The effect of sodium-free and potassium-free solutions, ionic current inhibitors and ouabain on electrophysiological properties of smooth muscle of guinea-pig ureter.

1. The effects of Na-free and K-free solutions, tetraethyl ammonium (TEA), Mn2+, verapamil and ouabain on the electrophysiological properties of the smooth muscle cells of guinea-pig ureter have been studied, using the double sucrose-gap method. 2. TEA (5 mM) increased the amplitude and duration of both the initial spike component and the subsequent plateau of the action potential. The repetitive spike discharge on the plateau was abolished. The amplitude and duration of the phasic contraction was increased. The threshold for excitation was lowered while the resting potential and membrane resistance were unaffected. 3. In Na-free solution the duration of the action potential decreased mainly due to the suppression of the plateau. A similar effect was produced by exposure to K-free solution and also by ouabain. 4. Mn2+ (2 mM) suppressed the spike component and raised the threshold for excitation. The amplitude of the remaining part of the action potential was markedly increased but the contraction was rapidly abolished. The resting potential and membrane resistance were unchanged. When Mn2+ was added to Na-free solution it produced an increase in the amplitude and duration of the remaining part of the action potential but the phasic contraction was abolished. 5. Verapamil did not specifically block the fast component of the action potential but initially increased the amplitude of the spike and shortened the plateau. Subsequently, both the action potential and the phasic contraction became smaller. 6. The observations indicate that the phasic contractions are triggered by the initial spike component of the action potential, whereas the plateau is associated with the amplitude and particularly the duration of the contraction.


The mechanism of the excitatory action of catecholamines and histamine on the smooth muscle of guinea-pig ureter.

1. The ionic mechanism of the excitatory action of catecholamines and histamine on the smooth muscle cells of guinea-pig ureter was studied with the double sucrose-gap method. 2. In normal conditions adrenaline and noradrenaline in a concentration of 10(-5) g/ml., and histamine in a concentration of 10(-6) g/ml., prolonged the duration of the plateau of the action potential and increased the amplitude and duration of the phasic contraction. Sometimes these changes were accompanied by a slight depolarization of the muscle membrane and by a small increase (with noradrenaline) or decrease (with histamine) of the membrane resistance. The amplitude and duration of the fast spike component of the action potential were not changed. 3. Isoprenaline in a concentration of 10(-5) g/ml. either caused no change or it decreased the duration of the plateau, reduced the amplitude of contractions and reduced excitability. 4. Tetraethyl ammonium (TEA; 5 mM), which blocks the delayed outward K current, did not prevent the increase in the duration of the plateau nor the increase of the amplitude and duration of the contractions by noradrenaline and histamine. 5. In Na-free or in K-free solution or in the presence of ouabain, i.e. in conditions in which the Na-gradient across the membrane was reduced, noradrenaline and histamine were unable to increase the duration of the plateau and the amplitude and duration of the contraction. 6. In the presence of Mn2+ (2 mM) which suppressed the spike component of tha action potential and the phasic contraction, theeffects of noradrenaline and histamine were almost abolished. 7. The results suggest a dual ionic mechanism of the alpha-action of catecholamines and of the action of histamine on the smooth muscle of ureter: (1) these drugs affect the passive ionic permeability of the membrane in a manner that results in depolarization; (2) they specifically activate the potential-dependent conductance of the slow Na channels, thereby increasing the plateau duration. The increased amplitude and duration of the contraction is the result of their primary effect on the plateau of the action potential.


Firing rate and recruitment order of toe extensor motor units in different modes of voluntary conraction.

1. The discharge properties of individual motor units in different modes of voluntary contraction were studied with electromyographic techniques in the short toe extensor muscle of normal man. 2. The short toe extensor muscle consisted of type I and type II muscle fibres in about equal proportion. In some subjects there was type-grouping so that recordings with sufficient selectivity could easily be obtained. 3. Certain motor units could be driven continuously, attained regular firing intervals even at a firing rate of 10/sec, increased slowly in firing rate with increase in contraction strength, had maximum firing rate below 30/sec during sustained contraction but above 60/sec in twitch contraction. 4. Other motor units could not be dirven continuously, did not fire repeatedly at rates below 20/sec, increased rapidly in firing rate with increase in contraction strength and attained firing rates above 100/sec. 5. There were intermediate forms between continuously firing low frequency motor units and intermittently firing high frequency motor units. 6. In a prolonged contraction of constant strength only continuously firing motor units were active. 7. On rapid accelerations, however, both continuously and intermittently firing motor units were active and played about the same role. 8. This applied also to prolonged series of accelerations as in rhythmically alternating movements. 9. In twitch contractions selective activation of intermittently firing motor units occurred if the muscle was relaxed prior to the twitch and great effort was used to elicit the twitch and minimum duration of the twitch was intended. 10. It is suggested that continuously firing low frequency motor units have type I muscle fibres and intermittently firing high frequency units have type II muscle fibres and that the order of recruitment and the relative roles of the two motor unit types are adapted to the mode of contraction.


Voltage-clamp analysis of a self-inhibitory synaptic potential in the buccal ganglia of Aplysia.

1. In cholinergic neurones BL4, BL5, BR4, and BR5 of Aplysia buccal ganglia, each action potential is followed, in the same cell, by a curare- and high-Mg-sensitive hyperpolarizing after-potential which is enhanced by Ca. 2. In voltage-clamped neurons, substracting currents recorded in curare from currents recorded in sea water reveals that this potential is due to curare-sensitive currents which rise to a peak, then decay exponentially with an apparently voltage-independent time constant of 43 msec. Currents are produced by a voltage-independent, Ca-enhanced, conductance change with a 0-26 mumho peak and a -64 mV reversal potential. The curare-sensitive conductance is also sensitive to high Mg. 3. Both after-potential and curare- or Mg-sensitive current follow each action potential without failures, even in threshold-raising 80 mM-Ca-144-mM-Mg solutions. 4. Both after-potential and current decrease with repetitive firing or short inter-spike interval, possibly due to receptor desensitization. 5. The Mg- and curare-sensitive conductance is also blocked by 1 mM-ACh. 6. The data are consistent with the hypothesis that the hyperpolarization following action potentials in each of these four neurones is produced by a self-inhibitory synaptic mechanism.


Do authoritarians hold authoritarian attitudes? The case of South Africa.

This study attempted to check, in an authoritarian culture, Ray's hypothesis that there is no relationship between authoritarian behavior and authoritarian attitudes. Scales measuring these two variables were administered to 38 white Afrikaans-speaking South African college men and women (average age 20.74 years). The correlation between the two scales was--.21 which is not significant. The results were therefore seen as a confirmation of Ray's hypothesis.


The relationship of dogmatism to the nonrecognition of perceptual ambiguity.

The relationship between dogmatism and the nonrecognition of perceptual ambiguity was investigated in 84 male and female colloge students. Significant but small nagative correlations were found between Rokeach's Dogmatism scale and two indicators of perceptual ambiguity: Necker cube perspective reversals and binocular retinal rivalry alternations in dominance. The nonrecognition of perceptual ambiguity was discussed within a psychoanalytic ego defense framework.


The effect of fear on the aggressive responses of anger aroused and revenge motivated subjects.

In a 3 x 2 between Ss design employing 54 male college students, one group of Ss was given neutral feedback (neutral condition) by a confederate (C), and another group was insulted by a C (anger condition). Both of these groups were given an immediate opportunity to aggress against a second C. A third group was insulted by one C and given the opportunity to aggress against that same C one day later (revenge condition). Ss were also told that the target either would or would not have the opportunity to retaliate (fear and no fear conditions). Fear significantly depressed aggression only in the revenge condition, and the revenge condition was the only feedback condition in which the level of aggressiveness was above that of the neutral condition (p less than .05). It was speculated that anger might serve as a disinhibitor of responses suppressed by fear.


Effects of controlled illumination levels upon verbal response latency in a color-word interference task.

When Ss in previous research were tested on a color-word interference task, the stimuli were generally said to have been presented in a well-lighted room, or with adequate lighting, or with a good light source, and the like. The present research attempted to find out the difference in performance between (a) Ss performing the task under a level of illumination of 5 ft-c, (b) Ss performing the task under a level of illumination of 150 ft-c, and (c) a control group performing the same task under a level of illumination of 50 ft-c. Results indicated that the Ss of both the 5 and 150 ft-c groups took significantly longer and made significantly more errors than the control group. It was concluded that levels of illumination under which the color-word interference task is performed significantly affect performance.


Dogmatism and related personality factors among Egyptian university students.

The Dogmatism Scale and 13 personality tests measuring authoritarianism, rigidity, neuroticism,and extremeness were administered to 250 male and female students at the University of Cairo, Egypt, to investigate whether there are any differences in dogmatism and its underlying personality characteristics associated with the Egyptian culture in comparison with the American and English cultures. The Egyptian mean dogmatism score was larger than the comparable means obtained for American and English college students (p less than .001). However, with use of Hotelling factor analysis and the varimax orthogonal rotation method, dogmatism was found to be almost independent of the rigidity and extremeness scores, indicating that in cultures where strength of believing can be considered a part of the socially accepted norms (e.g., Arab Eastern cultures), dogmatism rests on different cognitive and personality processes than in the West.


Perception of crowding and personal space as a function of locus of control, arousal seeking, sex of experimenter, and sex of subject.

Twelve male and female college students served as Es and individually administered the following tests to a total of 72 male and female college students: Mehrabian and Russell's scale of Arousal-Seeking Tendency (AST), the Nowicki-Strickland scale of locus of control (ANSIE), a crowding perception test (CPT), and a figure placement task measuring perceived comfortable interpersonal distance (CID). Contrary to prediction, zero correlations were obtained between AST and CPT scores and between ANSIE scores and CID distances involving strangers. Low but significant correlations between CPT and CID scores were obtained. Analysis of variance of CID scores revealed a significant interaction between sex of S and locus of control that was not easy to interpret, and significant effects of degree of acquaintance, status, and sex of an approaching peer. A significant sex of E effect indicated that distances were larger with a female than with a male E. AST scores were larger for female than for male Ss, and larger with a male E than a female one.


Microteaching, feedback, dogmatism, and nonverbal perceptiveness.

This exploratory study examines the relationship between various conditions of feedback in peer microteaching, the personality dimension dogmatism, and nonverbal perceptiveness. Ss were 74 trainee teachers who were assigned to feedback conditions on the basis of dogmatism scores and then participated in a seven-week treatment period. The statistical procedure known as part correlation was used to gain measures of the extent to which Ss changed their nonverbal perceptiveness. This measure of change in nonverbal perceptiveness was related to dogmatic tendencies and feedback conditions. Although no consistent relationship was found to exist between dogmatism and change in nonverbal perceptiveness, there was a strong indication of dogmatic Ss changing their nonverbal perceptiveness when involved in the treatment condition peer microteaching with public feedback.


Some aspects of influence and acceptability for appointed and elected group leaders.

Two experiments (NS = 48 and 52 male college students, respectively) are reported on the relative influence of appointed or elected leaders and members if four-man discussion groups in a decision-making task. Leaders were either appointed by the E or elected by the group, and groups received either success or failure feedback. The influence of elected leaders increased after failure feedback and decreased after success feedback, which was precisely opposite to the direction of influence shift for appointed leaders. The second experiment examined this effect further, after leaders were replaced by appointment or election, and with the identical success or failure feedback as before. The hypothesis that the newly elected leader would be more influential than the newly appointed leader was only partially supported. The elected leader who succeeded the initial leader was found to have had significantly higher influence than the average group member from the very outset.


Personality correlates of semantic habits in the deaf.

The relationships between personality characteristics and semantic habits were explored with use of The Sixteen Personality Factory Questionnaire, Form E, and a measure of semantic habits. Ss were 102 deaf male and female college students. The results, analyzed separately by sex, showed a few significant relationships. Deaf males who were emotionally less stable and affected by feelings tended to prefer positive and negative evaluations. Relaxed, tranquil, and unfrustrated deaf males tended to neglect positive and negative evaluations and to prefer categorical responses to detail ones. Serious and sober deaf females tended to neglect negative evaluations.


[Cerebral malformations in the oro-facio-digital syndrome of Papillon-Leage and Psaume (author's transl)].

Six children with an oro-facio-digital syndrome (Papillon-Leage and Psaume) underwent pneumoencephalography. In 3 cases, the examination was normal. In 3 cases, severe abnormalities were discovered. These abnormalities included: agenesis of the corpus callosum (3/3); a markedly asymmetric skull with enormous porencephalic cavities (2/3); heterotopia of the grey matter (2/3). There were no differences in neurological state nor I.Q. between the children with cerebral malformations and those with a normal pneumo-encephalogram. The association of agenesis of the corpus callosum and porencephaly is significant, and even more so if heterotopia is also present. In the presence of these abnormalities, the diagnosis of oro-facio-digital syndrome may be made even when the clinical picture is untypical.


[Parieto-occipital overlap in the normal infant and in hydrocephalus (author's transl)].

Parieto-occipital overlap is a common phenomenon in the newborn. As a result of the compression of the superior longitudinal sinus which it causes, it has grave consequences on the cerebral circulation. It may be responsible for deep cerebral infarctions by the deviation of blood supply which its causes. The phenomenon of overlap is greatly accentuated in the hydrocephalic child.


[Acro-osteosclerosis in the course of sarcoidosis (author's transl)].

The authors report two cases of acro-osteosclerosis occurring during sarcoidosis. Condensation lesions involve above all the distal and proximal phalanges of the hands. Comparison of these cases with those in the literature indicates that these particular types of bone changes in association with sarcoidosis are more common than indicated in the studies of Jüngling (occurrence estimated at 54% of subjects suffering from sarcoidosis with bone localisations). This acro-osteosclerosis is however not specific to sarcoidosis. It is seen in patients suffering from rheumatoid arthritis, Hodgkin's disease and other haematological disorders. It has also been seen in normal individuals in X-rays taken at the time of a traumatic accident.


[Radiological appearances of hydatid cysts of the kidney. 10 confirmed cases (author's transl)].

Ten cases of hydatid cyst of the kidney are reported. The problem was invariably unilateral and isolated, involving the left kidney in 8 cases and the right kidney in 2 cases. IVP reveals a syndrome of a renal mass, sometimes enormous. Peri-cystic calcifications were visible in 7 cases, very localised in 5 cases and diffuse in 2. In 3 cases the kidney was non-functioning. No communication between the cyst and the excretory pathway could be seen at IVP in the two cases where it existed anatomically. Cystic parietography, partial or total, was visible in 4 cases. The mass was always avascular, without spur sign. The picture is very similar to that of a necrosed carcinoma of the kidney. Arteriography was not felt to be any more helpful than IVP in demonstrating the wall of the cyst. By contrast, changes in the trunk of the renal artery were common. The authors discuss the means avaliable for the radiological exploration of hydatic cysts of the kidney, in relation to the technical possibilities possessed in countries where the problem is endemic.


[Periostitis or, rather, periosteal appositions in paediatrics (author's transl)].

In relation to a case of multiple fatigue fractures definitely diagnosed by scintigraphy and xerography, the authors report two other previous cases of spontaneous fractures at a single site in which the diagnosis was made only after surgical biopsy and histological examination. Recalling the frequent confusion arising in children between periosteal appositions and osteomyelitis or Ewing's sarcoma, and the different radiological phases of this type of fracture, they stress the necessity for a maximum effort to demonstrate the key element in the diagnosis: the cortical fissure. The latter is often minimal, at the limit of visibility and developing late. Thus repeated examinations and the use of special radiological techniques are necessary.


[Traumatic carotid-jugular fistula (author's transl)].

The authors report a case of complex traumatic carotid-jugular fistula, and insist on the interest of strict identification of vascular injuries and their haemodynamic consequences, by angiographic study from upper thoracic aorta. Further, the post-operative examination permist verification of the vascular reconstitution.


[Carotid dolichosiphon. One case (author's transl)].

A report of the case of a 68 year old patient with a 9,5 cm long ectasia of the cisternal portion of the left internal carotid. On the basis of this case, the authors review the pathology due to such dolichomega-arteries and the aetiology of arteriectasia which are partly dysplasic in origin.


[Extraperitoneal appendicular calculi (author's transl)].

Two retrocecal and extraperitoneal appendix cases are showed. Atypical clinical signs, slow evolution, perforation and abscess were found. Radiological diagnosis is based by seeing the calculus and the appendix by means of barium enema. When appendix calculus is demonstrated and clinical signs are present, a surgical operation must be order urgently. Profilactic appendicectomy is recommended when no symptoms.


[An enormous gastro-intestinal hairball (author's transl)].

A case of a gastro-duodenal hairball is reported in a neurotic 19 year old woman. The case is remarkable because of the unusual length of the foreign body and the coexistence of two gastric ulcers which led to partial gastrectomy.


[Acute emphysematous cholecystitis. One case (author's transl)].

Acute emphysematous cholecystitis is a rare condition. Its preoperative diagnosis is based upon radiological studies which should include a film in the dorsal decubitus position, a lateral and a film in lateral decubitus with the ray horizontal. The presence of air within the gall bladder lumen; and in a part or all of the wall. Additional findings: the presence of air in the peribiliary space; the presence of gas within the biliary tract, rarely reported, is of special interest in the case reported here. Gangrenous cholecystitis must be differentiated essentially from: 1 degree an internal biliary fistula 2 degrees air in a neighbouring organ 3 degrees lipomatosis.


[Ureter opening into the seminal vesicle (author's transl)].

The authors present a case of ectopic opening of the left ureter into the seminal tract. This was a very young child (14 months). The diagnosis was made on intravenous pyelography on direct signs (opacification of the malformation). There was a wide communication between the latter and the posterior urethra as was shown on retrograde urethrocystography. The urinary tracts on the side of the lesion were very fine, and there was an outline of a very mildly functional kidney. Embryologically it is a case of absence of separation between the ureteral bud and the Wolffian canal.


[Pneumoperitoneum. A remarkable technique for its detection (author's transl)].

A study made in 30 cases indicated that, in contrast to current habits, the emergency erect plain film of the abdomen used to detect a pneumoperitoneum should be taken in expiration. A film in inspiration may be considered to be a supplementary view.


[Arteriography of the traumatised hand. Indications, methods and results on the basis of 150 investigations (author's transl)].

The authors review the indications of arteriography in trauma of the hand. The results are analysed and their value with regard to operative technique discussed. The method used is very simple. Study of the vascular distribution of the hand is essential both pre- and postoperatively.


A contraception record card for use in general practice.

This paper describes a contraceptive record card and flow sheet. The aim of the card is to produce better surveillance of contraceptive care by promoting the collection and array of important information for clinical decision-making.The purpose of this paper is to initiate the adoption of a standardized card for general use.


Looking after diabetics in general practice: a trainee project.

An audit of diabetics in one general practice indicates that diet did not play as full a part as expected in management. More than 10 per cent of patients cannot test their own urine properly. Management of the diabetics may be improved by a surgery organized especially for them.


The prognostic value of human placental lactogen levels in threatened abortion in general practice.

We report the first use of human placental lactogen as an indicator of the outcome of threatened abortion in general practice. The results were not found to be helpful in clinical management.


Whooping cough--a retrospective study of hospital admissions.

A retrospective survey was carried out on admissions to hospital for the complications of whooping cough. The number of admissions throughout a decade remained proportional to the total number of cases of whooping cough notified. Children under one year constituted 12.7 per cent of total notifications, but 57.3 per cent of hospital admissions. There were 12 deaths among 2,972 hospital admissions in the years 1965 to 1974; all were in children under 12 months, and ten were in babies under six months.


Primary care in Transkei.

A period of ten weeks working in an African hospital is described. The quality of service that can be given by British general practitioners in rural African hospitals is discussed and the educational aims of such a venture are explored. It is concluded that there is scope for such arrangements and that considerable mutual benefits may result.


Synthesis and analgesic activity of human beta-endorphin.

The solid-phase synthesis of human beta-endorphin is described. A yield of 32% is achieved based on starting resin. The synthetic product behaves as a homogeneous peptide in partition chromatography, paper electrophoresis, thin-layer chromatography, disc electrophoresis, amino acid composition, and a tryptic map. The synthetic beta h-endorphin possesses antinociceptive properties as estimated by the tail-flick, hot-plate, and writhing tests in mice. When applied centrally, beta h-endorphin is 17-48 times more potent than morphine. It is 3.4 times more potent than morphine when injected intravenously. The analgesic responses are blocked by the specific opiate antagonist, naloxone.


Synthesis of cephalotaxine esters and correlation of their structures with antitumor activity.

Twenty-two new esters of natural (-)-cephalotaxine with synthetic acids possessing widely divergent structural features have been synthesized. Murinichloroethyl carbonate (27) esters of cephalotaxine are the most active of this group; this activity is less than that of harringtonine and other naturally occurring cephalotaxine esters. Other synthetic esters exhibiting activity are methyl cephalotaxylfumarate (4) and the trichloroethyl carbonate of cephalotaxyl-L-mandelate (21). The specificity of this experimental tumor system apparently requires esters of (-)-cephalotaxine for tumor inhibition because methyl cephalotaxylitaconate (7b) prepared from the synthetic (+) enantiomer of cephalotaxine is inactive.


Antitumor agents. 21. A proposed mechanism for inhibition of cancer growth by tenulin and helenalin and related cyclopentenones.

Evidence is presented that sesquiterpene lactones or ketones containing the O=CC=CH2 moiety, e.g., tenulin and helenalin, alkylate the thiol group of reduced glutathione and L-cysteine in vitro. A proposal is offered that this mechanism of action is responsible for the observed potent in vivo antitumor activity of these agents in the Ehrlich ascites and Walker 256 carcinosarcoma and to a lesser extent in the P388 leukemic screen. Inhibition of tumor growth is thought to occur due to the O=CC=CH2 system alkylating by rapid Michael addition the SH biological nucleophiles of key regulatory enzymes of nucleic acid and chromatin metabolism. This proposition is in accord with the ability of these agents to inhibit DNA synthesis and gene activity of Ehrlich ascites cells.


Pyrimidinylpropenamides as antitumor agents. Analogues of the antibiotic sparsomycin.

A series of pyrimidinylpropenamides 9 and their oxidation products 10 was prepared, as analogues of sparsomycin (1), for antitumor evaluation. Syntheses involved condensation of the appropriate amino alcohol 5 with acid 8. The resulting sulfides 9 were then oxidized with NaIO4 or H2O2 to sulfoxides 10. Activity was studied in lymphocytic leukemia P-338 and KB cell culture. With the exception of the n-decyl analogue, all of the deoxygenated compounds 9 were inactive regardless of the stereochemical form. In the sulfoxide series 10, those compounds prepared with an L configuration at the asymmetric carbon were also inactive. The completely racemic sulfoxides, on the other hand, displayed substantial antitumor activity (ILS = 37-61% in P-388; ED50 = 1.2-2.4 mug/ml in KB) suggesting that both the presence of a sulfoxide moiety and a D configuration at the chiral carbon atom were structural requirements for a positive antitumor response. There appeared to be a large tolerance for the group substituted at the sulfoxide moiety, however.


Potential antitumor agents. Some sulfur-substituted derivatives of alpha- and beta-2'-deoxythioguanosine.

A series of ten S-substituted derivatives of the alpha and beta anomers (1a and 1b) of 2'-deoxy-6-thioguanosine has been prepared by S-alkylation of the parent nucleosides and/or by mercaptide displacement reactions on 6-chloro intermediates. Against L1210 murine leukemia all beta anomers were active but potency was reduced relative to 1b. Most S-alkyl alpha anomers were inactive in this test. Limited testing against P388 murine leukemia showed all alpha-anomer derivatives to be inactive but the beta anomers were more effective than the parent. S-Substitution sharply reduced acute toxicity in both series. In vitro DNA and RNA synthesis inhibition data are also reported. The antitumor activity of these derivatives and of the 2',5'-di-O-acetyl derivatives of 1a and 1b against lymphoid leukemia L1210 is reported. Some results with the lymphocytic leukemia P388 and an in vitro assay of the inhibition of nucleic acid synthesis are also given.


Ring D oxygenated Spirolactones. Characterization of human metabolic product of spironolactone.

15alpha-Hydroxycanrenone (1b) was prepared from canrenone (1a) by microbiological oxidation with a penicillium species. The product was identical with one obtained from the metabolism of spironolactone(3) in human. Oxidation of 1b with Jones regent furnished the corresponding 15-oxocanrenone (1d) which underwent base-catalyzed beta elimination to generate an alpha,beta-unsaturated cyclopentenone system. 15alpha-Hydroxycanrenone (1b) failed to show antimineralocorticoid activity at the screening dose of 2.4 mg while the oxo derivative 1d exhibited approximately 15% the activity of 3. Since the activity of canrenone is 38% that of spironolactone, introduction of the carbonyl group at the 15 position of canrenone resulted in a reduction in activity. This effect is opposite to that observed with 6-dehydroprogesterone.


Uptake and fate of water-soluble, nondegradable polymers with antiviral activity in cells and animals.

Poly(9-vinyladenine) and poly(1-vinyluracil) which are nondegradable, soluble polymers are taken up partially by mammalian cells grown in culture. The polymers remain associated with cells for several generations. In mice, after ip application, polymers slowly accumulate in liver, spleen, and thymus and remain there for as long as a month. Thus, these polymers which suppress the replication of murine leukemia viruses also accumulate in organs where the virus replicates. However, their antiviral activity does not reflect the amount of polymer found in these animal tissues. We propose that the polymers are gradually segregated into a group of cells or into subcellular organelles away from primary sites of virus replication. The results suggest that for a directly acting polymeric drug, a half-life over 24 h is without advantage.


Antagonists of slow reacting substance of anaphylaxis. Synthesis of a series of chromone-2-carboxylic acids.

A series of substituted chromone-2-carboxylic acids was synthesized and tested as antagonists of SRS-A induced contractions of isolated guinea pig ileum. This work led to the discovery of sodium 7-[3-(4-acetyl-3hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate (FPL 55712) which is the first reported specific antagonist of SRS-A. Some structural requirements for biological activity within this series are discussed.


Synthesis and central nervous system activity of quinazolones related to 2-methyl-3-(o-tolyl)-4(3H)-quinazolone (methaqualone).

A number of derivatives of 2-methyl-3-(o-tolyl)-4(3H)-quinazolone bearing new substituents on the 2-methyl group have been synthesized. It was established that most substitutions at this position reduce or remove the CNS depressant activity of methaqualone. From the series prepared only the 2-fluoromethyl derivative or certain isothiouronium salts, which could be hydrolyzed in vivo to the 2-mercaptomethyl derivative, showed activity of the same magnitude as methaqualone.


Potential long-acting anticonvulsants. 1; Synthesis and activity of succinimides containing an alkylating group at the 2 position.

The synthesis of succinimide derivatives in which alkylating groups have been attached to the 2 positions of the ring or to the para position of the 2-phenyl substituent is described. The alkylating groups used were (a) alpha-haloacetyl, (b) alpha-haloacetamido, (c) maleimido, and (d) maleamyl. These compounds were prepared as potential long-acting anticonvulsants. Several of these derivatives exhibited activity against metrazole-induced seizures comparable to phensuximde, The maleimide 16 and the bromoacetamido derivative 23 exhibited a duration of action of at least 3.5 h.


In vitro O-demethylation of the psychotomimetic amine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane.

The possible relationship between metabolism and psychotomimetic activity among the methoxylated 1-phenyl-2-aminopropanes led to our investigation of the in vitro O-demethylation of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (1, DOM, STP). Employing a sensitive and highly selective stable isotope dilution assay, we observed that rabbit liver homogenates biotransform the amine 1 to its 2-O-demethyl, 5-O-demethyl, and bis (O-demethyl) metabolite metabolites. Both monophenolic metabolites are enriched in their S enantiomers. The bis(O-demethyl) metabolite has structural, chemical, and electrochemical similarites to the sympatholytic agent "6-hydroxydopamine". The possible significance of metabolic O-demethylation in terms of the psychotomimetic properties of amine 1 is discussed.


Elucidation of the structure of the antineoplastic agents, 2-formylpyridine and 1-formylisoquinoline thiosemicarbazones.

The geometrical isomers of the antineoplastic agents 2-formylpyridine and 1-formylisoquinoline thiosemicarbazones were synthesized and their structure was studied by spectroscopic methods. It was found that the compounds previously described in the literature and tested for carcinostatic activity were isomers with E configuration which probably contained minor amounts of Z isomers.


Narcotic antagonists. Synthesis and evaluation of some subsituted 1,2,3,4,5,6-hexahydro-1,4:2,6-dimethano-3-benzazocines.

A seres of (+/-)-N-substituted 6-ethyl-or -methyl-8-hydroxy-1,2,3,4,5,6-hexahydro-1,4:2,6-dimethano-3-benzazocines has been prepared from 6 hydroxytropinone. The N-cyclopropylmethyl compounds 10a and 10b were found to be strong narcotic antagonists approximately equivalent to nalorphine. Only slight analgetic activity was found in any of these compounds including the two N-methyl analogues.


Dibenz[b,e]oxepinalkanoic acids as nonsteroidal antiinflammatory agents. 2. Dihydro-10-oxofuro-and -thieno[3,2-c][1]benzoxepin-8-acetic acids.

4,10-Dihydro-10-oxofuro[3,2-c][1]benzoxepin-8-acetic acid and 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid were evaluated in the carrageenan paw edema assay with the thieno analogue being ten times more active than the furano compound and 1.3. times more active than indomethacin. The therapeutic ratio (antiinflammatory activity/gastric irritation liability) of the thieno analogue was 25 times that of indomethacin.


Influence of zinc-ligand mixtures on serum zinc levels in rats.

The influence of various salts, chelates, and other complexes of zinc given by gavage on serum zinc levels in rats was studied. Serum zinc concentrations were determined over 6 hr after administration of zinc sulfate at doses of 5, 10, 20, 50, and 100 mg of zinc/kg. Serum zinc levels following doses of zinc salts and complexes were compared with those after zinc sulfate. Phytic acid, aminopolycarboxylic acids (including edetate disodium), and penicillamine significantly suppressed increases in serum zinc concentration. Some natural amino acid-zinc sulfate  mixtures (those with lysine, cysteine, glycine, and histidine) produced greater levels than the equivalent dose of zinc sulfate alone. Several thiocarboxylic acids, such as mercaptoacetic acid and thiosalicylic acid, also increased serum zinc concentrations. These observations form a basis for attempted modification of zinc absorption in other species.


Female and male medical students: differences in specialty choice selection and personality.

Sex differences in specialty choices, specialty beliefs, and personality characteristics of female and male medical students were analyzed. Subjects included 95 female and 166 male medical students from the University of Colorado School of Medicine and the University of California, San Diego, School of Medicine. Results from a personality measure, the Adjective Check List, and from measures of students' beliefs as to status, similarity-to-self, and social desirability of various specialties revealed significant differences between men and women on specialty choice, ratings of status and social attractiveness of the specialties, and personality characteristics. It appears that for female medical students specialty choices and general personality characteristics have changed to less traditional and stereotypic positions in the past few years.


Physician profiles in training the graduate internist.

Twenty-one members of a graduate internal medicine training program were studied to determine whether feedback of simple ambulatory practice profiles would prove valuable in their training program. Each physician was profiled every three months with regard to number of patients seen, average cost of ancillary testing per visit, average time per visit, and success at obtaining patient compliance. Physicians were randomly selected to receive or not receive profiles. Patients treated by both groups were similar. Variation among physicians' productivity and use of resources ranged from 250 percent to 1,200 percent. Distributing profiles did not statistically affect cost, time, or number of patients seen but did correlate with an increase in compliance. The marked variation observed in physician performance suggests that attention to style of practice during training could produce a significant increase in the amount of services delivered for each health dollar consumed.


A study of the recruitment of physicians into three northern New York counties.

Learning that 60 physicians had been recruited into three northern New York rural counties in recent years, the authors initiated a study to determine whether the number was correct, some characteristics of these new physicians, and the factors which had led them to settle in the area. After verifying 60 to be the correct number, the authors obtained information from 59 physicians, most of whom were interviewed in person or by telephone; local hospital administrators supplied information about the remainder. Four-fifths of the total group considered themselves to be specialists, either board certified or eligible. Half moved into the area with a guarantee of income for a period of years. The proximity of a university medical center was reported not to have played a significant role in relocation decisions. Within one year after the conclusion of this survey, six of the new physicians had left the area and one had moved to emergency room practice. Their average stay in the area had been 1.9 years. Thus, successful recruitment is only one step in the provision of rural health care.


University of Ottawa modified systems program.

A modified systems program has been developed at the University of Ottawa which incorporates advantages of the systems approach into whole-class teaching without increasing demands on staff. Basic science instruction is given in the first two years in preclinical departments. A total of 387 lecture and laboratory hours previously assigned to organ pathology and clinical departments are allocated to committees representing 12 systems. This program emphasizes pathology and pathophysiology and is supervised by a Coordinating Systems Committee. It begins in November of the second year and continues one year concurrently with instruction in clinical skills and basic science. A clinical clerkship occupies the final 18 months of the curriculum. Program effectiveness is measured by student evaluation of each lecture, multiple-choice examination, lecture monitoring, handout surveillance, and annual review of each system. This organization coordinates teaching of a single subject by many disciplines, and evaluation exposes flaws in teaching.


Consultations in internal medicine: a training program resource.

At the Milton S. Hershey Medical Center of the Pennsylvania State University an internal medicine consulting resident sees all medical consultation requests not directed to a specific subspecialty division. An audit of a nine-month experience on the consult service was compared with that of a general medicine ward service. The audit revealed that consulting residents were exposed to a quantitatively and qualitatively different spectrum of medical problems than were found on the ward service. The interdisciplinary aspects of the experience expand the consulting internist's fund of knowledge and complement outpatient exposure to other specialties, such as surgery and obstetrics-gynecology. Chief medical residents at 36 university medical centers were surveyed regarding the nature of the internal medicine consultation programs in their institutions. The survey indicated that half the programs were service oriented rather than educational and were not felt to be of profit to the medicine residents.


Interdisciplinary education in child abuse and neglect.

The increased need for professionals working with children and their families to understand, identify, and in some cases treat and follow up situations of child abuse and neglect has led to the offering of a structured graduate interdisciplinary course to students in various types of professional training. This initial effort represents an attempt not only to aid students in gaining insight into the dynamics of child abuse but also to encourage interdisciplinary communication among students from law, medicine, social work, education, and other fields which will hopefully continue into their professional life. Based on the experience accumulated from two offerings, a description is presented of the objectives, content, methodology, problems, and short-term evaluation of this course.


Electrical properties and active solute transport in rat small intestine. I. Potential profile changes associated with sugar and amino acid transports.

Addition of D-glucose to the mucosal fluid resulted in a significant depolarization of the mucosal membrane potential (V-m) in rat duodenum, jejunum, and ileum accompanied by an increase in the transepithelial potential difference (PDt). On the other hand, L-glucose did not induce PDt and Vm changes. Glycine applied from the mucosal side also induced Vm-depolarization and PDt-increment in the ileum. Phlorizin added to the mucosal fluid or ouabain added to the serosal fluid inhibited the sugar-dependent changes in PDt and Vm. According to the analysis with an equivalent circuit model for the epithelium, it was concluded that an actively transported solute induced not only a depolarization of the mucosal (brush border) membrane but also a hyperpolarization of the serosal (baso-lateral) membrane of an epithelial cell, so that the origin of solute-induced PDt changes should be attributed to changes in emf's at both membranes. The hyperpolarization of the serosal membrane in the presence of an actively transported solute was attributed to a mechanism of serosal electrogenic sodium pump stimulated by the increase in the extrusion rate of Na+ co-transported into the cell with sugar or amino acid.


Electrical properties and active solute transport in rat small intestine. II. Conductive properties of transepithelial routes.

The transepithelial resistance, the cell membrane resistance and the ratio of resistances of the serosal (baso-lateral) to the mucosal (brush border) cell membrane were measured in rat duodenum, jejunum and ileum by means of microelectrode techniques. These measured values were not affected in the presence of actively transported solutes in the mucosal bathing fluid. Contribution of an electrical conductance through the extracellular shunt pathway to the total transepithelial conductance was quantitatively estimated using an electrically equivalent circuit analysis. These values estimated in respective tissues of small intestine were approx. 95% of the total transepithelial conductance, remaining unaffected by an active solute transport. From these data, the changes in emf's of the mucosal and serosal membrane induced by D-glucose or glycine were separately evaluated.


Comparative study of the thiourea carrier in erythrocytes.

A densimeter technique was used to measure the rate of exit of thiourea from erythrocytes of various species of mammals. The cells were first equilibrated with a 200 mM thiourea solution in 1% NaCl. An aliquot of these cells was added to 1% NaCl containing 4.6-23.1 mM thiourea. Facilitated diffusion was demonstrated in each case. Using exit times or initial rates, calculations of half-saturation constants (phi) in mM and maximum transport rates (K) in isotones per min were made by three different methods. The following values were obtained: human-phi=60, 42, 35; K=1.2, 2.9, 0.9; rabbit-phi=46, 33, 32; K=0.8, 2.1, 0.8; mouse-phi=46, 40, 30; K=3.4, 8.5, 3.2; rat-phi=65, 42, 23; K=6.1, 15.3, 3.7; ox-phi=107, 63, 88; K=0.6, 1.4, 0.4; sheep-phi=56, 38, 56; K=0.9, 2.2, 0.6; and pig-phi=110, 64, 49; K=1.6, 3.6, 1.1.


Observations on the regulation of cell volume and metabolic control in vitro; changes in the composition and ultrastructure of liver slices under conditions of varying metabolic and transporting activity.

Liver slices incubated at 1 degree C underwent swelling of both cellular and intercellular compartments, as judged by electronmicroscopy. The ultrastructure showed marked changes, including disorganization of the cytocavitary network and plasma membrane and alterations of mitochondria. Restoration of metabolically favorable conditions (oxygenated medium at 38 degrees C) caused a nearly complete recovery of ultrastructure closely associated with extrusion of water; measurements of inulin space and electronmicroscopy both indicate a recovery of cell volume, with intercellular spaces remaining somewhat expended. The fluid lost was a roughly isotonic solution of Na+ and Cl-, while K+ was reaccumulated in exchange for Na+. Cyanide prevented recovery. Ouabain and oligomycin each partially prevented fluid extrusion, but had little effect on ultrastructural recovery except to induce intracellular vesicles containing particles of thorium dioxide derived from sinusoidal spaces. The vesicles were, however, markedly different in form with each inhibitor. There are, thus ouabain-sensitive and insensitive components of volume regulation; the former appears to depend on the coupled transport of Na+ and K+ and the latter, we suggest, on a secretion of Na+ and Cl- into vesicles which release their contents into the bile canaliculi by an oligomycin-sensitive mechanism. Mitochondria showed conformational changes between orthodox and condensed forms, but these could not be directly related to tissue energy states; the numbers of mitochondrial dense granules bore a closer relation to tissue ATP.


Tracer flux ratios: a phenomenological approach.

The kinetic behavior of tracer flows across epithelial membranes is examined and attention is called to the condition under which unidirectional tracer flows may be described by first order rate equations. It is shown that the first order nature of the tracer rate equation when combined with simple thermodynamic constraints on tracer flow yields a relation between the ratio of the unidirectional rate coefficients and thermodynamic driving forces. The form of this relation is examined for the case of simple diffusion and in the presence of coupled process.


Cation permeability ratios of sodium channels in normal and grayanotoxin-treated squid axon membranes.

Permeabilities of squid axon membranes to various cations at rest and during activity have been measured by voltage clamp before and during internal perfusion of 4 X 10(-5) M grayanotoxin I. The resting sodium and potassium permeabilities were estimated to be 6.85 X 10(-8) cm/sec and 2.84 X 10(-6) cm/sec, respectively. Grayanotoxin I increased the resting sodium permeability to 7.38 10(-7) cm/sec representing an 11-fold increase. The potassium permeability was increased only by a factor of 1.24. The resting permeability ratios as estimated by the voltage clamp method before application of grayanotoxin I were Na (1): Li (0.83): formamidine (1.34): guanidine (1.49): Cs (0.87): methylguanidine (0.86): methylamine (0.78). Grayanotoxin I did not drastically the resting permeability ratios with a result of Na (1): Li (0.95): formamidine (1.27): guanidine (1.16): Cs (0.47): methylguanidine (0.72): methylamine (0.46). The membrane potential method gave essentially the same resting permability ratios before and during application of grayanotoxin I if corrections were made for permeability to choline as the cation substitute and for changes in potassium permeability caused by test cations. The permeability ration choline/Na was estimated to be 0.72 by the voltage clamp method and 0.65 by the membrane potential method. Grayanotoxin I decreased the ration to 0.43. The permeability ratios during peak transient current were estimated to be Na (1): Li (1.12): formamidine (0.20): guanidine (0.20): Cs (0.085): methylguanidine (0.061): methylamine (0.036). Thus the sodium channels for the peak current are much more selective to cation than the resting sodium channels. It appears that the resting sodium channels in normal and grayanotoixn I-treated axons are operationally different from the sodium channels that undergo a conductance increase upon stimulation.


Comparative analysis of the hindgut in two species of protura (Insecta, Apterygota).

The proturan hindgut consists of two regions, with different ultrastructure. The anterior region is organized into three primary longitudinal folds alternating with three smaller, secondary ones. In Acerentomon each primary fold in a cross section contains one or two cells showing all the structures which are involved in water reabsorption. The cells of the secondary folds do not seem engaged in a similar function. In Eosentomon the primary folds present a more complicated organization. Each of them consists of one central cell concerned with reabsorption and two lateral ones. Beneath these cells, on both sides of the fold there is a longitudinal muscle fiber. The posterior region of the hindgut does not seem capable of modifying the gut contents.


Ultrastructure and histochemistry of the supportive structures associated with the radula of the slug, Limax maximus.

The odontophore and connective tissue-filled portion of the radular sac (called the "collostyle") of the slug, Limax maximus, were examined by light and electron microscopy. While both of these structures grossly resemble vertebrate cartilage, neither is composed of a type of tissue with the microscopic appearance and histochemical properties of cartilage. The roughly U-shaped odontophore possesses a thin capsule composed of connective tissue. The parenchyma of the odontophore consists of modified muscle cells which are organized into irregular groups by incomplete trabeculae composed of conventional muscle cells. The odontophoral cells are variable in size; they contain glycogen-filled "cores" as well as bundles of peripherally located filaments resembling myofilaments; and they are innervated like muscle cells. The nuclei of the cells are located eccentrically in the glycogen-filled portions of the cells and typically contain prominent nucleoli. The nuclei are surrounded by multiple small Golgi complexes and pleomorphic dense bodies resembling lysosomes. The extracellular matrix of the odontophore is very sparse and contains glycogen and fibrillar material but no histochemically demonstrable acidic mucosubstances. The collostyle consists of a gelatinous type of tissue somewhat like vertebrate mucoid connective tissue. The abundant extracellular matrix contains cross-banded filaments, a flocculent material disposed in wavy indefinite strands, and small electron-dense particles. The matrix contains histochemically demonstrable neutral and weakly acidic mucosubstances. The cell population of the collostyle includes solitary muscle cells and fibrocytes containing large quantities of glycogen.


Tergal modifications associated with abdominal glandular cells in the Blattaria.

Tergal abdominal modifications of 30 species of Blattaria (Dictyoptera) were studied by means of histological scanning electron microscopy techniques. Despite marked anatomical diversity of the glands, only a few basic types of cells are present. Male tergal glands which are involved in sexual behavior generally have glandular cells filled with electron transparent vacuoles (type 3a) and those with dense myeloid secretion (type 3b); in addition some have large cells without ducts, not in contact with the cuticle and surrounded by other cells (type 2). External setae, usually associated with these structures, are mechano-receptors or mechano-chemoreceptors. Glands not involved in courtship (e.g., defensive glands) usually have large glandular cells with a ductule that reaches the end apparatus secreted by the glandular cell itself (Type 3) but lack types 2, 3a, and 3b. Species which do not have distinctive tergal modifications may have concentrations of microscopic pores or openings associated with glandular cells on certain segments. The chemistry of the secretions produced by tergal glands is unknown for most species. This paper emphasizes the need for behavioral and biochemical studies to elucidate the biological significance of cockroach tergal glands.


The fibrocartilage skeleton and related structures of the ventral pouch of balaenopterid whales.

The mandibular symphysis of rorqual whales, whales of the genera Megaptera and Balaenoptera, is characterized by a Y-shaped fibrocartilage structure that lies in the substance of the muscular ventral pouch of these animals. The stem of the structure joins with the symphysis and is usually indicated externally by an unfurrowed median strip of blubber that has been called the "cutwater" by earlier writers. The arms of the Y pass back and are superficially indicated in all rorqual whales as a ridge running parallel to the rami of the mandibles. This fibrocartilage skeleton of the pouch is most closely related to the mylohyoid muscle. The function of the fibrocartilage Y is probably linked with the jaw mechanics of these whales, but its precise function is otherwise not known.


Sense organs on the antennal flagellum of psocids (Insecta, Psocoptera).

The sense organs on the antennal flagella of five species of winged psocids belonging to two families of Psocoptera, Psocidae and Leptopsocidae, have been examined, All agree in possessing tactile hairs, thick-walled chemoreceptors and long, porous chemoreceptors. Thin-walled chemoreceptors were identified in all species except Metylophorous novaescotiae. Coeloconic chemoreceptors were present in all species except Echmepteryx hageni. Campaniform sense organs were found only in Metylophorus novaescotiae and Psocus leidyi.


Structural correlates of forelimb function in fur seals and sea lions.

Dissections, manipulation of ligamentary preparations, analysis of limb proportions, and quantitative aspects of forelimb myology are used to correlate forelimb morphology in fur seals and sea lions (sub-family Otariinae) with previously published data as to their locomotor function (English, '76a). Comparisons to structure and function in generalized fissiped carnivores are then used to elucidate locomotor adaptations in fur seals and sea lions. Unique features of forelimb function during swimming in these pinnipeds include the amounts of abduction-adduction and rotary movements used. Modifications of the size, attachments and fasicle architecture of the muscles and the structure and range of possible movement of the joints suggest that in fur seals and sea lions these movements (1) take place about the glenohumeral (shoulder) joints, (2) that the movements are probably finely controlled, and (3) that they contribute to the generation of massive forward thrust via the cooperative activity of muscles capable of generating large amounts of force throughout the range of movement. Recovery movements occur through a similarly large range, and modifications of forelimb anatomy either to minimize or overcome water resistance are noted. The adaptive significance of these modifications is interpreted as allowing fur seals and sea lions to swim at speeds necessary to feed on the fast swimming prey presumably abundant in their adaptive zone.


Initiation of the actinotrichial development in the early fin bud of the fish, Salmo.

Ultrastructural analysis of initial development of actinotrichia, the skeleton anlage of the pelvic fin buds, was performed on the rainbow trout, Salmo gairdneri. It shows that the first actinotrichial rudiments appear in the subepidermal space of the pseudoapical cap. No mesenchymal cell bodies or their filopods are present. Hyaloplasmic protrusions of the basal epidermal cells are seen in the subepidermal space, limited by a dermoepidermal boundary reduced to a discontinuous thin adepidermal lamina without a collagenous layer. These morphological data suggest that the epidermal pseudoapical cap probably initiates the development of actinotrichia. Later, mesenchymal cells invade the subepidermal space and are probably involved in the further growth of actinotrichia.


Development of bioluminescence and photophores in the midshipman fish, Porichthys notatus.

Correlative studies of luminescent responses, light and electron microscopy of Porichthys photophores during development were conducted. The photophores differentiate as an outgrowth of the basal cell layer of the epidermis, from which they delaminate into the dermis. Reflector cells are formed from dermal fibroblasts. Early photophore cells differentiate into three distinct cell types: photocytes, supportive and lens cells. Elaborate profiles of endoplasmic reticulum, Golgi bodies and vesicles suggest intense secretory activity in the early photocytes, while supportive and lens cells differentiate by two different transformations of the microfilament arrangement of primordial photophore cells. Luminescent capabilities of Porichthys photophores arise in two successive phases: (1) an aneural phase during which photophores become fluorescent, photocytes are in process of maturation and respond only to chemical stimulation and (2) a neural phase in which photophores luminesce upon electrical and pharmacological stimulation and are densely innervated with terminals showing relatively narrow neurophotocyte gaps. The presence of neural elements intimately associated with the early photophore anlagen suggests the involvement of the peripheral nervous system in the formation of photophores.


Synaptic organization of the nucleus rotundus in some teleosts.

Synaptic organization of the nucleus rotundus was studied with the electron microscope in three teleost species belonging to the same order. In spite of the different histological organization (non-laminated, incompletely laminated, and laminated), the same kinds of axon terminals (S and F) are observed in all species. A fibrous layer which is clearly formed only in the laminated nucleus is composed of F1 terminals and dendrites from a layer of small cells. The same kind of synapses formed between F1 terminals and dendrites of small cells are also found among glomeruli in the non-laminated and incompletely laminated nuclei. The main constituents of glomeruli are S and F2 terminals and dendrites of large cells in the non-laminated and incompletely laminated nuclei, and are S terminals and star-like structures which correspond to the tips of the dendrites of large cells in the laminated nucleus. The star-like structure contains numerous mitochondria and clusters of small polymorphic vesicles. Some of the vesicles aggregate at thickened cell membranes of the structure as in presynaptic dendrites.


Fine structure and role in behavior of sensilla on the terminalia of Aedes aegypti (L.) (Diptera: Culicidae).

The terminalia of male and female Aedes aegypti (L.) bear numerous hairs of various shapes and lengths, all of which are mechanoreceptors. Each hair is innervated by one bipolar neuron which contains ciliary rootlets, two basal bodies, and a region assuming the structure of a non-motile cilium. At the distal tip of the dendrite is a tubular body, a characteristic of cuticular mechanoreceptors. Covering the outer dendritic segment is a cuticular sheath which ends proximally in a net-like felt-work and distally attaches to the hair base. Each hair sensillum has two sheath cells. Presumed efferent fibers are associated with the sheath cells. On the insula of the female terminalia are a few campaniform sensilla, the domes of which are raised into small pegs. The sensilla on the terminalia function in copulation and oviposition and probably in warning. A sequence of neurological events is traced for copulation an oviposition. Other cuticular structures, viz., scales, microtrichia, acanthae, and aedeagal spines, which occur on the terminalia are not innervated.


Hepatotoxicity in Wistar rats following chronic methotrexate administration: a model of human reaction.

The effects of ip administration of methotrexate (MTX) on 3-month-old male Wistar rats were studied. We administered log doses from 125 to 2,000 mug/kg, five times per week for as long as 24 months. The massive doses were promptly lethal, and most rats receiving 500 mug or more/kg died within a few weeks. Severe hematopolietic depression and ulcerative gastrointestinal lesions were observed. Truly chronic intoxication was achieved with the lesser doses. Rats in this category developed serious liver damage, namely, varying degrees of fatty metamorphosis, necrosis, atrophy of hepatic cords, and fibrosis. Hematopoietic depletion occurred in the spleen and bone marrow. Hemosiderosis was prominent in the spleen and liver. Pulmonary lesions--chiefly emphysema, occasionally fibrosis--were found less consistently. These studies demonstrated the ability of MTX to induce lesions, most consistently hepatic, in the Wistar rat, and thus have provided an animal model to evaluate protective measures.


Cell-surface changes in Ricinus communis toxin (ricin)-resistant variant of a murine lymphoma.

A variant of the murine lymphoma cell line BW5147 that was 250 times more resistant than the parent to Ricinus communis II agglutinin (RCAII, ricin) toxicity (measured in the absence of serum) was selected by repeated exposure of cells to increasing concentrations of the lectin. Quantitative binding of the lectin, however, was decreased by only 30-40% in the variant. In contrast with several reported lectin-resistant variants, most surface glycoproteins on the parental and variant cell surfaces were similar, as judged by electrophoresis after lactoperoxidase-catalyzed iodination and RCAI-affinity chromatography. Surface studies showed that an RCAI- and RCAII-binding protein of about 80,000 daltons on the surfaces of parental cells is altered on the variant cells to a form with a lower apparent molecular weight. We suggested that this protein is important for entry of RCAII molecules in parental cells, but that its altered form on the variant cells no longer mediates efficient RCAII uptake, thus imparting toxin resistance. In addition, a protein of approximately 35,000 daltons, which does not bind RCAI, is weakly lactoperoxidase-iodinated on parental but not variant cells.


Lack of growth of a pregnancy-dependent mouse mammary tumor (TPDMT-4) in the absence of pituitary hormones.

Mammary tumors of line TPDMT-4, established in DDD mice, were characterized by growth during pregnancy and regression after parturition; this resulted in higher growth peaks in subsequent pregnancies in breeders and no growth in virgins. The effect of hypophysectomy on tumor growth in mice given 17beta-estradiol (E) and progesterone (P) or deoxycorticosterone acetate (DCA) was investigated. Growth of cancers occurred in E+P- and E+DCA-treated virgins, but not in cholesterol-treated virgins. Tumors did not grow to palpable sizes in cholesterol-, E+P-, and E+DCA-treated hypophysectomized virgins; this indicated that pituitary hormones were essential for tumor growth. Impalpable cholesterol-treated, 5 of 10 E+P-treated, and 3 of 6 E+DCA-treated hypophysectomized animals. The neoplasms showed ductal and tubular structures that were lined by a single layer of well-differentiated buoidal epithelium, which suggested that the tumor line might be derived from ductal cells.


Cocarcinogenic effects of n-alkanes and ultraviolet light on mice.

A comparison was made of the effects of repeated topical applications to mice of three n-paraffins (n-decane), n-dodecane, and n-tetradecane) on the carcinogenic potential of UV light at three wavelength regions: 254 nm, 290-320 nm, and greater than 350 nm. All three n-alkanes had a cocarcinogenic effect at 254 nm, whereas only n-dodecane was effective from 290 to 320 nm. Radiation at wavelengths longer than 350 nm, generally considered noncarcinogenic, produced tumors on the backs of mice treated with n-decane or n-tetradecane.


Effect of age, sex, and intestinal flora on the induction of colon tumors in rats.

Germfree and conventional Sprague-Dawley rats were assessed for their susceptibility to intrarectally injected N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N-methyl-N-nitrosourea (MNU). Adenocarcinoma of the colon was induced in germfree and conventional rats by both MNNG and MNU. The colons of germfree rats were more susceptible to the direct-acting carcinogens, as manifested by earlier morbidity and development of colon tumors (50% tumors within 30-35 wk), than were those of conventional rats (50% colon tumors within 48-50 wk). Germfree and conventional male rats were more susceptible to the carconogens than were their female germfree and conventional counterparts. Young (30 days old at the start of the experiment) germfree rats developed colon tumors more quickly (15-20 wk) than did older (60 days) germfree rats after intrarectal injections of MNNG. No colon tumors were observed in germfree and conventional rats after 75 weekly intrarectal injections with a buffer. Transplantation of an adenocarcinoma induced with MNU in a female rat to germfree and conventional rats showed that it was easily transplantable, required no immunosuppression, and had essentially the same morphologic characteristics as did the primary tumor.


Determination of enantiomeric homogeneity (optical purity) of cyclophosphamide by nuclear magnetic resonance spectroscopy.

The enantiomeric homogeneity of resolved samples of the chiral anticancer drug cyclophosphamide was evaluated directly by 1H and 31P nuclear magnetic resonance spectroscopy with the use of the optically active shift reagent tris-[3-(trifluoromethylhydroxymethylene)-d-camphorato]europlum(III). These measurements, in concert with optical rotatory dispersion spectroscopy, established that, for optically pure cyclophosphamide, [alphaD] = 2.3 +/- 0.2 degrees.


Superoxide dismutase activity of Ehrlich ascites tumor cells.

A crude extract of Ehrlich ascites tumor cell homogenate was found to contain three distinct bands of superoxide dismutase activity by polyacrylamide gel electrophoresis. Activity bands migrated approximately the same distance and were inhibited by cyanide ions. Isolated mitochondria produced two bands of activity that were also inhibited by cyanid. Ethanol-chloroform treatment of the homogenate had no observable effect on these bands of activity, which suggested that the cyanide-insensitive mitochondrial superoxide dismutase activity in these malignant cells was either present in concentrations below detectable levels or completely absent. Normal liver was used as a control for the detection system.


Retarded growth of lymphoma in immunodepressed mice.

Lymphoma cells were inoculated iv into normal and immunodepressed mice. In most instances the immunodepressed animals survived longer than their normal counterparts. This was true both with athymic and thymectomized animals that had been lethally irradiated and reconstituted with syngeneic bone marrow. The route of administration was critical, since increased survival of immunodeficient animals was not observed when the lymphoma cells were injected ip.


Chromosomal locations of satellite DNA in the MSWBS ascites tumor cell line.

In situ hybridization of mouse satellite complementary RNA to the chromosomes of the mouse ascites tumor line MSWBS revealed that the distribution of satellite DNA sequences paralleled the location of constitutive heterochromatin as defined by the C-banding technique.


Activation of intracisternal A particles in mouse liver by diethylnitrosamine.

Livers of 6- to 7-week-old male C3H/He, CBA, A, and BALB/c mice were examined by electron microscopy for the presence of intracisternal A particles (ICAP) after administration of diethylnitrosamine (DEN) in drinking water. In control mice, ICAP were extremely rare; they were found in the livers of only 2 mice (strains C3H/He and A; none in the other strains). By contrast, the treatment of mice with DEN greatly enhanced the appearance of ICAP in the liver cells of all strains. Within 2 weeks of the treatment, ICAP were found in 8-26% of liver cells examined in all mice and the number of ICAP/cell ranged from 3 to 12. Aside from mild disorganization of the rough endoplasmic reticulum, such as segmentation and vesiculation, liver cells of carcinogen-treated mice showed none of the consistent abnormalities that characterize the appearance of ICAP. The reactivation of ICAP (which are usually suppressed in adult mice) by DEN may become a useful marker for analysis of the sequential alterations of the liver that lead to the development of hepatoma during carcinogenesis.


Cerebellar gliomas in children.

We studied the relationship of histologic features to survival in a population of 132 children with cerebellar gliomas (excluding medulloblastomas). These children had their initial tumor operation at The Children's Hospital Medical Center of Boston between 1l927 and 1968. A classification system that accentuates differences in survival was derived on the basis of clustering of histologic features and survival. This division was supported by the existence of differentially distributed symptoms and signs and by differences in resectability. The two major subgroups of cerebellar gliomas had different patterns of clinical characteristics. Cerebellar glioma A had any of the four histologic features of microcyst, leptomeningeal deposit, Rosenthal fiber, or focus of oligodendroglia; children with glioma A had a 10-year survival rate of 94%. Glioma B, encompassing the histologic features of perivascular pseudorosette, high cell density, necrosis, mitosis, and calcification, was clearly defined but histologically less uniform; children with glioma B had a 10-year survival rate of 29%. These two groups accounted for 90% of the cerebellar gliomas in childhood.


Secular trends of cerebellar gliomas in children.

Temporal changes in the histologic composition of cerebellar gliomas were examined in a population of 132 children operated on between 1927 and 1968 at The Children's Hospital Medical Center of Boston. Linear trends with time were examined for clinical features, histologic features, and tumor types. We found evidence of an increasing occurrence of glioma A and its associated features during the 41-year study period. This tumor type is associated with a good prognosis and is histologically well defined. Glioma B, a tumor type associated with a poor prognosis, was relatively stable with respect to time and, therefore, differed markedly from glioma A. Foci of oligodendroglia, a glioma A feature, clustered by year of surgery within a relatively short time span. This feature had a survival rate and a male sex proportion quite different from those of the other histologic features investigated.


Immunochemotherapy of malignant melanoma with chlorambucil-bound antimelanoma globulins: preliminary results in patients with disseminated disease.

Thirteen consecutive patients with inoperable recurrent malignant melanoma were treated by immunochemotherapy with the use of chlorambucil noncovalently bound to goat or rabbit antihuman melanoma globulins. The next consecutive 11 patients fulfilling the criteria for admission into this study were treated with chemotherapy only, i.e., dimethyltriazenoimidazole carboxamide (DTIC). Follow-up was for a minimum of 29 months or until death. Two patients showing an objective response to immunochemotherapy had disease confined to lymph nodes and cutaneous sites; 5 others showed stabilization of cutaneous, nodal, and visceral disease, and 6 patients showed progression of their disease. The median survival of the responders and stabilizers was 20 months, but only 3.5 months for patients with disease progression. None of the 11 patients treated with DTIC had objective tumor regression, and all died within 11 months of the start of treatment with a median survival of 3 months. Immunochemotherapy significantly prolonged the survival compared to that in the DTIC-treated group (P less than 0.05). No hematologic or renal toxicity was detected after immunochemotherapy, but 2 patients in this group developed anaphylactic reactions. Skin reactivity tests to dinitrochlorobenzene and purified protein derivative were of no prognostic value


A new class of infectious agents detectable by the production of chorioallantoic membrane lesions by human lymphoblastoid cell lines and their culture supernatants.

Intravenous injection of cells and their tissue culture supernatants (CS) from human lymphoblastoid cell lines (LCL) induced the formation of lesions on the chorioallantoic membrane (CAM) of the chicken embryo. Injection of cells and CS from non-LCL and normal human lymphocytes induced few or no lesions. Irradiated chick embryos were more sensitive to lesion formation than were nonirradiated embryos. The log10 CAM lesions induced in irradiated (500 rads) embryos were a linear function of the log10 cells (from LCL) in the inoculum; the slope was 1.0, within experimental error. The formation of CAM lesions did not depend on the presence of Epstein-Barr virus (EBV) since lesions were also induced by cells and extracts derived from EBV genome-free LCL. Lesion-inducing activity associated with CS was filterable through 0.22-mu filters, sedimented at 78,000 x g, and sensitive to inactivation by heat (56 degrees C for 30 min), UV irradiation, chloroform, sera from chickens immunized against CS, and certain human sera. Lesion-inducing activity associated with cells and extracts was resistant to 5,000 rads of gamma-radiation. B2/B2 embryos (the B locus is the major histocompatibility locus of chickens) were more sensitive to lesion formation than were B15/B21 and outbred embryos; this suggested a genetic influence on lesion formation. Our data suggest that the irradiated chicken embryo may be a highly sensitive and useful means for the detection of an unidentified or unknown agent or agents that may play an important role in human oncogenic lymphocyte transformation or might interact with transforming viruses.


Influence of renal insufficiency on levels of serum ribonuclease in patients with multiple myeloma.

Serum RNase levels were measured in 34 patients with multiple myeloma and compared with 51 normal controls and 28 non-myeloma patients on chronic hemodialysis. Nineteen of the myeloma patinets with creatinine clearance (CCr) greater than 50 ml/minute had mean serum RNase levels that were statistically indistinguishable from those of the normal controls. The 15 myeloma patinets with CCr less than 50 ml/minute had mean RNase levels much higher than normal controls or myeloma patients with normal renal function. Patients without myeloma but on hemodialysis for chronic renal failure of varied etiologies had markedly elevated serum RNase levels. A strong correlation between RNase levels and renal insufficiency, as measured by CCr, has thus been demonstrated. In addition, case histories of 5 representative myeloma patients were analyzed in greater detail; they illustrated the rise and fall of RNase levels as a function of the status of their renal insufficiency, regardless of the extent of the underlying myeloma. We concluded that the serum RNase level was an indicator of renal function, and was not a biomarker either for the presence or extent of the plasma cell tumor.


Inhibition of DNA synthesis of synchronized RSa cells by human leukocyte interferon.

A human leukocyte interferon preparation suppressed DNA synthesis and subsequent mitosis of synchronously growing virus-transformed human RSa cells. DNA synthesis was inhibited completely when interferon was added to cell cultures in late G1 phase, but was not so inhibited when interferon was added in G1/S boundary phase. Overall protein synthesis was reduced only slightly by interferon treatment. The findings suggested that critical events leading to the inhibition of DNA synthesis and subsequent mitosis by interferon action take place in late G1 phase or S phase.


Leukocyte migration studies in gastric cancer detection: an approach toward improved specificity and sensitivity.

Peripheral blood leukocytes from patients with gastric cancer and various other malignant and nonmalignant diseases and peripheral blood leukocytes from apparently healthy volunteers were tested in the leukocyte migration inhibition test with the use of 4-5 different 3 M KCl extracts of gastric cancer tissue. An operational criterion for defining sensitization of patients' leukocytes was developed; i.e., evidence in an individual sample of leukocytes of either decreased or increased migration areas (migration index less than or equal to 0.79 and larger than or equal to 1.20, respectively) with 3 or more antigen extracts. With this as an indicator of sensitization, it was found that 91% of patients with gastric cancer (39/43), comparto 5% (5/94) and 3% (1/32) of patients with nonmalignant, nongastric diseases and normal controls, respectively, were reactive. Patients with various nongastric cancers were sensitized in 36% (49/135) of cases. Gastritis and gastric, as well as duodenal, ulcer did not influence the reactivity of patients' leukocytes, but considerable sensitization was found in patients with atrophic gastritis or intestinalization. When classified in the usual manner, i.e., by considering the reaction with individual tumor extracts, the specificity and the sensitivity of the test was markedly diminished: More false negative determinations were found in the group of gastric cancer patients, and the percentage of false positives in the group of nonmalignant diseases increased. The results gave evidence of tumor-associated antigens in gastric cancer patients, against which the host elicited a cellular immune response. The high incidence of positive reactivity of leukocytes from patients with gastric cancer, together with the considerable cross-reactivity of leukocytes from patients with nongastric cancer, pointed to the expression of antigens with organ-related and widespread specificities.


Marital status and incidence of ovarian cancer: the U.S. Third National Cancer Survey, 1969--71.

As determined in the U.S. Third National Cancer Survey, 1969--71, the incidence of ovarian cancer was 60-70% higher in women who had never married than in those who had. This relationship was present in both whites and blacks and in all age groups over 25 years. Among ovarian epithelial tumors, those for which the incidence rates between never-married and ever-married women differed most were endometrioid and clear cell tumors. The incidence of tumors of germ cell and sex cordmesenchyme origin, however, showed no relationship to marital status.


Investigations of cigarette smoke dosages in inhalation experiments with Syrian hamsters. I. Concentration of cigarette smoke in the inhalation chamber and of carbon monoxide in the blood.

We tested 20 different smoke inhalation machines and determined that 60% of the gas phase and 40% of the total paritulate matter reached the inhalation chamber; the remainder was lost in the exhaust gases. After determining these concentration percentages, we were able to calculate precisely the dosage of each puff of smoke administered to Syrian hamsters in our smoking machine. We also determined that the CO-Hb content in the blood of the hamsters rose to 60%; this CO-Hb value was a limiting factor for time of exposure to smoke, since too-high concentrations of CO-Hb would have killed the animals. On the basis of these results, we concluded that the animals should be exposed as long as possible to attain a high dose of smoke, but because of toxic effects the exposure time should not exceed 20 minutes, and the CO-Hb content should not exceed 60%.


Investigations of cigarette smoke dosages in inhalation experiments with Syrian hamsters. II. Uptake of cigarette smoke by the animals; comparisons of the influence of the gas phase and the whole smoke of different cigarettes.

An increased CO2 content (CO2 enrichment) in the smoke-air mixture was measured in an inhalation chamber containing Syrian hamsters. Since these additional CO2 concentrations originated from the animals' expiratory air, the level of CO2 (CO2 enrichment) was considered a function of the respiratory capacity. Results obtained with this method of characterizing the respiratory behavior of hamsters in inhalation experiments led us to conclude that the vapor phase of cigarettes reduced respiration up to 45% and the whole smoke, up to 60%. Qualitative and quantitative differences in the composition of the vapor phase and particulate phase as offered in animal inhalation experiments for comparing different cigarettes did not induce measurable differences in the respiratory behavior. Therefore, such inhalation experiments were found to be suitable for comparing the relative effects of different cigarette types. Estimations on the inhaled amounts of TPM led to results that were similar to those obtained in experiments with radioactively labeled smoke.


Cellular quantitation of in vivo effects of 1-beta-D-arabinofuranosylcytosine on leukemia L1210.

We derived a cellular model for the use of the cytidine analogue 1-beta-D-arabinofuranosylcytosine (ara-C) against L1210 leukemia in vivo from dose- and time-survival studies. We employed a quantitative assay for leukemia colony-forming cells to construct dose- and time-survival curves for single, divided, and infused doses of ara-C. Time-survival curves for a large dose range of ara-C indicated not only cell killing but also progression delay effects in vivo. Divided dose studies showed the extent of cell killing (optimum effect) to be dependent upon both the dose and the interval of time between administration of the drugs. When the drug was given as an infusion, the extent of cell killing was as great as that produced by the best fractionation schedule, an effect which was verified in terms of therapeutic efficacy in leukemic mice.


Response of transplanted AKR leukemia to combination therapy with amphotericin B and 1,3-bis(2-chloroethyl)-1-nitrosourea: dose and schedule dependency.

A number of different amphotericin B (AmB)-1,3-bis(2 chloroethyl)-1-nitrosourea (BCNU) treatment regimens were evaluated with our model of transplantable AKR leukemia. We found that dose levels and treatment schedules were critical in determining the number of survivors. A 4-day treatment regimen of 0.5 mg AmB/mouse on days 1, 2, 3, and 4 and 0.2 mg BCNU/mouse on day 4 was found to be the most effective and has been chosen as our standard regimen. The efficacy of the treatment regimen depended on the presence of a large tumor burden, and the response was abolished when the mice were preirradiated or treated with the immunosuppressive agent, cyclophosphamide. These results, as well as others which we discuss, supported our notion that AmB affected host immune response to the tumor.


Circulating tumor cells in murine myeloma.

BALB/c mice bearing subcutaneous ADJ-PC5 myelomas had hematologic findings suggestive of a preleukemic syndrome: thrombocytopenia, anemia, leukocytosis, and megakaryocytic hyperplasia. Six BALB/c myelomas were successfully transplanted sc by fragments or cell suspensions of spleens from mice bearing a subcutaneous tumor, though typical myeloma cells were difficult to visualize by light microscopy in these spleens. The fidelity of transmission of the ADJ-PC5 myeloma by this procedure was shown by the retention of idiotypic specificity of the immunoglobulin produced by the tumor in a radioimmunoassay. The tumorigenic cell that homed to the spleen was apparent as early as 8 days after sc transplantation of the myeloma. The spleens of tumor-bearing mice, however, could destroy or suppress the expansion or growth of a limited number of cells that had migrated to the spleens. Tumorigenic cells present in the peripheral circulation constituted 2-3% of the leukocytes. These cells, however, had reduced levels of the murine myeloma viral and cell-associated antigens, were difficult to detect by an indirect immunofluorescence assay, and did not rapidly divide in this environment, as indicated by the very low number of cells detected by autoradiography.


Histologic analyses of experimental tumors from mouse blastocyst-derived cell lines.

Previous work has shown that established cell lines can be derived from cultured mouse blastocysts. Although these cell lines differed from one another morphologically, immunologically, and biochemically, it has not been easy to determine what embryonic cell type (if any) each cell line represents. We showed in this report that these blastocyst-derived lines could produce tumors in syngeneic mice at low yields and presented the results of histologic analyses of the tumors which we carried out to learn more about the kinds of cells present in each of the lines. Tumors derived from cell line MB2 contained two kinds of cells. Most of the cells were similar to those found in so-called "parietal yolk sac carcinomas," secreted Reichert's membrane-like material, and could be found in subsequent transplant generations. The other cell type resembled trophoblast giant cells morphologically and did not survive transplantation. These results showed that MB2 contained cells which were either parietal endoderm cells or a closely related precursor. The tumor derived from MB4 consisted of small, closely packed cells intermixed with larger cells with foamy cytoplasm and occasional giant cells. Cells in subsequent passages of the tumor were often organized into acinar clusters. Biochemical evidence has suggested that MB4 cells resembled one or both components of visceral yolk sac. Visceral yolk sac sarcomas have not previously been reported; the MB4-derived tumor may prove to be the first. Tumors derived from line MB31 contained both fibroblastic and epithelioid cell types which could not be more definitively identified. Cultures derived from each kind of tumor in each case contained cells morphologically characteristic of those in the originally inoculated population. Our results showed that tumors produced from blastocyst-derived cell lines did not resemble the teratocarcinomas which formed when blastocysts were implanted into an ectopic site in vivo: They did not contain a wide variety of cell types, nor did they possess pluripotent embryonal carcinoma "stem" cells characteristic of the teratocarcinoma. That each blastocyst-derived line gave rise to a different kind of tumor suggested that each line may have been made up of cells "trapped" at some stage characteristic of the development of a particular embryonic or extraembryonic tissue. However, each tumor did contain at least two distinct cell types; this suggested that cells in the blastocyst-derived lines, though restricted to their developmental potential, may not yet have been completely determined.


Prenatal exposure to diethylstilbestrol in mice: toxicological studies.

The effect of prenatal exposure to diethylstilbestrol (DES) on the postnatal development of male and female genital tract function was studied. The placental transfer or radiolabeled (3H or 14C) DES was studied in pregnant mice. DES-associated radioactivity in the fetal plasma approximated that in maternal plasma 1/2 hr after intravenous administration of [3H]DES; 3H activity corresponding to DES in the fetal genital tract was about threefold higher. The decrease in reproductive capacity of female offspring from mice treated with DES during gestation was dose-related; a low incidence (10% or less) of cancer of the vagina, cervix, and/or uterus was also observed in these mice. Male offspring exposed prenatally to the highest dose (100 microng/kg) of DES in this study also had lower reproductive capacities. Lesions in the genital tract of these mice included epididymal cysts, inflammation, cryptorchidism, and nodular masses in the seminal vesicles and/or prostate gland. Such lesions and sterility were not observed at the lower DES doses. Histological studies with neonatal mice raise the possibility that Müllerian duct tissue may represent a site for the transplacental toxicity of DES in both the male and female fetus.


Evaluation of chemical flame retardants for carcinogenic potential.

Tetrakis(hydroxymethyl)phosphonium chloride (THPC) and Pyroset TKP, which is the mixed acetate/phosphate of the same phosphonium base, are widely used in flame-retardant cotton fabrics, particularly in children's sleepwear. THPC degrades thermally and under certain chemical conditions to yield hydrochloric acid and formaldehyde (CH2O). In solution, the latter two compounds are in equilibrium with the known potent carcinogen bis(chloromethyl)ether (BCME). A sample of commercial THPC contained from 4% (at pH 0.4) to 14% (at pH greater than 4.5) free CH2O. The material, as supplied by the manufacter, showed pH 0.4. Gas chromatographic analysis of aqueous commercial THPC did not reveal any peak chracteristic of BCME under conditions where 0.1 ppm of the material can be detected. Application to mouse skin of THPC ( 2 mg in 0.1 ml DMSO) and of Pryset TKP (7 mg in 0.1 ml DMSO), three times per week for 400 days with 20 female ICR/Ha Swiss mice per group, gave one squamous carcinoma in the THPC-treated group. THPC was inactive as an initiating agent in two-stage mouse skin carcinogenesis with phorbol myristate acetate as promoter. Both agents were active as tumor promoters, using a single application of 7,12-dimethylbenz[a]anthracene (20 microng in 0.1 ml acetone) as initiator. With THPC as promoter (2 mg in 0.1 ml DMSO, thrice weekly) 3 of 20 mice bore papillomas which progressed to squamous carcinoma. With Pyroset TKP as promoter (7 mg in 0.1 ml DMSO) 7 of 20 mice bore papillomas of which two progressed to squamous carcinoma.


Dominant lethal studies with technical chlordane, HCS-3260, and heptachlor: heptachlor epoxide.

Male albino mice in groups of eight were each given single doses, either by gavage or by intraperitoneal injection, of either technical chlordane (50 or 100 mg/kg), HCS-3260 (50 or 100 mg/kg), or heptachlor:heptachlor epoxide (25:75) (7.5 or 15 mg/kg). The males were subsequently mated with three untreated females for six consecutive weeks. No dominant lethal changes among females that had mated with the treated males were produced.


Effects and residues of dietary hexachlorobenzene in growing swine.

Crossbred weanling gilts were fed a standard ration containing 0, 1, 10, or 100 ppm purified hexachlorobenzene (HCB) for 13 wk. No mortalities, ill health, neurological disorders, or significant depressions in weight gain were observed. Postmortem examination revealed brightly fluorescent livers at all levels of HCB. The group receiving 100 ppm had a tendency for smaller spleens, larger livers with swollen hepatocytes, and decreased lymphocytes. HCB accumulated in the dissectable fat of growing swine to concentrations five- to sevenfold higher than the dietary concentration; residues in 11 other tissues examined were below the dietary concentration.


Toxic effects of caffeine on growth and metamorphosis of the larvae of Musca domestica.

The somatic effects of caffeine were studied by using a rapidly proliferating insect developmental system. The results show that caffeine is a potent growth inhibitor of housefly larvae. Puparium formation is also severely affected, which sud when larvae are treated with higher concentrations of caffeine. The results indicate that caffeine may have several target sites of action; these are briefly discussed.


Duration of interferon inhibition following single and multiple injections of morphine.

The increase in mouse serum interferon that occurs in response to poly I:C administration is markedly attenuated by injection of a narcotic preceding the polynucleotide challenge. A single injection of morphine is capable of inhibiting the mechanism(s) responsible for increasing serum interferon levels for a period of at least 9 days following the narcotic injection. Daily single injections of morphine for 5 or 10 days prior to poly I:C challenge do not amplify the extent of the decrease in serum interferon over that measured for a single injection, even though the amount of narcotic injected is increased on each successive day of the 5 or 10 day period. The implications of this relationship for the phenomenon of narcotic tolerance are evaluated and discussed as they relate to the immune processes.


Production of aflatoxicol from aflatoxin B1 by postmitochondrial liver fractions.

Fish liver postmitochondrial supernatant preparations in the presence of carbon monoxide were used to prepare purified aflatoxicol from aflatoxin B1 in high yield (23-38%). Such fish liver postmitochondrial and postmicrosomal supernatant preparations were five to ten times more active in making aflatoxicol than rat or human liver preparations under the same conditions.


Dose-dependent pharmacokinetic profile of silvex following intravenous administration in rats.

The pharmacokinetic profile of silvex was defined in rats after single intravenous doses of 5 and 50 mg/kg 14C ring-labeles silvex. Clearance of silvex from plasma at the 5 mg/kg dose was linear with a half-life of 16.2 hr, while clearance at the 50 mg/kg dose was nonlinear. Activities of 14C recovered in excreta were 94.1 and 95.1% of the administered doses at 5 and 50 mg/kg, respectively. Excreta was collected for 192 hr at 5 mg/kg and 216 hr at 50 mg/kg. Urinary excretion of 14C activity accounted for 80.5 and 68.7% of the administered dose at 5 and 50 mg/kg, respectively; fecal excretion accounted for 13.7 and 26.4% of the administered dose at 5 and 50 mg/kg, respectively. Urinary excretion of silvex is saturated at the 50 mg/kg dose. Significant amounts of silvex are excreted in bile and undergo enterohepatic circulation. Concentrations of silvex in liver and kidney are higher than those in fat, brain, and muscle 8 and 216 hr after administration. In a companion oral study, silvex was extensively if not completely absorbed. The pharmacokinetic data presented indicate that statistical projection of experimental results with large doses of silvex to predict the hazard of exposure to small amounts is not justified because the capability to excrete silvex in urine has been saturated.


Cytogenetic investigations on mice treated with lead.

Dietary lead at different dose levels was given to female C57B1 mice for periods up to 3 months. No severe chromosome or chromatid aberrations were observed at any dose level and the frequency of chromatid gaps increased significantly only at the highest doses. (0.5 and 1% of lead in the diet). The number of micronuclei in polychromatic erythrocytes also remained at control levels after lead treatment, whereas known mutagenic agent such as Myleran and Mitomycine C raised their incidence markedly. Taking into account also the data in the literature, it is concluded that lead per se probably has no mutagenic action on mammals.


Effect of potassium cyanate on carbon monoxide and hypoxic hypoxia-induced lethality.

Pretreatment of mice with potassium cyanate for 15 days resulted in a significant increase in hemoglobin-oxygen affinity (decrease in P 50) and a significant protection against hypoxic hypoxia-induced lethality. However, cyanate pretreatment had no significant effect on carbon monoxide-induced lethality. Oxygen consumption in cyanate-treated mice was significantly lower than in controls in room air but not different in hypoxic environments. Whether the protective effect of cyanate on hypoxic hypoxia-induced lethality is due to the increase in hemoglobin-oxygen affinity or attributable to a non-hemoglobin-related action of cyanate remains unresolved. Regardless, the need exists to reevaluate the current concept that changes in hemoglobin affinity for oxygen correlate with susceptibility to hypoxemic states. In addition, data presented together with previous findings support the concept that carbon monoxide lethality is not solely attributable to a carboxyhemoglobin-induced hypoxemia.


pT, a new classification system for toxic compounds.

The use of pT, the reciprocal of the logarithm of the molar concentration of harmful compounds, allows a simple, quantitative expression of the potential for toxicity of a wide variety of compounds on a molar basis. Comparison of representative toxic compounds gives a valuable perspective on some chemical hazards shared by the biomedical community and society.