initial (3 min) total uptake of the various amino acids in the Zajdela cells, was 3-10 (average 7) times more, and the intracellular concentration of the labeled amino acids taken up 14-45 (average 31) times more, than in normal liver. At the high amino acid concentrations, the total uptake in the Zajdela cells, at 60-120 min was 2-5 (average 3.5) times more, and the intracellular concentration of the amino acids taken up 8-18 (average 13) times more, than in normal liver; the corresponding values for the premalignant liver and the solid hepatoma were in between those for normal liver and the Zajdela cells. Further, the rate of the total uptake of amino acids, their intracellular concentration, the proportion of the amino acid taken up utilized for protein synthesis, the rate of incorporation of the amino acid taken up into protein, and the cellular growth rate, seemed to be correlated in the four cell/tissue preparations studied. In most cases, the rate of the net uptake fell drastically with time, the uptake virtually stopping after 90-180 min, probably due to lack of serum in the incubation medium.


Amide transport channels across toad urinary bladder. Urea and other small amides cross the toad urinary bladder by a vasopressinsensitive pathway which is independent of osmotic water flow. Amide transport has characteristics of facilitated transport: saturation, mutual inhibition between amides, and selective depression by agents such as phloretin. The present studies were designed to distinguish among several types of transport including (1) movement through a fixed selective membrane channel and (2) movement via a mobile carrier. The former would be characterized by co-transport (acceleration of labeled amide flow in the direction of net flow of unlabeled amide), the latter by counter-transport (acceleration of labeled amide flow in the opposite direction). Mucosal to serosal (M leads to S) and serosal to mucosal (S leads to M) permeabilities of labeled amides were determined in paired bladders. Unlabeled methylurea, a particularly potent inhibitor of amide movement, was added to either the M or S bath, while osmotic water flow was eliminated by addition of ethylene glycol and ethanol could not be demonstrated. Methylurea did not alter water permeability or transmembrane electrical resistance. The demonstration of co-transport is consistent with the presence of ADH-sensitive amide-selective channels rather than a mobile carrier.


Budding by oozooids in the polystyelid ascidian Metandrocarpa tayori Huntsman. Larvae of the stolidobranch ascidian Metandrocarpa taylori molt a thin sheath upon settling, then metamorphose and radiate a larval complement of vascular ampullae upon the substrate. These ampullae thereafter regress, "rest" in a reduced condition for several weeks, and then regrow into the oozooid's definitive array of vascular ampullae in accompaniment to the development of the oozooidal vascular nest of test-vessels. Pallial buds emerge some four months after the larva settles; the oozooid has by then grown to a length of at least 2 mm and its vascular nest is surrounded by at least 16 vascular ampullae. Oozooids bud one to five buds (mean, 2.6) in a rather short period of blastogenic vigor, then persist in the colony. Late buds are frequently aborted. Buds appear anywhere around the basal margin of the oozooid, but more often on the left than the right and more often posteriorly than anteriorly. As other studies have observed with blastozooids, this study notes an integration of budding and the disposition of the elements of the test-vessel system of oozooids. Buds emerge oriented tangentially to the parental basal margin at the bud-site, then often rotate to point their anterior ends away from the parent. No larvae metamorphosed into oozooids with situs inversus viscerum, but in this study two oozooids extruded blastozooids showing this anomaly; these blastozooids budded "reversed" zooids in turn, so that entire clonal lines showed the anomaly.


Cell division and tissue repair following localized damage to the mammalian lung. Small local wounds on the surface of the mouse lung, produced by cauterization, healed by a typical reparative process involving cell migration and increased cell division in alveolar and bronchial tissues. The local cell division response closely resembled the compensatory cell division response in the same organ which follows unilateral pneumonectomy or unilateral collapse of the lung: initially there was an increase in the rate of DNA synthesis followed by an increased rate of entry into mitosis, both of these functions returning to normal levels within a few days. It is therefore suggested that both types of response are governed by a single regulatory mechanism. The results do not support the view that the rate of cell division is regulated by systemically-circulating mitotic control factors and it is proposed that changes in the cell division rate, both in the reparative and in the compensatory types of response, are determined by local alterations in the concentration of regulatory metabolites. The magnitude of the cell division response was much greater in bronchial than in alveolar tissue, a result which is consistent with the view that new alveolar tissue may be produced by the proliferation and diffentiation of bronchial cells.


The functional anatomy of the hindlimb of some African Viverridae (Carnivora). The functional anatomy of the hindlimb of 12 species of viverrids was studied with relation to locomotion. The animals were allocated to primary locomotor categories on the basis of their anatomy and locomotion. The climbing, arboreal walking category (Nandinia binotata) is characterized by a small sacroiliac articulation, the iliopsoas inserts onto a medially located lesser trochanter and the femoral condyles are not posteriorly placed. The hindfoot is plantigrade and its structure permits considerable movement. The pads are soft and the claws retractile. Representatives of the arboreal and terrestrial walking and jumping category (Genetta genetta, G. servalina, G. tigrina) have a plantigrade forefoot and digitigrade hindfoot. The lesser trochanter is more posteriorly placed than in the climbing category. A previously undescribed muscle, the caudofemoralis profundus extends from several anterior caudal vertebrae to the femur. The tibio-astragular joint restricts supination of the foot. There is little mediolateral movement in the digitidgrade foot. The claws are retractile. In the general terrestrial walking and scrambling group (Helogale parvula, Mungos mungo, Atilax paludinosus, Bdeogale crassicauda, Herpestes ichneumon, H. sanguineus) the animals have essentially similar hindlimbs except for size differences and modifications to the feet. Helogale and Mungos have large medial epicondyles on the humerus and large terminal phalanges. Bdeogale has a vestigial first metatarsal, while Atilax can splay its digits. In all species the distal phalanges are non-retractile. The trotting category (Civettictis civetta, Ichneumia albicauda) is characterized by longer epipodials and metapodials and a more proximal position of muscle bellies. Most of the adaptations minimize rotation, adduction and abduction of the leg and supination of the foot. The metatarsals are closely adjoined and the distal phalanx is stout and non-retractile. There appear to be two levels of locomotory adaptation. Major adaptations affect the whole appendicular skeleton and are used to assign animals to primary locomotor categories. Minor adaptations occur mainly in the foot and indicate the more specific habits of the animal.


Tongue evolution in the lungless salamanders, family plethodontidae. I. Introduction, theory and a general model of dynamics. Plethodontid salamanders capture prey by projecting the tongue from the mouth. An analysis of theoretical mechanics of the hyobranchial skeleton is used to formulate a working hypothesis of tongue movements. Predictions that the skeletal elements of the tongue are included in the projectile and that the hyobranchial skeleton is folded during projection are central to the analysis. When decapitated in a particular way, salamanders project the tongue, and it is not retracted. When these heads are fixed and sectioned, examination confirms the predications. In turn, these observations are used to refine the working hypothesis and to generate a general model of tongue dynamics for plethodontids. Muscles performing the major roles of projection (subarcualis rectus I) and retraction (rectus cervicis profundus) are identified. The skeleton is folded passively along a morphological track having the form of a tractrix. Predictions concerning the shape of the track and the exact configuration of the folded skeleton are confirmed by study of sectioned material. The skeleton unfolds along the track during retraction and is spread into the resting state. The model developed herein will be used as a basis for predictions concerning selection patterns in the family and for analytical purposes in comparative and evolutionary studies.


The extrinsic blood vessels of the ovary of the sheep. The extrinsic ovarian blood vessels were studied in 134 ewes. In view of recent evidence that uterine luteolysis may involve venoarterial transfer of prostaglandin F2alpha in the ovarian pedicle, particular attention was paid to the interrelationships between veins and arteries. The ovarian artery and utero-ovarian vein are large vessels of conventional structure and lie in close apposition. Their walls are slightly thinner on their apposing sides. The ovarian branches of the ovarian artery are very tortuous, and closely intertwined with the plexiform ovarian branches of the utero-ovarian vein. An extensive plexus of small veins surrounds the ovarian artery and its ovarian branches. Within this plexus are many thin-walled, dilated regions, interspersed with narrow, thick-walled segments. Valves are inconstantly present at sites of entry of branches of the plexus into the major veins. Small numbers of arterio-venous anastomoses are present in the distal part of the ovarian pedicle. Unless blood can flow in a veno-arterial direction through arterio-venous anastomoses or capillary beds, the structural barrier between uterine venous and ovarian arterial blood is substantial.


Feeding adaptations in the hairs and tongues of nectar-feeding bats. Scales on the hairs of pollinating bats spread out at an angle to the main hair shaft. In contrast, the hairs of most bats not associated with plants are relatively smooth. Both megachiropteran and microchiropteran flower-feeding bats show this divaricate scale structure which may aid in the collection of a heavy coating of pollen. Some of the pollen is transferred to subsequent flowers, but most is groomed from the fur and ingested as the only reliable nitrogen source for the bat. The tongues of nectar-feeding bats also show structural modifications which allow efficient uptake of the carbohydrate fraction of the diet. Structural specializations of the hiars and tongue are analogous to those seen in other nectar-feeding animals.


Oral food processing in two herbivorous lizards, Iguana iguana (Iguanidae) and Uromastix aegyptius (Agamidae). The anatomy and function of the feeding apparatus in Iguana iguana and Uromastix aegyptius were studied by dissection, cinematic and cineradiographic techniques. The feeding behavior of these species differs from that of insectivorous lizards in the cropping action involves movement of both the upper jaw around the atlantooccipital joint and the lower jaw around the mandibular joint; and in Uromastix only, streptostylic movement of the quadrate. Often movements of the whole head play a supplementary role in the cropping action. In both species the feeding apparatus has been modified to facilitate cropping. In Iguana the pleurodont dentition is multicusped and laterally compressed. Each tooth forms a shearing blade whose function does not require contact with other teeth. In Uromastix the dentition is acrodont and the cheek teeth are massive and lack cusps. Occlusion is necessary for shearing plant material. The skull system of Uromastix also has a number of modified structures which allow protraction and retraction of the lower jaw to facilitate cropping while maintaining a gape equivalent to that in Iguana. It is suggested that the differences in the feeding apparatus between Iguana and Uromastix are attributable to differeces in the mode of tooth replacement and implantation.


Synthesis of immunoglobulin and Marek's disease virus antibody in susceptible and relatively resistant chickens. The levels of IgM, IgY, and IgA and the development of specific antibody to Marek's disease virus (MDV) and sheep red blood cells (SRBC) in young chickens susceptible and resistant to Marek's disease were compared after exposure to MDV. No significant difference was noted in the immunoglobulin levels. However, the antibody response to MDV and SRBC occurred more rapidly in susceptible birds. The initial titer of antibody to these antigens was higher. These differences in response, however, were transient. At 3 weeks post exposure, the levels of IgM antibodies to MDV and antibodies to SRBC were similar in the two lines of chickens. At 6 weeks, the levels of IgY antibodies to MDV and antibodies detected by the agar gel precipitation test were similar.


Transmission of BCG-associated tumor resistance from maternal to newborn guinea pigs. Resistance to line-10 hepatocarcinoma was studied in the newborn offspring of inbred strain-2 Sewall Wright guinea pigs that had recovered from this tumor after prior administration of subcellular components of Mycobacterium bovis strain BCG. These mothers gave birth to 15 offspring, 53% of which resisted repeated challenges with this tumor. Offspring of mothers who had been given only BCG components were similarly tested. Complete protection was observed in 23.5% of 17 babies and attenuation of disease in many others. All control offspring from normal, untreated mothers succumbed to this tumor. Resistance was associated with delayed cutaneous hypersensitivity reactions to tumor and mycobacterial antigens.


Antigenic cross-reactivity between adenocarcinoma of the breast and fibrocystic disease of the breast. Peripheral lymphocytes obtained from 12 of 13 patients who had fibrocystic disease (FCD) of the breast were specifically cytotoxic to breast adenocarcinoma cells, as measured in vitro by the microcytotoxicity test. Sera from 6 women with active FCD or metastatic breast cancer could specifically block the cytotoxicity of lymphocytes from either population of patients against cancer cells. This implied extensive antigenic cross-reactivity between benign and malignant hyperplastic disease of the breast. Sera from 4 individuals clinically free of FCD or breast fibroadenoma (FAD) neutralized the blocking activity in the sera of patients with metastatic breast cancer. Patients "cured" of FCD or FAD represented a pool of potential plasma donors for immunotherapy of recurrent breast cancer.


Trisomy of the long arm of chromosome No. 1 in human leukemia. We encountered a karyotypic abnormality, i.e. a trisomy of part of or the whole long arm of chromosome No. 1, in 4 patients with leukemia; 3 with acute myeloblastic, leukemia (AML) and 1 with chronic myelocytic leukemia (CML) in the blastic phase. Q- and G-banding techniques revealed that in two patients with AML and in the one with CML, this karyotypic abnormality was not an initial one and was apparently associated with clinical progression of the disease. This chromosome change is a common karyotypic abnormality in blood disorders, especially in AML, and possibly bears a relationship to selective growth advantages of the leukemia cells.


Development of fewer tumor colonies in lungs of athymic nude mice after intravenous injection of tumor cells. The formation of tumor colonies was compared in the lungs of athymic nude and normal littermate mice after an iv injection of transplantable syngeneic tumor cells. Each of 5 tumors tested formed fewer colonies in the lungs of nude recepients.


Factors involved in concanavalin A agglutination of KB and NC37 cells grown in suspension culture. NC37 and KB cells grown in suspension culture remained agglutinable at 23 degrees C by concanavalin A (Con A) after sufficient glutaraldehyde fixation to prevent lateral mobility (clustering) of Con A binding sites. In contrast, at 4 degrees C agglutination of the fixed cells was blocked. No significant differences in 3H-Con A binding were observed between unfixed cells and glutaraldehyde-fixed cells at 23 degrees C and unfixed cells at 4 degrees C. Con A bound to fixed cells at 4 degrees C produced agglutination when the cells were washed and then warmed to 23 degrees C. Thus a cold-sensitive factor unrelated to the binding of Con A or the clustering of Con A sites is necessary for agglutination to occur.


Protein and RNA synthesis in pituitary tumors from F344 rats given implants of estrogen. The synthesis of total proteins, growth hormone, and prolactin and the incorporation of radioactive precursors into RNA was studied in Pituitaries from normal F344 rats and rats given implants  of 15 mg diethylstilbestrol (DES). Prolonged DES treatment (greater than 50 days) induced pituitary tumors in male and female rats. The tumor tissue had a high rate of cell protein synthesis and an unusual capacity to synthesize a single-protein hormone (prolactin). After 17 days of DES treatment, the increase in prolactin synthesis in the hyperplastic pituitaries was not as marked as that in the tumors. At the time of tumor induction and high prolactin synthesis, incorporation of uridine or cytidine into RNA was not stimulated, and orotic acid incorporation in tumors from male rats was decreased. During early estrogen treatment (5 and 17 days), significantly less uridine was incorporated into RNA. These data suggested that the increment in protein and hormone synthesis promoted by DES may be related to a decrease in RNA turnover.


Oncogenic response of rats with x-ray-induced microcephaly to transplacental ethylnitrosourea. The relation of congenital malformations to tumor development was examined. Pregnant Sprague-Dawley rats were given 200 rads of X-rays on the 15th or 16th day of gestation and injections of 10 mg ethylnitrosourea (ENU)/kg 1-4 days later, or they were irradiated or injected only. Surviving weanlings that had been irradiated had micrencephaly and other malformations. Offspring exposed to ENU only had no external deformities. By 15 months of age 16.7% of the offspring exposed to X-rays and ENU prenatally had developed neurogenic tumors, whereas 62.2% of those exposed to ENU alone had developed tumors. Those only irradiated had no tumors. Both of the former groups developed oligodendrogliomas, mixed gliomas, ependymomas, and schwannomas, but the first manifestations of tumors occurred later in the group receiving the combined treatment. This delay persisted furing the subsequent period of the study.


Natural antibodies to human lymphocytes in murine strains. Murine strains vary greatly in their content of natural antibodies to human lymphocytes; sera from NZB, B10.BR/TSn, DBA/J, and B10.S mice reacted with more than 90% of the panel of human lymphocytes, yet those from other strains did not react. These levels of natural antibodies to human lymphocytes did not correlate with the H-2 type of mice, but appeared to be a dominant character with incomplete penetrance. Since sera from germfree mice also contained natural antibodies to human lymphocytes, their formation was not influenced substantially by bacteria.


Antitumor immunity. II. Viability, tumorigenicity, and immunogenicity of neuraminidase-treated tumor cells: effective immunization of animals with a tumor vaccine. A dimethylbenzdithionaphthene (DBDN)-induced fibrosarcoma showed reduced transplantability if previously treated with Vibrio cholerae neuraminidase (VCN). However, the reduced transplantability of VCN-treated tumor cells was not associated with any loss of their viability or tumorigenic capability, but appeared to be due to their increase in immunogenicity. High doses of VCN-treated tumor cells could grow even in normal individuals. Lower doses, which did not induce tumor development in normal individuals, did so if injected into immunosuppressed animals. Although X-irradiation of VCN-treated tumor cells reduced their tumorigenic potential, it did not impair their increased immunogenic properties. Thus a suitable method for the preparation of a "tumor vaccine" was provided. The immunization of animals with the vaccine and a working hypothesis regarding its mechanism of action were described.


Antigenic changes of L5178Y lymphoma after treatment with 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide in vivo. Immunologic alteration of the L5178Y lymphoma was obtained in vivo after treatment with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DIC). A single dose of 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) "CURED" MICE CHALLENGED WITH L5178Y cells that had been treated with DIC (L5178Y/DIC) for four transplant generations; BCNU did not cure mice bearing the parent tumor. The L5178Y/DIC, treated in vivo for five transplant generations, id not grow in syngeneic mice. L5178Y/OIC cell growth and incidences of death were similar to those of parent cells when inoculated into heavily immunosuppressed mice. Adoptive transfer of lymphocytes from spleens of mice sensitized to the drug-altered tumor specifically protected immunosuppressed mice bearing the L5178Y/DIC tumor. Little protection was afforded by lymphocytes immune to the parent L5178Y tumor, whereas nonimmune lymphocytes or lymphocytes immune against unrelated tumors were completely ineffective. Anti-L5178Y/DIC lymphocytes did not cure mice challenged with the parent L5178Y tumor. Irradiated (400 R) mice previously sensitized to L5178Y/DIC cells rejected 10(2)-10(7) inocula of L5178Y/DIC cells and died when the parent L5178Y was used for challenge. It was concluded that antigeni( alterations of L5178Y cells occurred in (BALB/ctcr X DBA/2Cr)F1 mice after treatment with DIC in vivo.


Ultrastructural studies of surface features of human normal and tumor cells in tissue culture by scanning and transmission electron microscopy. Human tumors of a variety of histopathologic types have been established in tissue culture. The surface features of these cell lines were investigated by scanning electron microscopy (SEM) with the use of new techniques for specimen preparation. Tumor cells demonstrated striking degrees of surface activity with numerous microvilli, filopodia, blebs, and ruffles. Intercellular contacts were also prominent in cultures of most solid tumors observed by SEM. At low cell density, normal human fibroblasts exhibited some surface features such as microvilli and blebs, but at higher cell density they lacked extensive surface modifications. By transmission electron microscopy (TEM), the cytoskeleton of normal fibroblasts was shown to be well organized, with parallel orientation of microfilaments, filaments, and microtubules. These structures were also in tumor cells, but they lacked the degree of organization of fibroblasts. Desmosomes were readily demonstrated in normal fibroblasts and carcinoma cells in culture but not in sarcomas, melanomas, or tumors of neural origin. These studies have provided the first correlative SEM and TEM analyses of solid human tumor cells of diverse pathologic types in vitro.


Stomach cancer in Japan.

Stomach cancer in Japan. A study of 783 patients with stomach cancer and 1,566 hospital controls in Hiroshima and Miyagi prefectures of Japan showed that farmers, representing mostly the lowest socioeconomic class, had higher risk of developing stomach cancer. The usual inverse gradient in risk by social class was in the urban population of Miyagi, but not Hiroshima, prefecture. The study in Japan did not reproduce the association of stomach cancer with consumption of salted/dried fish and salt-pickled vegetables described for the Hawaiian Japanese. Salted/dried fish and pickled vegetables were more widely used by farmers than by nonfarmers in Japan or by Japanese migrants to Hawaii. The ability to detect associations for these typical Japanese foods in Hawaii stemmed from the fact that these reduced levels of use were more completely expressed by the Hawaiian-Japanese controls than by patients. The lower risk of developing stomach cancer for lettuce and celery users agreed with the Hawaiian-Japanese findings, and the combined results supported conjectures on possible protective food effects. Lettuce, in particular, warranted attention from this viewpoint, since similar findings have been consistently reported.


The zinc glycinate marker in human colon carcinoma. In an attempt to identify new tumor markers in human colon carcinoma, we produced antisera in rabbits tolerant to normal human tissue antigens and immunized with zinc glycinate-treated extracts of liver metastases from a colon carcinoma. These antisera reacted with carcinoembryonic antigen and with an additional component present in the tumor extracts but not detected in the extracts of normal tissues. The new component, the zinc glycinate marker (ZGM), had an alpha2 mobility on immunoelectrophoresis, was soluble in 1 M perchloric acid, and had a molecular weight of approximately 2X10(6), as indicated by its elution pattern on Sepharose 6-B chromatography. It differed from alpha fetoprotein, nonspecific cross-reacting antigens (NCA, NGP, or CCA III), ferritin-like molecules, and blood group substances A, B, H, Lewis a, and Lewis b. The ZGM was similarly identified in saline or zinc glycinate extracts of 11 of 23 carcinomas of the colon. With routine hematoxylineosin staining, no histologic differences were apparent between tumors bearing the antigen and those without it.


Mutagenicity of metronidazole: presence of several active metabolites in human urine. Mutagenic activity was found in the urine of 10 patients given therapeutic dosages of metronidazole orally or per vagina. Paper chromatographic separation revealed that mutagenicity in the urine was associated with unmodified metronidazole and at least four of its known urinary metabolites. Activity was also recovered in a region of the chromatogram heretofore not assigned to a metronidazole metabolite.


Spontaneous tumors in the Dunkin-Hartley guinea pig. Seventy-nine spontaneous neoplasms in Dunkin-Hartley guinea pigs were observed over a 9-year period in the Fort Detrick guinea pig colony. Sixty-three of the neoplasms were found during approximately 8,500 necropsies performed on animals under 27 months of age. The remaining 16 tumors were in 34 breeders maintained after 27 months of age on a natural life-span study. Of this group, 10 (29.4%) developed neoplasms by the termination of the study, when the animals were 80 months of age. The skin tumor, trichofolliculoma, of which there were 29, comprised the largest tumor classification.


Occurrence of hematopoietic neoplasms in Virginia oysters (Crassostrea virginica). A neoplastic disease of the hematopoietic system of oysters was found in tray-cultured native and laboratory-bred populations and was associated with mortalities during field monitoring. The disease, characterized by nuclear abnormalities and intensive proliferation of hemocytes, was first observed at the Virginia Institute of Marine Science in 1963. Cases rarely occurred during 14 years (1959-1973 inclusive) of regular sampling and monitoring of thousands of oysters. However, two groups exhibited a high susceptibility to this disease in a program of intensive inbreeding to achieve genetic resistance to oyster pathogens.


Antibodies in normal rabbit serum that react with tissue-specific antigens on the plasma membranes of human adenocarcinoma cells. Indirect viable cell immunofluorescence studies revealed, on the plasma membrane of cultured adenocarcinoma cells from the human colon and rectum, a tissue-specific antigen that reacted with a component of normal rabbit serum. The use of G200 column chromatography and monospecific antisera prepared against class-specific heavy chains of rabbit immunoglobulin indentified the reactive components in rabbit serum as IgM. Examination of normal and malignant cells from various human tissues by immunofluorescence and adsorption studies showed that rabbit serum reacted only with cells derived from the intestinal epithelium.


Antibody-dependent, cell-mediated cytotoxicity with autochthonous lymphocytes and sera after infection with Moloney sarcoma virus. Antibody-dependent, cell-mediated cytotoxicity in the Moloney sarcoma virus (MSV) system was analyzed in terms of the ability of autochthonous antibody to induce or potentiate cytotoxicity by lymphocytes from animals infected with MSV. As previously demonstrated in microcytotoxicity assays, the lymphocytes from regressor animals taken 30 days after virus infection were consistently more cytotoxic than those from tumor-bearing animals 15 days after infection. Antisera from the regressors potentiated the activity of regressor lymphocytes from the same animals. Also, antisera from tumor bearers, 15 days after virus injection, induced cytotoxicity by the animals' autochthonous lymphocytes which, by themselves, were not cytotoxic. In an independent assay for antibody, both groups of sera produced cytotoxicity by control nonimmune lymphocytes. Specificity controls indicated that both antibody and lymphocytes were required for the induction of cytotoxicity against the target cells in vitro. Normal sera placed on the target cells in the same concentrations induced no cytotoxicity by the immune lymphocytes, and immune sera alone placed on the target cells caused no cytotoxicity. The cooperative activity between antibody and lymphocytes may be a factor that accounts for the observed high incidence of spontaneous tumor regression.


A new culture model facilitating rapid quantitative testing of mitotic spindle inhibition in mammalian cells. A new culture model, which facilitated both mass screening of potential anticancer drugs acting on microtubules and quantitative experiments with known "antitubulins," was found to have the following advantages: use of mammalian cells (either transformed or not), simplicity of the techniques (phase-contrast microscopy or simple microscopy after Giemsa staining), and ease with which it lent itself to quantification. The model was based on the uniform multimicronucleation response induced by antitubulins in MO cells. The specificity (towards antitubulins) of this response was ascertained by the use of many substances, including most of the known antitubulins and a number of nonrelated cytostatic or cytotoxic compounds. The uniformity of the response was established with the use of time-lapse observation of large numbers of cells and quantitative approaches. The results obtained in this model with the standard antitubulins (colchicine, vinblastine, vincristine) showed similar effects. The major difference between colchicine and the Vinca alkaloids was that colchicine was less reversible, which might be an indication of stronger intracellular binding. The Vinca alkaloids acted synergistically with colchicine when threshold subactive doses were combined, although it is known that they bind at a different site on tubulins. A number of substances that have been claimed or were suspected to interfere with microtubules were tested. The results showed that the following substances were indeed active with MO cells: colchicine, vinblastine, vincristine, podophyllotoxin, rotenone, griseofulvin, mercaptoethanol, benomyl, methyl benzimidazol-2-yl carbamate, and R 17934. Compounds that were inactive on these mammalian cells in culture included isopropyl carbanilate and melatonin, both of which have been shown to be active in other systems.


Radiotherapy of spontaneous fibrous connective-tissue sarcomas in animals. The clinical records and follow-up data obtained over 13 years on the results of radiotherapy of spontaneous fibrous connective-tissue sarcomas in dogs, cats, and horses were reviewed. The results obtained from the treatment of fibrosarcomas and sarcoids of horses indicated that radiation administered with 60Co is important in the medical and surgical management of these tumors. Fibrous connective-tissue sarcomas in horses were radioresponsive. When radiotherapy was applied postoperatively, the probability of a 2-year cure approached 50% for all prescribed radiation doses of less than 2,000 to greater than 4,000 rads. If radiation doses of 4,500-6,000 rads were used, a 2-year cure rate may approach or exceed 60%.


Susceptibility of normal and transformed cell lines to cytostatic and cytocidal effects exerted by macrophages. Activated, nonimmune macrophages exerted profound effects on the proliferation and viability of eukaryotic target cells in vitro. Pronounced macrophage-mediated cytostasis was exerted on every rapidly proliferating cell line examined, irrespective of transformation, species derivation, cell type, or growth characteristics. However, the magnitude of cytostasis effected differed markedly among the 40 cell lines tested. There was no evident correlation between susceptibility to cytostasis and degree of transformation. Transformed cell lines with high and with low malignant attributes were affected equally. A comparable pattern was discerned for cytocidal effects of macrophages, in which the susceptibility of transformed targets was independent of the degree of malignancy.


Effects of Rauscher leukemia virus infection on BALB/c mouse embryos. The effects of Rauscher leukemia virus (R-MuLV) infection on BALB/c mouse embryos were described. In mice infected with R-MuLV 12 days before mating, there were no embryos 8 days after possible conception, whereas in those infected either 8 days or 1 day before mating, pregnancy was established. The most striking effect of R-MuLV infection on the microscopic properties of the embryos was vast "apoptosis" in the mesoderm. The XC test with trypsinized embryo cells showed numerous polykaryons, which suggested that active leukemia virus was present in the embryonal tissue. Indirect immunofluorescence studies with specific rabbit antiserum to R-MuLV demonstrated the presence of virus antigens in the embryonal tissue. Vast immunofluorescence was also found in trophoblastic cells and embryonal membranes. We concluded that R-MuLV in BALB/c mice was transmitted from mother to embryo through the placenta and thereby caused excessive cell death, especially in the mesoderm.


Humoral antibody response and tumor transplantation resistance elicited by fetal tissues in mice. Immune responses to fetal antigen immunization were studied in C57BL/6 (B6), C3H/HeN (C3H), and BALB/c (BALB) mice. In tests by the isotopic antiglobulin technique, the mice could be grouped in three classes according to their antibody responses: good responders (B6), poor responders (C3H), and nonresponders (BALB). In tumor transplantation experiments, protection against syngeneic tumor-cell challenge, after fetal tissue immunization, was observed only with B6 mice. In addition, experiments on B6 mice showed that resistance to tumor challenge after fetal tissue immunization depended on the quantitative expression of fetal antigens by the tumor cells. Our results indicated that, in addition to other well-known factors, the effectiveness of fetal tissue immunization in tumor-challenge resistance depended on both host responsiveness and the amount of fetal antigen expressed by the tumor cells.


Leiomyomas and leiomyosarcomas of the kidney in 4-day-old BUF rats given methylazoxymethanol acetate intraperitoneally. The effect of age and sex on the development of renal tumors was studied in inbred BUF male and female rats 4 days, 5, 8, 12, 24, or 52 weeks old. Methylazoxymethanol (MAM) acetate was injected ip (20 mg/kg body wt) once weekly for 9 weeks. Animals 52 weeks old died from hepatic and/or renal necrosis; however, animals of other ages survived 24-42 weeks. Female rats 4 days old were susceptible to the development of leiomyomas and leiomyosarcomas of the kidney, whereas 4-day-old male rats had a few leiomyomas. Adenomas and carcinomas of the kidney and nephroblastomas were not observed. It was concluded that the aglycone of cycasin, MAM, is important in the induction of leiomyosarcomas of the kidneys in 4-day-old rats.


Is Hodgkin's disease infectious? Discussion of an epidemiologic method used to impute that it is. A method proposed by MacMahon for the differentiation between familial and environmental causes for disease has recently been applied to demonstrate an environmental etiology for Hodgkin's disease. It is shown that the method, which depends on the comparison of time-of-onset differences with age-at-onset differences for familial pairs with disease, is biased toward results suggestive of an environmental etiology when applied to data of the kind typically analyzed--data restricted to instances in which both members of a familial pair develop disease in a specified, limited time interval. Other features of such data are discussed.


Effects of fasting on growth and glycolysis of the Ehrlich ascites tumor. C57BL/6 male mice bearing the Ehrlich escites tumor were subjected to two schedules of intermittent starvation, and the effect on the tumor's growth and production of lactic acid was determined. Fasting resulted in a linear dose--response inhibition of tumor growth, but did not alter its lactic acid production.


Tumor-promoting activity of cigarette tar in rat skin exposed to irradiation. A threefold increase (P=0.006) in the number of skin tumors induced by beta irradiation was demonstrated in rats after surface applications of cigarette tar. The effect appeared due to a tumor-promoting activity of the cigarette tar rather than to an additive tumorigenic effect of the two agents.


Enhanced growth rate of transplanted mammary adenocarcinoma induced in C3H mice by dietary linoleate. Three-month-old C3H female mice were given injections of 5-mg pieces of mammary adenocarcinoma and were then fed diets that either were fat free or contained saturated fat (15% hydrogenated cottonseed oil) or linoleate (1-15% corn oil). After 6 weeks, the tumors in mice fed the linoleate diet weighed 3-4 times more than those in mice fed the fat-free or saturated-fat diets. Despite a linoleate-free diet, tumors contained appreciable amounts of linoleate and arachidonate (approximately 2 and 9% of the total fatty acids, respectively). When the level of dietary corn oil was increased from 1 to 15%, the linoleate content of the tumors increased from 4 to 18% of the total fatty acids. However, in these instances, the tumor arachidonate levels increased to maximum values even when the 1% corn oil diet was used. These observations showed that mammary tumor growth was depressed by a fat-free or saturated-fat diet and enhanced by dietary linoleate. Furthermore, they suggested that the growth rate was related to the arachidonate content rather than the linoleate content of the tumors.


Effect of leupeptin, a protease inhibitor, on induction of bladder tumors in rats by n-butyl-n-(4-hydroxybutyl)nitrosamine. Leupeptin, isolated from Actinomycetes, is a potent and specific inhibitor of proteases. We found that the administration of leupeptin enhanced that size of urinary bladder tumors induced in rats by the oral administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). BBN was given as a 0.05% solution in the drinking water for 6 weeks, and then animals were fed a diet with or without 0.1% leupeptin for 30 weeks. The average weight of the bladders with tumors in rats fed a leupeptin diet was about eight times that of rats on a diet without leupeptin, though the incidences and average numbers of tumors in the bladders were similar in the two groups.


Antitumor activity of Corynebacterium parvum extracts. Extracts of Corynebacterium parvum produced by mild hydrolysis of the whole organisms had antitumor activity if given iv 1 day before iv administration of fibrosarcoma cells or if given ip or sc in admixture with these cells. A lipid component seemed responsible for these effects. Unlike whole bacteria, they had little immunotherapeutic activity if given 3 days after sc tumor implantation unless absorbed onto latex. However, organisms treated with acid did not have any immunotherapeutic effect in this system either. The extracts, therefore, did have some antitumor activity, but full activity may depend on the integrity of the whole bacterium.


Promoting effect of sodium deoxycholate on colon adenocarcinomas in germfree rats. The promoting effect of sodium deoxycholate (DC) on colon carcinogenesis was studied in female F344 germfree rats. Animals received intrarectal (ir) instillations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 4 weeks (total dose, 16 mg/rat), then weekly ir doses of DC (total dose, 3 g/rat); the rats were autopsied 52 weeks after the first injection. DC increased the number of MNNG-induced colon adenocarcinomas. No tumors were in the colons of germfree rats given DC alone. It was concluded that DC (present in high concentrations in human stools) had a promoting effect on colon carcinogenesis in rats.


Quantitative microscopy of epidermoid lung carcinoma: correlation with survival time. Quantitative microscopy, including morphometry of tumor, stroma, and necrosis was used for the prognostication of pulmonary carcinoma. This was supplemented by the mitosis: necrobiosis ratio, reciprocal of cell count, and number of "apoptosis" bodies. Data for 15 short-term (4-19 mo) and 8 long-term (32-132 mo) survivors with epidermoid carcinoma were expressed as indexes. The morphometric index averaged 106.8 for short-term and 156.1 for long-term survivors, respectively. Addition of the other three indexes resulted in an average of 171.4 for short-term and 318.5 for long-term survivors. Morphometric index and the necrobiosis: mitosis ratio were of greater significance than the other two indexes. Discriminatory function analysis based on the weighted sum of the logarithms of the four indexes demonstrated their usefulness in classifying patients as short-term or long-term survivors. The error rate for the discriminant analysis was 3.5%.


Burkitt's lymphoma in the Mengo Districts of Uganda: epidemiologic features and their relationship to malaria. An epidemiologic study of 123 patients residing in the Mengo Districts of Uganda, with onset of symptoms of diagnosed Burkitt's lymphoma (BL) in the period 1959-68, revealed a substantial decline in incidence of BL during that decade. Other significant findings included differences by ethnic group in age of patient at onset of BL, a change in the proportions of patients by ethnic group over the decade, a lower incidence rate of BL in the countries of higher altitude, and a seasonal pattern of onset. There was no evidence of the time space clustering previously reported for BL in Uganda. The changing pattern of BL in the Mengo Districts was consistent with the hypothesis that severe malaria infection not only is important in the development of BL but also precipitates onset.


Melanomas of the eye and other noncutaneous sites: epidemiologic aspects. The Third National Cancer Survey, 1969-71, reported 432 patients with noncutaneous melanoma, 79% originating in the eye. As with skin melanoma, ocular tumors were more common in whites than blacks and predominated in females at younger ages and males after middle life. On the other hand, ocular melanoma did not show the strong North-South gradient seen with skin melanoma; this suggested no relation to sunlight exposure.


Correlation of in vivo malignancy with in vitro properties of human-mouse hybrid cells. The in vivo tumorigenicity of malignant mouse-nonmalignant human somatic cell hybrids was correlated with the in vitro characteristics. The renal adenocarcinoma mouse cell line RAG and the normal, diploid human cell line Wl-38 were used as the fusion parents. Five independent RAG Wl 38 hybrid clones were tested for concanavalin A (Con A) agglutination patterns, in vitro invasiveness, and tumor formation in immunosuppressed mice. Tests on the parental lines showed that RAG cells agglutinated at much lower levels of Con A than the Wl-38 cells. RAG cells overgrew Wl-38 cells in the in vitro invasiveness assay. RAG cells readily formed tumors in untreated adult or young immunosuppressed mice, whereas the Wl-38 cells did not. The five hybrid clones were all similar, since they had Con A agglutination levels intermediate to those of both parents, though patterns were more "tumor-like", overgrew the Wl-38 cells in the invasiveness assay, and formed tumors in immunosuppressed mice.


Dianhydrogalactitol (NSC-132313): pharmacokinetics in normal and tumor-bearing rat brain and antitumor activity against three intracerebral rodent tumors. Dianhydrogalactitol (DAG; NSC-132313), a hexitol epoxide, was used to treat intracerebral rodent tumors. DAG was most active against the murine ependymoblastoma [treated/controls (T/C)greater than 440%], less active against murine glioma 26 (T/C approximately 112-150%), and least active against rat 9L gliosarcoma (T/C approximately 100%). Application of a two-compartment open model for plasma disappearance of 14C-DAG in rats gave a volume of distribution at steady state of approximately 872 ml, a clearance of approximately 9.4 ml/minute, and an elimination constant of 0.025/minute. Entry of 14C-DAG was more rapid into the 9L tumor than into the normal brain. When a two-compartment series model for brain and tumor entry was applied, the t1/2 (half-time) for compartmental equilibrium was approximately 22 and 105 minutes in the brain, and 4 and 56 minutes in the 9L tumor. The drug rapidly entered the brain and tumor intracellular compartments. Binding to RNA was linear with time, and the absolute amount of binding was approximately six times greater for RNA than for DNA.


Pathogenesis of ascites in mice with peritoneal carcinomatosis. For clarification of the mechanisms underlying formation of malignant ascites, alterations in lymphatic transport from the peritoneal cavity and in peritoneal capillary permeability to protein were studied sequentially in mice inoculated ip with Ehrlich-Lettre ascites tumor cells. All animals developed detectable ascites within 5-7 days of the injection. Diaphragmatic and retrosternal lymph vessels became radiopaque within 30 hours of the ip injection of radiopaque contrast material in control animals without ascites and in 12 experimental mice receiving contrast material 1-3 days after injection of tumor cells. No lymph vessels were opacified in 3 of 4 animals when contrast material was injected on day 5 or in any animal receiving contrast material on or after day 7 following the tumor cell injection. We determined alterations in peritoneal capillary permeability in the second group by measuring the concentration of iv injected Evans blue dye in eluates of sections of peritoneum and contiguous underlying tissue removed 3 hours after injection of dye. Permeability averaged 1.5 times normal (P = 0.02) by day 3 after tumor cell injection, 2 times normal by day 5, and 3 times normal by day 7; it remained at the final level. Although lymph drainage became impaired within 24 hours of the detection of ascites, a progressive increase in capillary permeability began 2 days earlier and was probably the predominant alteration in pathogenesis of the effusion.


Biologic effects of plant toxins and aflatoxins in rats. After weaning, groups of rats were fed a semi-purified diet containing fiddlehead greens (the unfuried frond of the ostrich fern Matteuccia struthiopteris), mature bracken fern (Pteridium aquilinum), or cycad meal (Cycas circinalis), or this diet plus aflatoxin B1. The groups fed 1-10% fiddlehead greens for 70-73 weeks developed no tumors, whereas those fed mature bracken fern for 67 weeks developed small-bowel adenocarcinomas (3/17). Those fed 3% cycad meal for 64 weeks developed tumors of the liver (4/18), kidney (2/18), small bowel (1/18), and large bowel (6/18). Those given aflatoxin B1 and observed for 73 weeks developed liver tumors (11/15). Thus this study indicates that fiddlehead greens from M. struthiopteris are not toxic or carcinogenic.


Protective effects of amphotericin B against spontaneous and transplantable murine tumors. Two tumor systems were used to test prophylactic effects of amphotericin B (AmB). When 0.5 mg AmB was given ip every 2 weeks to AKR mice beginning at 8 weeks of age, the 50% tumor incidence for spontaneous lymphoma development was delayed 2-3 months. In the second tumor system, BALB/c mice received injections of either 20 or 50 mug AmB before receiving MOPC-315-C cells sc. The mice given the low dose of AmB demonstrated a decreased tumor incidence and a reduced tumor growth rate, when compared with controls. Opposite effects were found for the group administered the high dose; tumor incidence and rate of growth were increased.


Invasive behavior between sarcoma and fibroblast populations in cell culture. The mutual invasion in culture of a population of standard fibroblasts (chick embryo) and a population of cells from a transplantable mouse sarcoma (MC)M, BAS/56, or 311) or of neontal mouse fibroblasts has been estimated quantitatively. We arranged the confrontation of the pairs of populations by placing primary explants near each other. After fixation, the distance the cells had migrated from each explant was sampled in the space between the explants where they met and at the sides of the explants where they migrated freely. Measurements of nuclear overlap and orientation were also made. In the sarcoma as in the fibroblast population, homologous contact inhibition of movement probably produced an oriented migration from the explants before the populations met. Abot 12-24 hours after, mutual invasion was considerably greater in the sarcoma versus fibroblast than in the fibroblast versus fibroblast experiments. It is proposed that this difference was due to a difference of heterologous contact inhibition in the two types of experiment.


Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. II. Effect of cortisone acetate. Studies from this laboratory have demonstrated that the administration of cyclophosphamide (CY) and Corynebacterium parvum (CP) over a prolonged time to C3H mice with established measurable tumors resulted in complete arrest of tumor growth as well as partial and complete regressions in many instances. A study of the effect of two different doses of cortisone acetate (CA), administered two or five times weekly, on the tumor inhibitory properties of this chemoimmunotherapeutic regimen indicated that the addition of a corticosteroid to the CY-CP combination did not alter its tumor-inhibitory properties. There was no significant change when CA was administered with CP; however, tumor inhibition was enhanced to a degree approaching statistical significance when CA was added to CY at dose levels of 1.5 and 2.5 mg twice weekly. These results demonstrated that it may be possible in treatment of humans to administer a steroid in combination with a chemoimmunotherapeutic regimen without inhibition of the regimen's antitumor effects.


Aflatoxin B; specific antibodies and their use in radioimmunoassay. New Zealand White rabbits immunized with covalent conjugates prepared from polylysine and the O-carboxy-methyloxime derivatives of either aflatoxin B1 (AFB1) or an analogue, 5,7-dimethoxycyclopentenon (2,3-c) coumarin, produced antibodies that bind 3H-AFB1. The specificities of the antisera with respect to aflatoxins BI, B2a, G1, G2, Q1, P1, and some other structually related compounds were determined. Radioimmunoassays that can detect levels as low as 0.27 pmoles (0.06 ng) of AFB1-were used to analyze serum, urine, and crude extracts of corn and peanut supplemented with aflatoxin. In the foodstuffs, as little as 1 mug AFB1/kg was measured. The immunoassay was at least as sensitive and specific as other available analytic methods, but did not require the purification of samples by chromatography before analysis. The technique may be particularly useful in epidemiologic studies designed to study the possible relationship between chronic aflatoxin ingestion and cancer.


Metabolism of N-2-fluorenylacetamide in X/Gf mice: lack of correlation between biochemical interaction and carcinogenicity. A comparative study of the metabolism of the carcinogen N-2-fluorenylacetamide by mice of the X/Gf strain (resistant to the tumorigenic action) and the NiH Swiss strain (susceptible to the tumorigenic action) showed slight but not outstanding differences in metabolic patterns. The activated metabolite N-hydroxy-N-2-fluorenylacetamide was excreted by both strains, and the levels of carcinogens or metabolites bound to liver macromolecular constituents were comparable in the X/Gf and NiH Swiss mice.


Unusual cell junctional complexes in canine mammary adenoacanthomas. Unusual cell junctional complexes were described in spontaneously arising adenoacanthomas of canine mammary glands. These junctional complexes were a manifestation of bidirectional differentiation of tumor cell membranes.


Cellular immune reaction to human malignant melanoma and breast carcinoma cells. An in vitro microassay was used to study cytotoxic reactivity of lymphocytes of 19 patients with malignant melanoma, 8 patients with breast carcinoma, and 18 normal subjects on cell cultures of malignant melanoma and breast carcinoma. In each of the twelve experiments, peripheral blood lymphocytes from individuals with and without cancer were tested simultaneously on two or three different target cells. Cytotoxic reactivity, evaluated by a comparison of the number of target cells remaining after incubation with lymphocytes with those incubated with medium only, was found in 20 cancer patients (74%) and 13 individuals without cancer (72%). The strength of lymphocyte reactivity of the cancer and of the non-cancer group did not differ significantly. Of the 27 cancer patients, 8 were positive only on the homologous target cells, 7 only on the opposite cells, and 5 on both types; 7 were negative. Short-term melanoma cell cultures were more lysable than were established cell lines; however, no direct correlation between the growth rate during the test period and susceptibility to lysis was seen. The blood group of the lymphocyte donors had no influence on cytotoxic reactivity.


Therapy of transplanted lymphomas.

Therapy of transplanted lymphomas. Allogeneic cells or cell products containing murine leukemia virus were effective in curtailing growth of a transplanted CBA lymphoma, which was originally induced by Gross virus and then maintained by syngeneic cell passage. All allogeneic cells or products effective in therapy of this lymphoma expressed virus as tested by the XC cell in vitro infectivity assay. Some of the materials also expressed virus as assayed by oncogenicity in vivo. A therapeutic effect was not demonstrated with allogeneic cells or cell products laking these virus activities. Syngeneic lymphoma cells were ineffective. Protected animals did not develop lymphoma when rechallenged several months later. Mechanisms for this therapy with virus were proposed.


Racial and occupational variations in cancer of the testis: San Francisco, 1956-65. During 1956-65, white and nonwhite San Francisco male residents did not have equal risks of developing testicular cancer. The lower risk observed for nonwhites could not be attributed entirely to genetic factors, since among whites a risk gradient seemed to correlate directly with broad socioeconomic indices such as occupation and census tract of residence. Although incidence rates for testicular cancer have progressively increased in the United States and now parallel rates in Danish towns and rural areas, they are still lower than rates observed in Copenhagen, where a "technology" effect has been postulated. In this perspective, the San Francisco findings are compatible with a hypothesis that certain occupational groups may have become epidemiologic indicators of testicular carcinogens in a changing environment.


Lymphocyte plasma membranes. VI. Surface antigens of lymphocytes in chronic lymphocytic leukemia. Surface antigens from lymphocytes of patients with chronic lymphocytic leukemia (CLL) and from normal peripheral blood lymphocytes (PBL) were examined by radioimmunoassay; antisera to lymphocytes (ALS) were used to bind the labeled antigens. Cells from patients with CLL, normal PBL, thymus cells (THY), and cultured human lymphoblasts (CHL) were labeled by lactoperoxidase-catalyzed iodination. ALS (prepared against THY and CHL) were used to bind the labeled antigens solubilized in nonionic detergent. PBL resembled THY, but the CLL resembled CHL. Thus ALS(CHL) had greater potency for CLL antigens than for PBL antigens when compared to ALS(THY). Furthermore, the electrophoretic profiles of the immunoprecipitates from CLL cells revealed a peak of approximately 30,000-35,000 mol wt, which was not found for PBL or THY, but was associated with CHL.


Mouse skin assay of condensate from smoking products other than tobacco. The biologic activity of a smoking product other than tobacco (Cytrel) was compaed with that of an American-type blend of cigarette tobaccos by application of the smoke condensate (SC) to shaved mouse skin. In 4 nonsimultaneous experiments, SC's from the former were equivalent or lower in tumorigenicity than equal doses of those from the latter, studied simultaneously and under identical conditions; this was true for widely varying doses of SC's, ranging from 35 to 246 mg nonaqueous condensate (NAC) administered to each mouse/week for 63-92 weeks. The response to SC from smoking products other than tobacco ranged from a complete lack of epidermoid carcinomas and papillomas at the lower doses to an incidence of lesions in 25.3% of the animals at the highest dose. The SC from a typical American blend of tobaccos caused skin lesions in 18.7-39.1% of the animals. SC from type 324 Cytrel, applied at the even higher dose of 365 mg/mouse/week, caused papillomas or carcinomas in only 22.0% of the animals, as compared with 39.1% of mice after adminstration of 245 mg SC from the American blend of cigarette tobacco; this was the highest dose that could be achieved with a test material containing nicotine. SC from a 1:1 blend of Cytrel with cigarette tobacco produced considerably fewer skin lesions at the lower dose levels than did SC from tobacco. At the lowest dose of 35 mg/mouse/week, 2 and 18.7% of the animals had lesions, and at a 54-mg dose, 11.3 and 22.7% had lesions from the blend and tobacco samples, respectively. At an increased level (113 mg), the response was the same for the SC from a 1:1 blend and from cigarette tobacco. There existed an excellent dose-response relationship for SC from type 308 Cytrel tested at four dose levels: 8.4, 113, 246, and 383 mg NAC/mouse/week, with 0, 18.7, 25.3, and 57.7% of the animals exhibiting skin lesions, respectively. Based on the criteria inherent in the technique of "mouse skin painting", Cytrel variants appeared to be lower or equal in tumorigenicity than did cigarette tobacco.


Prognostic factors in canine mammary cancer. From a follow-up study of dogs surgically treated for mammary cancer, ten characteristics were analyzed statistically with special reference to their association with prognosis (expressed as survival for 2 years). The interrelations among five of the characteristics were also tested. The histologic type (descending range in malignancy: sarcomas greater than simple carcinomas greater than complex carcinomas), mode of growth (highly infiltrating greater than moderately infiltrating greater than expansive), clinical stage of complex carcinomas (large tumors and/or tumors involving the skin or underlying tissue greater than small, well-defined tumors), and size (greater than 15 cm greater than 11-15 cm greater than 5-10 cm greater than 0-5 cm) were of definite prognostic importance. The histologic grade was of possible prognostic importance. Localization, type of surgical therapy (mastectomy, block-dissection), growth in lymph vessels, involvement of regional lymph nodes, and duration of symptoms before treatment were not important to prognosis. A comparison between the factors associated with the prognosis of canine and human mammary cancer showed many similarities. However, the involvement of regional lymph nodes, important in women, was not so in bitches.


Histochemical patterns in early lesions and infiltrating adenocarcinomas induced in mouse duodenum by n-ethyl-n'-nitro-n-nitrosoguanidine. Intravillous, microcrater, and macroscopic invasive lesions induced in the mouse duodenum by N-ethyl-N'-nitro-N-nitrosoguanidine were examined histochemically. The cells of these neoplastic lesions and the proliferative zones of the normal crypts showed similar staining reactions in leucine aminopeptidase, alkaline and acid phosphatases, adenosine 5'-triphosphatase, and glucose-6-phosphate dehydrogenase. However, a slight decrease in succinic dehydrogenase activity and a slight increase in lactic dehydrogenase activity were observed in the intravillous and microcrater lesions compared to the activity in the proliferative zones of the crypts. The neoplastic cells of these lesions showed no mucus secretion. We discussed the origin of the neoplastic lesions using these and other findings.


Inconsistent response of B16 melanoma to BCG immunotherapy. We evaluated the potential of the B16 melanoma of mice as a model system for BCG immunotherapy of malignant melanoma. We studied a variety of treatment protocols: a) BCG given simultaneously but separately with a small number of B16 cells significantly inhibited tumor growth in only three of eight experiments. b) BCG injected directly into the tumor stimulated tumor growth in three of three experiments; the stimulation was at least partially attributable to the nutrient medium in which the BCG was suspended. c) The B16 tumor was weakly immunogenic and the addition of BCG to a tumor cell vaccine offered little improvement in subsequent resistance to tumor cell challenge: d) In a model of postsurgical residual tumor, metastatic to regional lymph nodes, BCG and tumor cell vaccination did not alter the development of nodal metastases. The B16 melanoma was not a useful model system for BCG immunotherapy, because the tumor inhibition was feeble, inconsistent, and not associated with augmented tumor immunity.


Intrasplenic tumor formation in the syrian hamster (Mesocricetus auratus) after tracheal implants and treatment with diethylnitrosamine. In two simultaneous experiments (A and B), tracheal tissue from 25 young Syrian hamsters was implanted in their mothers' spleens. In A, after tracheas from 3-week-old untreated donor offspring were implanted into their mothers, the mothers received 18 mg diethylnitrosamine (DEN)/kg body weight, sc, twice weekly for 20 weeks. Thereafter, the implants were removed and transferred to the spleens of other untreated offspring that were then similarly treated with DEN for 20 weeks. In B, the procedure was similar except that the donor offspring were pretreated with DEN for 20 weeks, beginning at the age of 8 weeks. The average treatment time for the implants in experiment A was 65 weeks; in B, 44 weeks. In A, only four implants demonstrated a papilloma or a papillary polyp. In B, such neoplasms developed after a much shorter treatment time, and in three cases, squamous cell carcinomas with invasive growth in to the splenic pulp were formed.


Immunostimulation of highly immunogenic target tumor cells by lymphoid cells in vitro. A highly immunogenic mouse tumor was studied with the use of microcytotoxicity test, performed at lymphoid cell:target tumor cell ratios ranging from 1:1 to 1,000:1 at various times during tumour growth and after tumor excision. Although the tumor was highly immunogenic, in vitro lymphoid cell-mediated cytotoxicity was shown only with lymphoid cells from hyperimmunized mice, i.e., mice that had "seen" the tumor more than once. Instead, the lymphoid cells harvested 2 and 3 weeks after tumor inoculation, as well as after excision of the tumor, stimulated the target cells. At 4 weeks after inoculation of the tumor, there appeared to be neither stimulation nor inhibition of the target tumor cells, though at this point the growth of this highly immunogenic tumor had been arrested in vivo.


Exogenous estrogens and breast cancer in women with natural menopause. Age, age at menopause, and calendar year at menopause were controlled as factors related to estrogen use. Data on 90 breast cancer patients and 83 conrols--all of whom had a natural menopause--showed no relationship between breast cancer and estrogen usage after the start of menopause symptoms.


Inhibition of cell-mediated cytotoxicity against tumor-associated antigens by suppressor cells from tumor-bearing mice. Spleen cells from mice bearing primary tumours induced by Moloney strain of murine sarcoma virus (M-MuSV) strongly inhibited the in vitro generation of specific secondary cell-mediated cytotoxic response of spleen cells from M-MusV regressor mice. These suppressor cells were resistant to treatment with anti-theta serum and complement or to X-irradiation. It appeared that suppressor cells may have had a role in limiting the host's immune response against tumor growth.


Murine colon adenocarcinomas: methods for selective culture in vitro. Two murine colon adenocarcinoma cell lines were established from primary cultures. The MCA-38 cell line was begun by treatment of the primary culture with trypsin to remove the fibroblastoid elements. The MCA-36 epithelial cells were sensitive to trypsin; therefore, the growth medium of MCA-36 primary cultures was augmented with collagenase to release the tumor-cell elements from the fibroblast network. These tumor elements were dissociated with trypsin and placed in tissue culture. Each cell line was cultured for at least 10 passages in vitro and gave rise to tumors when reimplanted in vivo.


Gas gangrene complicating limb trauma.

Gas gangrene complicating limb trauma. A consecutive series of 18 patients with clostridial myonecrosis has been reviewed. The two deaths were attributed to other causes. A treatment regimen including repeated debridement and excision of all non-viable tissue, and therapeutic antibiotics is outlined. Hyperbaric oxygenation has been omitted from our treatment program.


Radiographic detectability of occipital and temporal-parietal fractures induced in cadaver heads. Diagnostic performance based on a double-blind evaluation of test and control radiographs produced from nine different fractured cadaver skulls was compiled for six radiologists. The data resulting from two different diagnostic tasks were analyzed statistically for accuracy and confirmed interpretability including an assessment of task-related performance differences. Performance was found to be relatively independent of differences among radiologists and lesion location. Little overall correlation was found to exist between demonstrated ability to detect lesions radiographically, and visual confirmation of known lesions from the same films. These results suggest that overall performance was probably limited by a number of undefined clinical factors which influence the amount of meaningful information available from the resulting radiographs. The distribution of these degrading influences was not uniform within the population sampled so that certain radiographs proved to be particularly misleading when considered in terms of their apparent diagnostic value. As a result, even relatively large depressed fractures were in some instances considered radiographically uninterpretable.


Turnover of amino acids in sepsis and starvation: Effect of glucose infusion. The catabolism of glucose and amino acids has been studied in the normal, the fasted, and the fasted septic dog. The fasted septic dog oxidized more glucose and alanine, and had more gluconeogenesis from alanine and the five tritiated amino acids--glutamate, threonine, phenylalanine, leucine, and valine--as compared to the normal and equally fasted dog. Thus the total body protein catabolic state was characterized in biochemical terms. In contrast, following glucose infusion, the fasted septic animal responded much like the fasted animal in terms of decreased animo acid gluconeogenesis and decreased plasma concentrations of amino acids, fats and fat products, but considerably increased the oxidation of alanine. The increased alanine oxidation appeared to be primarily related to increased tissue clearance and increased plasma concentration. There was some suggestive evidence for enhanced oxidation of the tritiated amino acids including leucine and valine during glucose infusion. The protein catabolic state secondary to this sort of sepsis in dogs only on per os fluid support appears to be best characterized as a glucose catabolic state with alanine being oxidized directly. Such states are known to be ones of enhanced metabolic rate secondary to enhanced synthetic processes generally. This is probably related to enhanced sympathetic nervous system release of glucagon with insulin being normally responsive to glucose because of a normal plasma epinephrine.


Significance of the electrocardiogram in heart contusion due to blunt trauma. In a series of 24 patients with major blunt chest trauma, 11 presented evidence of heart injury upon re-examination of serial ECGs and four were confirmed at autopsy. The clinical diagnosis had been recorded in only one patient. In every case of closed chest trauma, regardless of the degree of visible injury, cardiac injury must be suspected. A presumptive diagnosis is then made, usually on the basis of ECG changes, which cannot be ruled out by any other cause. Even in some cases with normal ECGs the clinician's suspicion is the only guide. With a presumptive diagnosis made, the patient is treated as is any patient with an irritable myocardium; bedrest, avoidance of conditions which may precipitate arrhythmias, and of fluid overload, and treatment of these complications as they arise. Anticoagulants are usually avoided. Followup for long periods is indicated, because of the occasional emergence of chronic constrictive pericarditis or ventricular aneurysm.


The surgical management of hepatic trauma. The personal experience of 179 patients with hepatic injuries is reviewed by the author. Difficulties in diagnosis and other problems encountered are discussed. The methods of management of the injuries and his operative technique are discussed. The increasing incidence of violence and large-scale civil disturbances coupled with fast automobiles have shown the changing concept in the type of injuries and the need for more aggressive treatment.


Chain saw vs. face: another hazard of mechanized progress. Serious facial injuries can occur as the result of upward recoil of a chain saw into the operator's face. Six such cases have been discussed and the mechanism of injury as well as possible means of prevention presented.


Retained intrapulmonary bullet presenting with bronchial obstruction. A patient is presented who demonstrated migration of a retained intrapulmonary bullet 7 years after injury. This resulted in bronchial occlusion and post-obstructive lung infection without apparent hemoptysis. Lobectomy is considered the operative procedure of choice for this condition.


Complete avulsion of the renal pedicle with survival: case reports and literature review. Two cases of complete avulsion of the renal pedicle with survival are presented, and the nine previous cases in the available world's literature are reviewed. The young age of these patients and frequent association with trauma to other organs are discussed. Because of the common absence of hematuria, an intravenous pyelogram should be performed in all patients with significant nonpenetrating abdominal trauma, and a renal arteriogram is indicated if nonvisualization is present. A plea for immediate surgery is made, with consideration of vascular reconstruction. (See Addendum, p. 162).