5'-nucleotide phosphodiesterase activity of floxuridine-resistant mouse glioma. In tissue culture experiments, cells derived from glioma 26, a transplantable tumor of C57B1/6 mice, were sensitive to both floxuridine (5-fluorodeoxyuridine) and 5-fluorodeoxyuridine-5'-(5-iodo-3-indolyl)phosphate, an enzyme-mediated drug activated by 5'-nucleotide phosphodiesterase. When these compounds were tested on the tumor in animals at a level of 5 mg/kg for 5 days, tumor growth was inhibited  approximately 20% by both compounds. When higher levels of 5-fluorodeoxyuridine, 100 mg/kg four times weekly throughout the lifespan of the mouse, were given, the tumor, although inhibited at first, developed resistance and continued to grow until it killed the animal. Phosphodiesterase levels in the tumor rose as the tumor grew. On the other hand, thymidine kinase levels dropped as anticipated from the known 5-fluorodeoxyuridine-resistant hepatoma tissue culture data. This enzyme pattern was maintained in transplantable mouse glioma lines established from the resistant tumors. One of these lines, tested at a level of 5 mg/kg for 5 days, showed no response to 5-fluorodeoxyuridine but was still sensitive to 5-fluorodeoxyuridine-5'-(5-iodo-3-indolyl) phosphate. These experiments, therefore, offer a model system and a rationale for the design and study of more compounds that could be activated by the enzyme phosphodiesterase. Such compounds might be used alternatively when resistance to 5-fluorodeoxyuridine develops, a common clinical experience in the use of this anticancer drug.


Anticonvulsant activity and selective inhibition of nicotinamide adenine dinucleotide-dependent oxidations by 10-(2-arylimino-3-acetylamino-4-thiazolidonyl) phenothiazines. Several Several 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines and their corresponding cyclized 10-(2-arylimino-3-acetylamino-4-thiazolidonyl)phenothiazines were synthetized and characterized by their sharp melting points and elemental analyses. All compounds inhibited nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate and alpha-ketoglutarate selectively, whereas NAD-independent oxidation of succinate remained unaltered. All phenothiazine derivatives exhibited anticonvulsant activity, which was reflected by the 20-60% protection observed against pentylenetetrazol-induced convulsions in mice. The ability of substituted thiosemicarbazidophenothiazines to inhibit cellular respiratory activity was reduced considerably by cyclization to the corresponding substituted thiazolidinophenothiazines. On the other hand, cyclization generally resulted in increased anticonvulsant activity. Thus, the anticonvulsant activity possessed by these substituted phenothiazines bore no relationship with their ability to inhibit selectively the NAD-dependent oxidations. Selective inhibition of NAD-dependent oxidation of pyruvate and alpha-ketoglutarate in isolated rat brain mitochondria by some 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines was concentration dependent and competitive in nature.


Fragmentation of 3-oximino-4-chromanone. Heating either the methanesulfonate ester of 3-oximino-4-chromanone or 3-oximino-4-chromanone and an alternative acylating agent such as p-toluensulfonyl chloride or acetic anhydride in the presence of aqueous base afforded two major fragments: salicyclic acid and 2-carboxyphenoxyacetonitrile. These compounds are derived from two separate cleavage pathways involving the acylated oxime. In one pathway, fragmentation appears to be assisted by the ether ring oxygen; in the other, it is assisted by the alpha-carbonyl group of the oxime ester.


CNS depressant activity of pyrimidylthiazolidones and their selective inhibition of NAD-dependent pyruvate oxidation. Several 1-aryl-3-(2-pyrimidyl)thiocarbamides and their corresponding cyclized 2-arylimino-3-(2-pyrimidyl)thiazolid-4-ones were synthesized and characterized by their sharp melting points and elemental analyses. These thiocarbamides and thiazolidones possessed anticonvulsant activity against pentylenetetrazol-induced convulsions and potentiated pentobarbital-induced hypnosis in mice. Most of these thiocarbamides and thiazolidones selectively inhibited nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, where the use of added NAD dether hand, remained unaltered. The anticonvulsant activity of thiocarbamides and thiazolidones was unrelated to their ability to inhibit the respiratory activity of rat brain homogenates during oxidation of sodium pyruvate. Cyclization of thiocarbamides to the corresponding thiazolidones in general enhanced their CNS depressant and enzyme inhibitory effectiveness.


Investigations into the mechanism of reduction of ethanol sleep by thyrotropin-releasing hormone (TRH). Thyrotropin-releasing hormone (TRH), administered intraperitoneally, was found to antagonize ethanol-induced sleep and hypothermia in mice without affecting brain ethanol content. This reduction of the actions of ethanol was also apparent after oral or intracisternal administration of TRH. In addition, TRH reduced ethanol-induced sleep in rats, hamsters, gerbils and guinea pigs. Evidence that the pituitary-thyroid axis is not necessary for the effects of TRH was provided by observations that hypophysectomy did not reduce TRH antagonism of ethanol narcosis and findings that neither triiodothyronine nor thyrotropin mimicked its action. Certain analogs of TRH, which have little effect on the pituitary, were also found to antagonize ethanol-induced sleep and hypothermia. Pretreatment with the antiadrenergic drugs, alpha-methyltyrosine, phentolamine and propranolol did not antagonize the ability of TRH to reduce sleep induced by ethanol. However, after intracisternal administration of atropine methyl nitrate, TRH no longer caused a significant reduction of sleep, even though TRH antagonism of the ethanol-induced hypothermia was still apparent. In contrast, central administration of other anticholinergic drugs, such as delta-tobocurarine and hexamethonium, reduced ethanol-induced sleep and this effect was additive with TRH. Carbachol also reduced ethanol sleeping time and this effect was also blocked by atropine methyl nitrate. The antagonism of ethanol-induced sleep by dibutyryl cyclic adenosine 3', 5'-monophosphate was significantly reduced but not blocked by atropine methyl nitrate. Results provide evidence that TRH has a direct extrapituitary action on brain and that both TRH and ethanol may interact with central cholinergic systems.


Onset of chronotropic effects of nicotinic drugs and tyramine on the sinoatrial pacemaker in chick embryo heart: relationship to the development of autonomic neuroeffector transmission. Spontaneous electrical activity, recorded extracellularly from the sinoatriial pacemaker region in the isolated chick embryo heart, was inhibited by nicotine (10(-5)M) on the 11th incubation day and thereafter. Blockade of the inhibitory effects of nicotine hexamethonium, tetroditoxin and atropine supported the conclusion that nicotine initiated propagated impulses in postganglionic cholinergic nerves and released acetylcholine to act on atropine-sensitive receptors on pacemaker cells. Dimethylphenylpiperazinium, like nicotine, inhibited the sinoatrial pacemaker. The onset of the inhibitory effect of nicotine occurred within 1 day of the appearance of cholinergic neuroeffector transmission. The acceleratory action of tyramine (2.9 X 10(-5)M) increased markedly on the 20th incubation day, that is, within 1 day of the appearance of adrenergic neuroeffector transmission. The positive chronotropic effects of tyramine were opposed by cocaine and by propranolol. Nicotine also evoked pacemaker acceleration that was observed on the 21st incubation day and thereafter. However, the sympathomimetic effect of nicotine required elevation (2 times normal) of the external Ca++ concentration. Ontogenetic and pharmacologic evidence support the conclusion that the drug-induced changes in pacemaker impulse frequency depended upon an interaction with autonomic nerves. The results are consistent with the hypothesis that the gap between morphologic innervation of the heart by autonomic nerves and the appearance of transmission is related, at least in part, to the amount of transmitter available for release.


Effects of amide-linked local anesthetics on adrenergic neuroeffector junction in cutaneous veins of dog. When changes in isometric tension of helical strips of dog saphenous veins were recorded, etidocaine caused a dose-dependent depression of the contractile responses to nerve stimulation, norepinephrine and K+. The response to nerve stimulation was significantly more depressed than that to exogenous norepinephrine. Similar results were obtained with lidocaine. In preparations incubated in solutions containing 3H-norepinephrine and mounted for superfusion and isometric tension recording, etidocaine depressed the contractions and diminished the release of 3H-norepinephrine evoked by nerve stimulation. Thus, in addition to an inhibitory effect on the responses of smooth muscle cells, amide-linked local anesthetic agents such as etidocaine depress adrenergic neurotransmission in the blood vessel wall, which helps explain their vasodilator properties in the intact organism. In unstimulated preparations and during contractions caused by K+, etidocaine increased the efflux of 3H-norepinephrine and deaminated metabolites. After incubation with the monamine oxidase inhibitor, pargyline, etidocaine augmented markedly the efflux of 3H-norepinephrine. During responses to tyramine, it augmented the release of 3H-norepinephrine more than the efflux of deaminated compounds. This suggests that etidocaine augments the leakage of norepinephrine out of the storage vesicles, making more catecholamines available for intraneuronal deamination.


Selective lithium inhibition of hormonal phosphaturic responses. The acute effects of intraperitoneal lithium on the phosphaturic responses to parathyroid hormone (PTH) and pharmacologic doses of vasopressin were studied in rats. Lithium significantly inhibited the phosphaturic response to PTH at a dosage of 90 mug/kg/hr but did not affect the response to 30 mug/kg/hr. Conversely, lithium eliminated the phosphaturic response to vasopressin at a dosage of 300 mU/kg/hr but did not affect the response to dibutyryl adenosine 3', 5'-monophosphate (db-cAMP), 10 mg/kg/hr. Renal lithium content was increased substantially after the larger dose of PTH and was diminished slightly after db-cAMP and the larger dose of vasopressin. The latter two treatments also inhibited renal lithium reabsorption whereas the smaller dose of vasopressin and both dosages of PTH did not. These results indicate that lithium interferes with the phosphaturic responses to certain dosages of pth and vasopressin and suggest that renal lithium reabsorption and tissue lithium uptake may in part determine the extent of this cation-hormonal interaction. In addition, a competitive type of interaction between lithium and vasopressin is postulated.


Positive inotropic activity of cholera enterotoxin on the embryonic chick heart. The characteristics of the positive inotropic effect of different preparations of cholera toxin on the isolated 4-day-old embryonic chick heart were investigated. Crude (CCT) as well as partially purified and purified (PCT)preparations of cholera toxin were shown to have positive inotropic activity. Contractility was increased within 1 minute and reached a maximum at approximately 40 minutes after exposure to toxin. Activities of all three toxin preparations were abolished by heating, their effects were prevented by addition of antitoxin, but nort propranolol, before exposure of the heart to toxin. The positive inotropic effect of PCT was not reversed by washing, but was reversed by subsequent addition of antitoxin. The  effects of CCT were reversed by insulin. Effects of both CCT and PCT were potentiated by theophylline, and both toxin preparations elevated tissue levels of cyclic adenosine 3',5'-monophosphate. A filtrate of CCT (MW is less than 30,000) exhibited similar cardiostimulant activity but displayed certain differences from the other toxin preparations. The filtrate was heat stable, and its effects were blocked by pretreatment with propranolol but not by antitoxin. The filtrate of CCT, unlike the toxin-containing preparations, did not stimulate intestinal fluid secretion in the dog.


Dopamine synthesis in rat brain striatal synaptosomes. II. Dibutyryl cyclic adenosine 3':5'-monophosphoric acid and 6-methyltetrahydropterine-induced synthesis increases without an increase in endogenous dopamine release. The effects of N6, O2'-dibutyryl cyclic adenosine 3':5'-monophosphoric acid (dibutyryl cyclic AMP), DL-6-methyl-5, 6, 7, 8-tetrahydropterine (6-MPH4) and tyramine on dopamine synthesis and endogenous dopamine release in rat brain striatal synaptosomes have been examined. Dibutyryl cyclic AMP (1 mM) produced a 100% increase in dopamine synthesis but had no effect on endogenous dopamine release. Veratridine (75 muM) did not further stimulate dibutyryl cyclic AMP-treated tissue. 6-MPH4 (0.1 mM) also stimulated synthesis without stimulating dopamine release. The stimulation produced by 6-MPH4 was additive to the stimulations produced by either dibutyryl cyclic AMP or veratridine. Tyramine (10(-4) M) inhibited synthesis, while increasing dopamine release. These data suggest that 1) dopamine-releasing agents may have differential effects upon dopamine synthesis, depending on their mechanism of release, 2) dopamine synthesis can be stimulated independently of endogenous dopamine release and 3) the pteridine cofactor necessary for tyrosine hydroxylation is not normally present at saturating levels.


The membrane potential of rat diaphragm muscle fibres and the effect of denervation. 1. Resting membrane potentials of rat diaphragm muscles were measured in vitro after previous denervation for 0-10 days. In some experiments denervated muscles were incubated in vitro for 3 hr while in others they were cultured for 15-24 hr to allow adequate exposure to drugs before recording. 2. It was found that resting membrane potentials, within 2-5 mm of the site of nerve section were significantly lower, within 3 hr, than resting membrane potentials measured more than 9 mm away from site of nerve section. This difference could be reduced or abolished by bathing preparations in solutions containing adrenaline (10 muM), noradrenaline (10 muM) or isoprenaline (10 muM) or dibutyryl cyclic AMP (10 muM-0-25 mM in the presence of 2 mM theophylline). Cyclic AMP (0-5 mM) was ineffective. 3. Application of solutions containing dibutyryl cyclic AMP for 3 hr also raised the resting membrane potential of muscles denervated 4-5 days previously. Culture studies showed that this effect was sustained when the time of incubation was 24 hr. 4. Incubating freshly denervated preparations with cycloheximide (22 mug/ml.) or actinomycin D (1 mug/ml.) did not prevent the development of the early (3 hr) fall in resting membrane potential despite a concomitant inhibition of RNA or protein synthesis. Culturing freshly denervated muscles in solutions containing cycloheximide (10 or 25 mug/ml.) which blocked 93% of protein synthesis, did not prevent the expected drop in resting membrane potential after 15 or 24 hr. 5. It was found that exposure to ouabain (1 or 5 mM) produced a rapid (15 min) fall in resting membrane potential in innervated and denervated preparations treated with dibutyryl cyclic AMP but not denervated preparations. After 5 days denervation cyclic AMP levels in muscle were increased by about 40%. 6. It is suggested that upon denervation an electrogenic action of a NA+-pump is blocked and that dibutyryl cyclic AMP and catecholamines are capable of stimulating this pump.


[Adrenocortical responses to ACTH (author's transl)]. To characterize by a mathematical model the dynamics of adrenocortical responses to ACTH, the concentration of plasma corticosterone was measured following a series of injections and perfusions of ACTH to dexamethasone-treated male rats. A similar slope was observed during the rise of plasma corticosterone following graded pulse inputs, and the steady-state corticosterone secretion rate was shown to increase proportionally to the perfusion rate of ACTH up to saturation corresponding to maximal secretion. The data will be used, concurrently with our model of the dynamics of plasma cortiscosterone, for the identification of a mathematical model of the adrenocortical response to ACTH.


The attitudes of nursing students and others about mental illness. Student nurses tend to report somewhat moderate attitudes toward mental illness in that they appear to be less radical than psychology students, but less conservative than teacher-students in education. The student nurses' attitudes are similar to those of psychiatric residents, but more radical than psychiatric nurses.


What are mental health nurses doing?

What are mental health nurses doing? In the analysis of a select set of questions from a questionnaire designed to survey the major roles of the MHN in a large metropolitan DHR, a number of trends were suggested: 1. A majority of the nurses surveyed functioned highest in the nurse-clinician area, with the majority being able to participate in planning and evaluating of their roles. 2. The role of nurse-therapist appears to still be the least practiced function. 3. It appears that, overall, the outpatient nurse is able to function more independently than is the inpatient nurse. The impression from this sample of MHNs is that they are being asked to participate in areas which have been traditionally considered the territory of other disciplines, such as: therapy, policy-making, and family contacts. Hopefully, nursing will continue to expand its role as a team member of the multidisciplinary community mental health center.


It's the staff that keeps the patients talking. This article is a critical look at the ingredients necessary to encourage chronic psychiatric patients to speak in a group setting. This study suggests that those chronically hospitalized patients with little speech can be encouraged to increase their verbalizations. Staff presence was the critical factor in the increase of patient speech. The opportunity to gain unusual privileges did not substantially increase the patient speech. In essence, this study indicates that as the amount of conversation from the nursing staff increases, a corresponding increase in patient verbalization occurs.


Group home program.

Group home program. The success in this program was defined in terms of staying out of the hospital or in not regressing to a more intensive level of care requirement. By these criteria, we have been successful. Nine chronic patients have lived in the group home. Of these nine, two have become totally independent, five live in the group home, one went to a family care home, and one to a nursing home due to physical disease. Not one of the group is in a psychiatric institution, and only one had a setback. Presently, plans to expand this program with the assistance of a community group are being formulated.


Organic organizational research in a psychiatric inpatient setting. The author proposes that most traditional methods of collecting data about life in mental health settings tend to produce inaccurate information. He suggests a procedure of information-gathering that may be useful and illustrates the theory of organic research in application with a case study of a psychiatric inpatient setting attempting to develop a recreational program.


Psychophysiological reactions as a function of life stress and behavioral rigidity. Studies have shown that vulnerability to disease is a function of psychosocial factors. This study hypothesized that disease onset is antedated by life changes and is influenced by the individual's "behavioral rigidity." The subjects were 160 female college students from three undergraduate general elective courses. An index of life change (LCI) was administered to each subject, presenting descriptions of important pressures and conflicts, with instruction that she indicate which ones she had personally experienced during the past calender year. A test of behavioral rigidity was also administered. Responses to the LCI indicated that low life change subjects reported significantly fewer illnesses than did the high life change subjects. The results supported the hypothesis that life stress plays a significant role in the development of illnesses. Responses to the behavioral rigidity measure and subsequent analysis of the interaction between this variable and life change did not prove to be statistically significant. It should be noted, however, that high flexibility subjects did report fewer illnesses than low flexibility subjects within the low and high life change groups. Additional studies must be undertaken in order to assess the trend found for interaction effects.


The application of psychotherapeutic conceptual models in nursing practice. Nurses, in order for their practice to be at a scientific level, need to consciously apply laws of change and stability of human behavior that have been identified by the behavioral sciences--especially psychotherapeutic theories. These are separated into several conceptual models which are organized around assumptions of the etiology of human behavior based on scientific observation and experimentation. They differ in emphasis and manipulation of the psychic elements of magic, faith, adaptation, and intellect. The beginning practitioner will probably find applying concepts from one model at a time most effective. She should base her choice on the congruence of the assumptions and emphasis of the models and her nursing assessment of the problem and her own philosophy of nursing. Her resulting choices of nursing intervention using a psychotherapeutic model should yield predictable goal attainment.


The "herd approach" to bovine reproductive disorders. Part I: The diagnosis and management of infectious infertility. The authors describe the methods employed by the Artificial Insemination Section of the Division of Veterinary Services in collaboration with the Reproduction and Bacteriology Section of the Veterinary Research Institute, Onderstepoort when herds are examined for infertility. A "herd" rather than an "individual animal" approach is advocated and certain infectious causes of infertility are discussed.


Synthesis and antiviral activity of 5- and 5'-substituted thymidine analogs. The 5'-O-p-tolylsulfonyl derivatives of 5-chloro-, 5-bromo-, and 5-iodo-2'-deoxyuridine were synthesized and converted into the corresponding 5-halo-5'-azido-2',5'-dideoxyuridines (5-7). Reduction of 5-chloro-5'-azido-2',5'-dideoxyuridine (5) afforded 5-chloro-5'-amino-2',5'-dideoxyuridine (10, ACIU); however, similar efforts to prepare 5-bromo-5'-amino-2',5'-dideoxyuridine (11) and 5-iodo-5'-amino-2',5'-dideoxyuridine (12) by reduction of the corresponding 5'-azido precursor resulted in the formation of 5'-amino-2',5'-dideoxyuridine (9). 5-Bromo-5'-amino-2',5'-dideoxyuridine (11, ABrU) and 5-iodo-5'-amino-2',5'-dideoxyuridine (12, AIU) were prepared by halogenation of the 5-mercuriacetate of 5'-amino-2',5'-dideoxyuridine. The 5'-amino-2',5'-dideoxy analogs of 5-methyl-, 5-chloro-, 5-bromo-, and 5-iodo-2'-deoxyuridine possess antiviral activity against herpes simplex virus but exhibit no inhibitory activity against sarcoma 180 (murine) or Vero (monkey) cells in culture.


Inhibition of separated forms of phosphodiesterases from pig coronary arteries by uracils and by 7-substituted derivatives of 1-methyl-3-isobutylxanthine. A series of 7-substituted 1-methyl-3-isobutylxanthines was designed in an attempt to increade the specificity of the 1-methyl-3-isobutylxanthine (MIX) structure for one of the two cyclic nucleotide phosphodiesterase peaks isolated by DEAE-cellulose chromatography of the soluble fraction of the intima + media layer of pig coronary arteries. A series of 1,3-dialkyluracils was of low potency as inhibitors of either peak I or peak II. The 7-substituted xanthines were prepared by alkylation of MIX with the corresponding alkyl or aralkyl halide in DMF containing K2CO3. These compounds were, in general, much less potent inhibitors of peak II activity than was MIX, but some of them retained the potency of MIX as inhibitors of peak I and, therefore, were relatively specific for inhibition of peak I. 7-Bzl-MIX was the most selective compound tested; it was a potent inhibitor of peak I activity but was much less effective as an inhibitor of peak II activity. Substitution of either electron-withdrawing (nitro) or electron-donating (methoxy) groups on the 7-benzyl moiety reduced the effectiveness of the 7-benzyl compounds as inhibitors of peak I. Chlorobenzyl substitution increased the potency slightly over the benzyl but not the selectivity between peaks.


Regulation of ion permeabilities of isolated rat liver cells by external calcium concentration and temperature. Regulation of ion transport through the plasma membrane was studied on single cell suspensions of hepatocytes, obtained after perfusion of rat liver with collagenase/hyaluronidase solution. Steady-state intracellular K and Na contents were shown to be markedly dependent on external Ca concentration and temperature, the sum of both ion concentrations remaining nearly constant. In contrast, steady-state intracellular chloride content was found to be independent of external Ca concentration, but dependent on temperature. Using the constant field relations, the passive permeabilities PK and PCl for potassium and chloride, respectively, were derived from the experimental data. At temperatures at and above 37 degrees C, with increasing external Ca concentration, PK, exhibits a sharp decrease at about 10(-4)M. In contrast, PCl at 37 degrees C was found to be independent of Ca concentration within experimental error. Earth alkali ions other than Ca, show marked but different effects on PK if compared at equal concentrations. Preincubation of the cells with cholesterol leads to a broadening of the dependence of PK on external Ca concentration. The above results, as well as those on the dependence of PK on external Ca concentration obtained by other authors, could be quantitatively described by a theoretical model of the plasma membrane proposed earlier. This model postulates regulatory binding sites, which cooperatively undergo a cation exchange of divalent cations by K+ ions from the external medium if the cation composition of the latter is altered.


The assessment of nocturnal REM erection in the differential diagnosis of sexual impotence. A new method for differentiating psychogenic from organic cases of sexual impotence is described based on the assesst of nocturnal REM erection in nine patients. It is our tentative impression that in psychogenic impotence nocturnal REM erection may be normal in amount and degree and an excellent indicator of erectile potential. In these cases a marked discrepancy exists between the amount and degree of nocturnal erection and the patient's daytime performance level attained during attempted coitus or masturbation. In the organic patients, on the contrary, such a discrepancy does not exist; instead, the maximal nocturnal erection attained corresponds closely to and mirrors the patient's impaired waking performance. This new method may be very useful in the diagnosis, prognosis, and decision as to type of treatment, especially in difficult cases.


Mouse mammary tumor virus as a model for viral carcinogenesis. Evidence is presented suggesting that genetic control may be the limiting factor in mammary tumor virus (MTV) positive mammary oncogenesis. Studies with hybrid mice involving high and low MTV-expressing murine strains suggest that expression of MTV in milk may not be as important in tumorigenesis as previously thought. The usefulness of the murine MTV model in the study of mammary malignancy is discussed.


Mammary gland as a morphological end point in carcinogenesis studies. The murine mammary tumor system is characterized by the presence of intermediate preneoplastic mammary cell populations. The intermediate mammary cell populations are characterized as either alveolar hyperplasias or ductal hyperplasias. The most frequently encountered preneoplastic cell population is the hyperplastic alveolar nodule, which has been extensively characterized with respect to its biological and hormonal properties. While the alveolar hyperplasias are seen predominantly in mice infected with the mammary tumor virus, ductal hyperplasias are seen primarily in mice treated with chemical carcinogens. Both types of lesions can serve as morphological end points for carcinogenesis studies in the mammary gland.


Estrogen-receptor binding: relationship to estrogen-induced responses. The relationship between nuclear binding of the receptor-estrogen complex (R-E) and estrogenic responses was examined. Nuclear-bound R-E was measured by the [3H] estradiol exchange assay, which permits the quantification of R-E as a function of either endogenous or non labeled estrogen. The quantity of nuclear R-E fluctuated as a function of blood levels of estrogen during the estrous cycle in the rat. This indicates that the accumulation of the R-E complex by the nucleus of uterine cells may be of physiologic significance and under the control of endogenous estrogen.


Vinblastine: influence on nerve conduction and synaptic transmission. Vinblastine injected into the eyes of pigeons had a detrimental effect on the amplitude of the postsynaptic evoked potential in the optic tectum; impulse conduction of the optic nerve was not influenced. The depression of the postsynaptic evoked potential was dependent on the dosage. Only 20 and 100 mug vinblastine had an influence; no influence was observed with 10 mug vinblastine. The reversible depression was seen from the third day after injection to between the 21st and the 28th day after injection, and in that period it remained constant. The latency of the response was not influenced by vinblastine.


The effect of trimethadione on brain energy metabolism and EEG activity of the conscious rat exposed to HPO. The use of trimethadione (TMO) as a protector in hyperbaric oxygen toxicity in the conscious rat has been examined in detail. The oxidation-reduction state of pyridine nucleotides was measured simultaneously with the EEG activity from the surface of the brain cortex. From the data obtained, a few parameters were calculated. The results show that in TMO-treated animals the time to the onset of convulsions, the time to the onset of NADH oxidation-reduction cycles, and the survival time were significantly longer than in the control group. The effect of TMO on the EEG shows that the tonic phase of the convulsive activity was almost completely abolished.


Ureteral metastasis from Wilms tumor.

Ureteral metastasis from Wilms tumor. Urothelial spread of Wilms tumor is uncommon and only 5 instances of ureteral metastases have been reported previously. A case of Wilms tumor with mid ureteral metastasis is presented and the literature is reviewed. Clinical implications and suggestions for surgical management are discussed.


Coxsackievirus and adenovirus infection. Association with acute febrile and juvenile rheumatoid arthritis. The prearthritic manifestations of juvenile rheumatoid arthritis in a 16-year-old boy were associated with a rise in coxsackievirus B3 and A9 neutralizing antibody titers from 1:16 to larger than or equal to 1:512, and 1:64 to 1:512, respectively. Recurrent polyarthritis followed and has persisted for three years. Adenovirus 7 was isolated from the pericardial fluid of a 9-year-old girl in whom juvenile rheumatoid arthritis then developed. Of 11 patients with acute, nonspecific, febrile arthritis subsequently studied, fourfold or greater antibody elevations occurred against coxsackieviruses in five, and against rubella and varicella-zoster virus in two. Antibody titers against other viral (and Mycoplasma) antigens remained stable. These findings suggest that coxsackieviruses, as well as other common viruses, may cause acute, nonspecific, febrile arthritis. In certain instances, such infection may be related to the development of juvenile rheumatoid arthritis.


Effects of polyamines on the proliferation of mammalian cells in tissue culture. Spermine, spermidine, putrescine and agmatine were examined for their cytotoxicity to mammalian cells in tissue culture. Spermine exhibited the highest cytotoxicity among them. It was followed by spermidine. Putrescine and agmatine showed little toxicity but rather acceleration of cell proliferation in some concentrations. Among 16 kinds of rat cells and strains and a mouse cell strain examined, liver cells, fibroblasts, and cells serially grown in a protein-free synthetic medium were sensitive to spermine in the order described. Normal liver cells were more sensitive than hepatoma cells, and normal fibroblasts were also more sensitive than sarcoma cells. Bovine serum albumin fraction markedly accelerated the cytotoxicity of spermine.


Isolation of low-virulent mouse hepatitis virus from nude mice with wasting syndrome and hepatitis. Mouse hepatitis viruses were isolated on DBT cell culture from affected livers in most nude mice having wasting syndrome and chronic hepatitis. These nude isolates were pathogenic for cortisone-treated ICR weanling mice but not for non-treated ones.


The effect of 2, 4-dinitrophenol on the growth of Bordetella pertussis in chick tracheal organ culture. Among various metabolic inhibitors tested, only 2, 4-dinitrophenol inhibited the growth of Bordetella pertussis in chick tracheal organ culture at concentrations nontoxic both for bacterial organisms and for ciliary motility of the tracheal fragments. Although this effect of 2, 4-dinitrophenol was reversible in its early stage, longer treatment with this inhibitor resulted in an irreversible inhibition of bacterial growth due to secondary damage of the tracheal fragments. From these observations, it was postulated that the energy required for bacterial growth might be derived from cellular metabolism sensitive to inhibition with 2, 4-dinitrophenol.


Relationship between the levels of intracellular cyclic nucleotides and mechanical responses induced by drugs. The tracheal smooth muscle dissected free from connective tissues was used as a test preparation, since isoprenaline caused a decrease in cyclic GMP in the muscle while it caused an increase in cyclic GMP in the remaining tracheal tissue. Acetylcholine, histamine and papaverine increased both cyclic AMP and cyclic GMP levels in the tracheal muscle. Isoprenaline increased the cyclic AMP level but decreased the cyclic GMP level. However, when tracheal muscle was incubated with isoprenaline in the presence of acetylcholine, isoprenaline did not cause a decrease in cyclic GMP but rather a significant increase in cyclic AMP after only 1 min incubation. These results indicate that the relaxation of the tracheal muscle by isoprenaline is initiated by the increase in cyclic AMP but is not associated with the change in cyclic GMP.


Mechanism of action of a new anti-inflammatory agent, naproxen (II). Effects of naproxen on activities of mucopolysaccharase, acid protease and collagenolytic enzymes in inflamed tissues. In order to elucidate the biochemical anti-inflammatory properties of naproxen, the effects of this compound on activities of mucopolysaccharase [beta-glucuronidase (beta-Gase) and lysozyme (LZ)], acid protease (APase) and collagenolytic enzyme (CL) in inflamed tissues were investigated by means of a proliferative inflammatory model in filter-paper-implanted rats. In the preventive test, naproxen strongly inhibited granuloma formation and exudate accumulation as did indomethacin and prednisolone. Although the inhibitory effects of naproxen on all these enzymes were quite evident, indomethacin failed to inhibit APase activity. Prednisolone did not significantly inhibit LZ and APase activities in granuloma. In the curative test, prednisolone caused a marked decrease in the weight of the granuloma already formed and in the volume of the exudate, but with naproxen and indomethacin there was only  a slight decrease. Naproxen and indomethacin induced slight but significant inhibition of LZ and CL activities, while prednisolone showing a weak inhibition of CL activity only. From these results, it may be concluded that anti-inflammatory and anti-rheumatic effects of naproxen are partly attributable to its inhibitory actions on these lysosomal enzymes.


[Treatment of primary hyperlipoproteinemias type IV with different biguanides (author's transl)]. In 12 patients with primary type IV hyperlipoproteinemia the lipid lowering effect of constant doses of the biguanides metformin, phenformin and buformin was compared. After a 2 months dietary period bodyweight and initial triglyceride and cholesterol plasma concentrations were stabilized. The three biguanides were given for two months each, and this 6 months drug period was followed by another dietary period. While, 0.15 g phenformin and 2.55 g metformin reduced triglycerides by about 50% the reduction by 0.30 g buformin was only half. This was due to 4 nonresponders with initial triglycerides of more than 700 mg/100 ml. In contrast the triglyceride lowering effect of the other two biguanides was positively correlated to the pretreatment triglycerides. The cholesterol lowering effect of biguanide treatment was far less pronounced. There were no significant alterations of body weight and no influence on basal insulin and glucose concentrations. In conclusion, all three biguanides tested in a dosis of 3 tablets each are effective in lowering triglycerides although differing in efficiency and depending from the degree of typ IV hyperlipoproteinemia.


[Stimulation of growth hormone and prolactin secretion with TRH in acromegaly (author's transl)]. Inappropriate stimulation of growth hormone (hGH)-secretion with TRH in acromegalic subjects has been shown previously, whereas prolactin (hPRL) secretion was reported to be blunted in active acromegaly. In this study TRH induced hGH and hPRL secretion was investigated in 23 active (mean hGH level: 68.5 +/- 19.9 ng/ml; +/- SE) and 15 inactive acromegalics (mean hGH level: 2.3 +/- 0.4 ng/ml; +/- SE). Fourteen of the active acromegalics showed a significant increase up to more than double of the basal hGH level after 200 mug TRH while in only one of the inactive acromegalics an inappropriate rise of hGH was induced by TRH. Basal hPRL levels were elevated in 9 and within normal range in 14 of the patients with active acromegaly. Except in 3 patients who had normal basal hPRL levels and in one patient with excessively elevated hPRL and hGH levels due to an hPRL and hGH producing adenoma, all patients had normal hPRL responses to TRH. In those with inactive acromegaly, 9 had hPRL levels below normal and only , out of the 15 patients showed a normal rise of hPRL after TRH. The patients who showed no hPRL response to TRH demonstrated also other signs of pituitary insufficiency due to the operative procedure. In contrast to a previous report these findings demonstrate that normal or enhanced hPRL secretion is found in active acromegaly. The inappropriate rise of hGH after TRH is compatible with a loss of specificity of the receptor for GRH of the adenoma cell and can be found also in patients with normal basal hGH levels after treatment suggesting that remaining adenoma tissue is present in the pituitary fossa.


Plasma alkaline phosphatase in mice with experimentally-induced osteosarcomas. No statistically significant difference in alkaline phosphatase levels was demonstrated in animals injected with the FBJ virus. However, there was a significant increase associated with the development of osteosarcomas in response to the iv injection of 1.0 uCi 90 Sr/g body weight into 11-18-mo-old Anl:CFl females. It was proposed that alkaline phosphatase determinations can be used as well as roentenographic analysis to detect 90Sr-induced tumors in mice.


Multiple testing for the detection of B virus antibody in specially handled rhesus monkeys after capture from virgin trapping grounds. Eight groups of rhesus monkeys totaling over 1,000 animals were captured in the virgin trapping grounds of Jammu and Kashmir, India. Individual caging and special handling technics were utilized to prevent cross-contamination during capture, holding, and subsequent shipment to quarantine facilities in the United States. Immediately following the arrival of the monkeys, 5 consecutive blood samples were obtained at approximately 2-wk intervals, and the sera were rested for neutralizing antibody against Herpesvirus simiae. In order to assure the greatest sensitivity possible, sera were not heat-inactivated and were tested against only 10 TCID50 units of virus in addition to the more commonly used concentration of 100 TCID50 units. The first test detected 80-90% of the positive animals within each group, and only 1 seroconversion was noted after the second test. Seventy-three percent of the adults, 36.6% of the young adults, and 12.4% of the juvenile macaques were found to be antibody-positive. Considering the measures employed to prevent cross contamination, these percentages probably reflect the true prevalence of B virus infection in these rhesus monkeys at the time of their capture in the wild.


Experimental viral infections of the inner ear. I. Acute infections of the newborn hamster labyrinth. Acute viral infections of the inner ear were produced in neonatal hamsters. Viruses were inoculated percutaneously through the temporal cartilage into the endolymphatic and perilymphatic spaces of the labyrinth or were inoculated intracerebrally to reach the perilymphatic spaces via the cochlear aqueduct. Selective vulnerability of inner ear structures was demonstrated using a variety of viruses. Influenza virus infected only the mesenchymal cells of the perilymphatic channels of the cochlea; mumps virus infected principally endolymphatic structures; herpes simplex virus infected primarily the sensory cells of the labyrinth; and rubeola and vaccinia viruses infected both perilymphatic and endolymphatic cells.


The induction of emphysema with elastase. II. Changes in connective tissue. Both clinical and experimental evidence implicate proteolytic enzymes active against elastin in the pathogenesis of emphysema. Paradoxically, however, the elastin content of emphysematous human lungs at autopsy has been normal. When emphysema was produced in hamsters by a single intratracheal injection of 25 units of porcine pancreatic elastase, the elastin content of the lungs was reduced from 1.40 +/- 0.22 mg. in controls to 0.43 +/- 0.10 mg. 24 hours after injection, and histologic sections showed that many elastic fibers had disappeared. The elastin content of the lungs gradually increased, approaching normal values by 2 months after injection. The incorporation of 14C-proline into elastin was markedly elevated during the first 2 weeks after injection, decreasing nearly to normal by 2 months. The synthesis of collagen was also increased, indicated by an increase in the collagen content of the lung, an increase in the prolyl hydroxylase activity, and an increase in incorporation of labeled proline into collagen. During the period of active resynthesis of elastin, small clumps of microfibrils and elastic fibrils were visible by electron microscopy within grooves on the surface of septal connective tissue cells in the lungs. Many elastic fibers seen in histologic sections up to 4 months after injection were of abnormal configuration and disorganized.


ATP-stimulated transmitter release and cyclic AMP synthesis in isolated chromaffin granules. ATP stimulates chromaffin granules from the bovine adrenal medulla to release epinephrine and specific soluble proteins. ATP analogs substituted in the beta-gamma position with either nitrogen or carbon were also found to be effective at inducing release from isolated chromaffin granules. However, an ATP analog substituted at the alpha-beta position with carbon was strongly inhibitory. Cyclic AMP was also found to be synthesized by isolated chromaffin granules under release conditions. ATP analogs were effective as substrates for adenylate cyclase in the same order as their efficiency for inducing release from vesicles. Hydrolysis at the beta-gamma linkage of ATP therefore is probably not necessary for release; however, hydrolysis at the alpha-beta position may be important in the release process. Cyclic AMP may be produced and play a regulatory role in this event.


DNA synthesis in cultured human fibroblasts: regulation by 3':5'-cyclic AMP. The addition of serum to density-inhibited human fibroblast cultures induced a wave of DNA synthesis, measured as [3H] thymidine incorporation into acid-precipitable material, beginning after 8-12 hr and reaching maximum levels of 16-24 hr. Addition of dibutyryl-3':5'-cyclic AMP (DBcAMP) together with serum inhibited [3H] thymidine incorporation by 75-95%. When DBcAMP was added for the first 4 hr of serum stimulation and then removed, the wave of DNA synthesis was not delayed. This suggested that serum could induce DNA synthesis even though cyclic AMP concentrations were maintained at high levels by DBcAMP during this initial period. These results are inconsistent with the hypothesis that it is the immediate transient reduction in 3':5'-cyclic AMP concentration following the addition of serum that triggers DNA synthesis. By contrast, DBcAMP added 8 hr after serum inhibited [3H] thymidine incorporation to the same extent as DBcAMP added at the same time as serum. This indicated that a step essential for DNA synthesis and occurring late in G1 was inhibited by high concentrations of 3':5'-cyclic AMP.


Insulin binding and glucose transport in the R3230AC mammary adenocarcinoma. Cells dissociated from the R3230AC mammary adenocarcinoma from intact and diabetic rats were examined for insulin binding and glucose transport. The Kd for insulin binding, approximately 10(--10) M, was similar in all tumors studied. However, the apparent number of receptor sites per cell increased in cells from diabetic rats. Kinetic analysis of 3-0-methyl glucose (3-OMG) entry showed both diffusional and passive carrier characteristics. Insulin (4 X 10(--9) M) in vitro did not affect diffusional entry, whereas the hormone altered the passive carrier system, as reflected by an increase in Km and Vmax. Insulin decreased initial velocity of glucose transport at 4--6 mM glucose levels but increased initial velocity of glucose transport at 20 mM glucose. An explanation of the role of insulin on tumor growth in vivo from effects on glucose transport in vitro is proposed.


Cooperative properties of hormone receptors in cell membranes. The binding of many polypeptide hormones to cell surface receptors does not appear to follow the law of mass action. While steady-state binding data are consistent in many cases with either heterogeneous populations of binding sites or interactions of the type known as negative cooperativity, study of the kinetics of dissociation of the type known as negative cooperativity, study of the kinetics of dissociation of the hormone receptor complex allows an unambiguous demonstration of cooperative interactions. Negative cooperativity, which seems to be wide-spread among hormone receptors, provides exquisite sensitivity of the cell at low hormone concentrations while buffering against acutely elevated hormone levels. The molecular mechanisms underlying the cooperativity are still largely unknown. Cooperativity may stem from a conformational transition in individual receptors or involve receptor aggregation in the fluid membrane (clustering) or more extensive membrane phenomena. Thus, new models of hormone action must be considered which integrate the progress in our knowledge of both the complex mechanisms regulating hormone binding to their surface receptors, and the dynamic properties of the cell membrane.


Hormone receptor mobility and catecholamine binding in membranes. A theoretical model. [3H]-Catecholamine binding to intact cells, isolated cell membranes, and to several isolated macromolecules has been shown by several laboratories to be neither stereospecific nor inhibited by known beta-antagonists. Since additional evidence indicates that this binding is not an artifact (i.e. due neither to the binding of a catecholamine oxidation product nor hormone binding to a catabolic enzyme such as COMT), the question remains as to whether this represents binding to a bona fide membrane receptor. Because all ligands which bind strongly or compete for this binding possess a catechol group, one possible explanation is that the binding affinity is primarily determined by the catechol moiety, whereas the correct stereoisomer of the side chain is necessary to activate the receptor. Thus, although binding is a necessary condition for hormone action, the necessary and sufficient condition for activation of adenyl cyclase is both the catechol group and the correct stereoisomer of the side chain. A theoretical model is developed here to provide a quantitative basis for this hypothesis. This model extends the current concept of distinct subunits in the adenyl cyclase system by separating the receptors from the catalytic sites and placing them at separate locations within the membrane. Utilizing the spare receptor model of Furchgott, and the mobility of macromolecules within a "lipid sea," the appropriate equations to predict both hormone binding and enzyme activation are derived. Using the observed affinity constants from catecholamine binding studies, it is then shown that this model can predict the experimental observation and hence explain the apparent dichotomy arising from binding enzyme activation studies.


Regulation of SV40-induced cell division and tumor antigen by dibutyryl adenosine 3'-5'-monophosphate. Simian virus 40 (SV40) induces cell division in microcultures of sparsely plated nongrowing mouse BALB/3T3 cells during acute infection at moderate multiplicities of infection (MOI = 10-100). The infected cells are killed when a MOI of 1,000 is used. SV40 tumor (T) antigen is synthesized in the infected cells, but viral DNA, virion antigen, and progeny virions are not synthesized (abortive infection). The addition of exogenous dibutyryl adenosine 3'-5'-monophosphate (dbcAMP) at the time of infection stimulates the SV40-induced cell division at all MOI and inhibits SV40-induced cell death at high MOI. The percentage of T antigen-positive cells, as monitored by immunofluorescence, is also increased by the addition of dbcAMP at the time of infection. This regulation of SV40-induced cell division and T antigen formation by exogenous dbcAMP occurs within the first 6 hr after infection at 37 degrees C and is dependent upon both the MOI and the concentration of added dbcAMP. The addition of dbcAMP to productively infected TC7 monkey cells has litte effect on the SV40-induced cell death or T antigen formation.


Cyclic nucleotides and cell growth.

Cyclic nucleotides and cell growth. Growth induction in resting fibroblast cultures by serum or growth factors induces a fast, transient cGMP peak which may constitute the intracellular signal for growth. A similar cGMP peak occurs when 3T3 cells arrested at the restriction point or in G0 by starvation for certain amino acids are induced for growth by readdition of the lacking nutrients. Both 3T3 and SV3T3 cells which are arrested randomly all around the cell cycle do not exhibit major changes in cyclic nucleotides after growth induction. Determination of intracellular cAMP and cGMP levels in normal and transformed fibroblasts under different growth conditions shows that the transition between growing and resting state (G0 arrest) is accompanied and probably induced by characteristic changes in cAMP to cGMP ratios. cGMP is decreased 2-5-fold in resting as compared to growing cultures, and increased 10-20-fold in activated cultures 20 min after serum induction. No major cGMP change was observed in growing, confluent, or serum-activated cultures of transformed cells. Measurement of guanylcyclase under unphysiological conditions (2 mM Mn++) in crude and purified membranes from 3T3 and SV3T3 cultures did not show increased enzyme activity in the transformed cells. Significant differences may only show up when synchronized cells pass through the restriction point in G1 phase. As a hypothesis it is proposed that transformed cells have an activated guanylcyclase system or a relaxed cGMP-pleiotypic response mechanism at the restriction point of their cell cycle.


Vasopressin-sensitive kidney adenylate cyclase: modulation of the hormonal response. Vasopressin-sensitive pig kidney adenylate cyclase is sensitive to several effectors, such as Mg2+, other divalent cations, and guanyl nucleotides. The purpose of the present study was to compare the main characteristics of adenylate cyclase activation by vasopressin, Mg2+, and GMPPNP, respectively. Mg2+ ions were shown to exert at least three different effects on adenylate cyclase. The substrate of the adenylate cyclase reaction is the Mg-ATP complex. Mg2+ interacts with an enzyme regulatory site. Finally, Mg2+ can modulate the hormonal response, with Mg2+ ions affecting the coupling function--that is, the quantitative relationship between receptor occupancy and adenylate cyclase activation. At all the magnesium concentrations tested, from 0.25 mM to 16 mM, adenylate cyclase activation was not a direct function of receptor occupancy. At low Mg2+ concentrations, adenylate cyclase activation dose-response curve to the hormone tended to be superimposable to the hormone dose-binding curve. These results suggest a role of magnesium at the coupling step between the hormone-receptor complex and adenylate cyclase response. Cobalt, but not calcium, ions could exert the same effects as Mg2+ ions on this coupling step. GMPPNP induced considerable adenylate cyclase activation (15 to 35 times the basal value). Activation by GMPPNP was highly time and temperature dependent. At 30 degrees C, a 20 to 60 min preincubation period in the presence of GMPPNP was needed to obtain maximal activation. The higher the dose of GMPPNP in the medium, the longer it took to reach equilibrium. At 15 degrees C, activation was still increasing with time after 3 hr preincubation in the presence of the nucleotide. GMPPNP was active in a 10(-8)M to 10(-5)M concentration range. Unlike the results obtained with lysine vasopressin, the kinetic characteristics of dose-dependent adenylate cyclase activation curves by GMPPNP were unaffected by varying Mg2+ concentrations except for the increase in velocity when raising Mg2+ concentration. It was not clear whether or not the activation processes by the hormone and by GMPPNP had common mechanisms.


Breast masses in males with carcinoma of the prostate. Breast masses in male patients who have prostatic carcinoma may represent gynecomastia secondary to estrogen therapy, metastasis of the prostatic carcinoma to the breast, or a primary carcinoma of the breast. Accurate diagnosis of this lesion by biopsy and, if possible, histochemical determination of acid phosphatase is essential to determine prognosis and treatment. The patient with breast metastases from a primary prostatic carcinoma will survive on the average only 4 mo. However, in the patient with prostatic carcinoma, surgical treatment for a primary breast carcinoma may extend survival considerably.


Erythropoietin levels in Wistar-Furth Wilms' tumor rats. Erythropoietin (ESF) levels were assayed in rats bearing the Wistar-Furth Wilms' transplantable tumor. Sites of tumor inoculation varied from subcutaneous, intramuscular, intrarenal (subcapsular), to intraperitoneal. Two-thirds of the animals exhibited ESF elevations without polycythemia, or severe anemia (HCT less than 30.0 vol%). The elevations of ESF were not detectably related to the time of sacrifice (age of the animal), size of the primary tumor, or number of gross metastatic foci. The diminished ESF response noted to animals given intramuscular tumor implantations is believed to reflect differences in tumor blood and lymphatic supply at the various sites of inoculation. The pattern of ESF responses in the Wistar-Furth Wilms' tumor model is thus quite similar to that which we have observed in man, and appears to represent an animal model for tumor-related ectopic hormone release. The nature of the hormone is believed to differ from that seen in normal physiological states.


Epicardial tumor-like angiofibromatous proliferative lesion. An unusual complication of coronary bypass surgery. The first report of an unusual complication of coronary bypass surgery for myocardial revascularization is presented. In a dog used for experimental studies of internal mammary artery (IMA)-coronary bypass and killed three months later, the postmortem examination of the heart showed a tumor-like epicardial angiofibromatous nodule at the site of the IMA-left anterior descending (LAD) coronary artery anastomosis. The lesion, consisting of plexiform vascular channels in a fibrocollagenous stroma, measured 2 by 1.5 by 1 cm. This was the only lesion found in the animal. It was speculated that the lesion might have arisen from a hematoma developing at the site of arterial anastomosis.


Quality-of-care assessment. I. Outpatient management of acute bacterial cystitis as the model. A study was undertaken to determine whether a process audit of outpatient medical care would correlate significantly with the outcomes of care and thus prove to be a valid method for assessing the quality of medical care in the outpatient setting. Acute bacterial cystitis in women was selected as the model for study. A series of 42 cases was reviewed by retrospective analysis of patient records supplemented by follow-up interviews and collection of a follow-up urine culture from each patient to document the outcome of treatment. No positive association was demonstrated between the processes for satisfactory care selected by the expert criteria committee and the observed outcomes. Reasons for this failure in the present study and for deficiencies of the process audit method in general are discussed.


Macrobodies in chick blastoderm.

Macrobodies in chick blastoderm. The results of this study show that the epiblast cells of chick blastoderm at Hamburger-Hamilton stage 1 contain macrobodies which themselves contain particles resembling the 'lining bodies' described by Bellairs. Since different structures ranging from macrobodies to light vacuoles have been found, it seems probable that their contents are utilized at this stage. Typically, they are surrounded by mitochondria, some of which have an abnormal internal structure. At later developmental stages neither macrobodies nor abnormal mitochondria were observed.


Lowering appointment failures in a neighborhood health center. Failure to keep appointments constitutes a barrier to the delivery of continuous care in many comprehensive health care facilities. At a neighborhood health center in Pittsburgh, Pa., 336 appointments were studied to determine whether reminder letters or reminder calls could improve compliance with appointments scheduled more than three weeks in advance. The failure rate in the control group was 38 per cent compared with 10 per cent for the letter reminder group and 9 per cent for the telephone reminder group. The differences in kept, cancelled, and failed rates between letter and telephone groups were not statistically significant (p greater than .05). The kept rate increased with patient's age in all three groups. Complicance was not affected by sex of the patient, length of time that appointment was scheduled in advance, or day of the week. Compliance was greatest among appointments scheduled for chronic illness follow-up and physical examinations, and least among appointments scheduled for "screening."


Basis and some diagnostic implications of electrocochleography. Electrocochleography (ECoG) involves the recording of electrical responses to sound from the vicinity of the cochlea. The technique, as we practice it, utilizes a trans-tympanic recording needle situated on the promontory of the middle ear. Filtered clicks in the frequency range between 500 and 8,000 Hz are presented to the ear under test at a rate of 10/sec. Repetitive clicks of a given frequency are first presented at high intensity and the responses summed (averaged) in a computer. The click is systematically lowered in intensity, and  an average is collected at each level until the normal dynamic range of hearing has been explored. Two major electrical indices are present in the recording: these are 1. the whole-nerve action potential (AP) derived from the first-order auditory neurons, and 2. the cochlear microphonic (CM) derived from the hair cells. Inspection of the whole nerve AP as intensity is lowered allows the estimation of the response threshold, which correlates well with behavioral threshold. Inspection of the relation between the CM and the AP allows qualitative differentiation to be made between pathology arising in the hair cell (sensory) and in the nerve (neural).


Aspiration cytology of salivary gland tumors: diagnostic experience from six years of routine laboratory work. Fine-needle aspiration cytology has been used as a routine diagnostic instrument in patients with salivary gland lesions during 1966-1972. A retrospective analysis of the primary cytologic reports correlated with the revised final diagnoses in 461 patients where a pathologic report is available, shows exact agreement in 63 percent, good and not misleading agreement in a further 18 percent, while false reports were initially given in 8 percent, and unsatisfactory specimens were obtained in 11 percent of the patients. On revision of the false reports it is found that with the present experience acquired over several years these can be reduced to under 5 percent. This analysis has also given indications upon which types of specimens are likely to cause diagnostic difficulties.


The development of sex differences in the adrenal morphology and responsiveness in stress of rats from birth to the end of life. The appearance and development of sex difference in the adrenal cortex of rats have been studied. Morphological and secretory differences between the adrenal cortex of female and male rats begin on the 40th day of postnatal life, when females respond in stress by a greater increase in plasma corticosterone concentration. The sex difference becomes fully manifest at the age of 55 days (females have heavier absolute and relative adrenal glands and respond to stressful stimuli by a greater increase in adrenal and plasma corticosterone concentrations). At the age of 11 to 23 months the adrenal corticosterone concentrations in stress are equal in both sexes, and the absolute adrenal weights are similar from 18.5 months until death. The body weight gain is equal in both sexes during the first 50 days of life and greater in males from day 50 to 1 year of age. After this age the body weight of males remains almost the same (315 to 322 g)8 while females continue gaining weight until the end of life (196 to 231 g). This possible causal relationship between the rhythm of growth and sex difference in the adrenal glands in rats is discussed.


Hypolipidemic principles of Cicer arietinum: biochanin-A and formononetin. Two isoflavones, biochanin-A and formononetin isolated from gram Cicer arietinum, have been shown to possess hypolipidemic properties for Triton WR-1339 induced hyperlipidemia in male albino rats, when administered as a crude extract or as individual compounds.


Oxidation of N-methyl-gamma-tocopheramine to a nitroxide. An unstable nitroxide identified by electron paramagnetic resonance spectra was obtained by oxidation of N-methyl-gamma-tocopheramine with peroxide and also by ultraviolet photooxidation.


Adenosine 3',5'-monophosphate and the regulation of rat hepatic sterol synthesis: a reexamination based on Sutherland criteria. Many investigators have reported that adenosine 3',5'-monophosphate (cyclic AMP) at supraphysiologic concentrations (10(-4) M) suppresses lipogenesis in rat livers in vitro. The data in this report demonstrate that the phosphodiesterase inhibitor theophylline does not suppress sterol synthesis by itself nor does it potentiate the cyclic AMP-mediated suppression. In addition the cyclic AMP-mediated effect was not specific as many structurally-related compounds including adenosine triphosphate, adenosine 5'-diphosphate, adenosine 5'-monophosphate, adenosine, coenzyme A, HMG coenzyme A, and guanosine 3',5'-monophosphate suppressed sterol synthesis. The phenomenon of cyclic AMP-suppression of sterol synthesis does not fulfill two of the four criteria defined by Sutherland to assess whether a given metabolic effect is mediated by cyclic AMP. Therefore, we conclude that the cyclic AMP mediated suppression of sterologenesis is not a physiologic effect of the nucleotide.


Glucocorticoids and triglyceride transport: effects on triglyceride secretion rates, lipoprotein lipase, and plasma lipoproteins in the rat. In order to elucidate the mechanism(s) of hyperlipidemia following glucocorticoid administration, dexamethasone (0.125 mg/Kg) was administered daily intramuscularly for 2 wk to male Sprague-Dawley rats and the effects on plasma triglyceride (TG) and cholesterol (Chol), lipoprotein neutral lipids, hepatic triglyceride secretion rates (TGSR; Triton), and epididymal fat lipoprotein lipase (LPL) were determined. Special measures were taken to maintain positive caloric balance and keep the weights of control and dexamethasone-treated animals comparable. Significant increases (p less than 0.001) in TG and very-low density lipoprotein (VLDL) triglyceride associated with no change in Chol and actual reduction in both triglyceride and cholesterol in low density lipoprotein (ldl) were observed in the steroid-treated animals. Dexamethasone treatment was associated with increased basal insulin and glucose levels, an insignificant increment in TGSR, and a highly significant reduction (p less than 0.001) in LPL. These findings suggest that glucocorticoid treatment increases splanchnic triglyceride production rates, but the resulting hypertriglyceridemia is primarily a consequence of impaired VLDL removal due to low adipose tissue LPL activity.


Simultaneous ectopic production of parathyroid hormone and calcitonin. Two patients with cancer were evaluated in whom there was evidence for the simultaneous ectopic production of parathyroid hormone (PTH) and calcitonin (CT). One patient had a gastric carcinoid and the other had a pancreatic islet cell carcinoma. Abnormal concentrations of parathyroid hormone and calcitonin were demonstrated by radioimmunoassay in the peripheral blood of each patient and in the gastric tumor. In the pancreatic tumor, immunohistologic studies also demonstrated the presence of CT and PTH and suggested that each hormone was produced by different cells of the tumor. Plasma concentrations of the hormones responded to functional tests of secretion and to tumor chemotherapy. These studies demonstrate the simultaneous ectopic production of the two physiologically antagonistic hormones, PTH and CT, and confirm their value as diagnostic markers for several types of malignancies.


Acquired increases of human erythrocyte purine enzymes. The alterations of three erythrocyte purine enzymes were studied in 12 patients with diseases associated with reticulocytosis, two patients with a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase, seven patients with severe megaloblastic anemia, and 14 normal subjects. The specific activity of adenine phosphoribosyltransferase was positively correlated (r = 0.81) with the reticulocyte percentate in ten patients with a normal hypoxanthine-guanine phosphoribosyltransferase. Two apparent types of alterations of this enzyme were distinguished: (1) increased specific activity with a normal half life as in megaloblastic anemia, and (2) a prolonged half life with or without an elevation of specific activity as in the deficiency of hypoxanthine-guanine phosphoribosyltransferase. Hypoxanthine-guanine phosphoribosyltransferase and phosphoribosylpyrophosphate synthetase were increased in megaloblastic anemia, but were not correlated with the reticulocyte percentage and did not have a consistent change in the half life in the other disorders studied. The data show that acquired disorders associated with reticulocytosis may cause an elevation of the specific activity of purine enzymes in peripheral circulating erythrocytes. Therefore, these factors must be carefully considered in the interpretation of an elevated level of enzyme activity.


The stimulus-secretion coupling of glucose-induced insulin release. XX. fasting: a model for altered glucose recognition by the B-cell. The rate of glucose uptake and oxidation, the output of lactate, the net uptake of calcium, the release of preformed or newly synthesized insulin and, possibly to a lesser extent, the biosynthesis of proinsulin are all diminished in islets removed from fasted rats and exposed to glucose. Theophylline and dibutyryl-adenosine-3',5'-cyclic monophosphate fail to fully restore a normal secretory response to glucose, despite the fact that they increase lactate production by the islets from fasted animals. The insulinotropic action of other secretagogues, including glyceraldehyde, leucine, beta-hydroxybutyrate, and sulfonylurea is unaffected by prior fasting of the donor rats. The islets metabolism of glyceraldehyde is also unaffected by fasting. These data indicate that fasting is associated with a block in glucose metabolism in the early steps of glycolysis, prior to the triose-phosphate level, and suggest that the insulin secretory response to glucose may be closely dependent on the rate at which the hexose is metabolized by islet tissue.


Fanconi's familial hypoplastic anaemia with some unusual features. A case of Fanconi's familial hypoplastic anaemia is described in a 48-year-old woman who had the usual haematological and constitutional abnormalities of this condition. Chromosomal studies on peripheral blood lymphocytes and direct marrow preparations demonstrated the chromosomal breaks previously described. The age of the patient and a congenital abnormality of breast development were unusual features, while the discovery of a benign liver tumour at necropsy is of interest, as the patient had received therapy with oxymetholone.


[Hospital-acquired hepatitis type B. Report of 6 cases (author's transl)]. Seroconversion was observed in 6 patients, indicating an infection with hepatitis virus B. All of these patients had been hospitalized with HBAg-positive persons a few weeks before, 5 of them because of acute hepatitis type A. While seroconversion was followed by acute hepatitis in 4 cases, the infection remained clinically silent in the other two patients. The second periods of illness were no attacks of relapsing hepatitis type A, as was indicated by HBAg. Vice versa superinfection of hepatitis B-patients with hepatitis virus A may occur, as is discussed in another case. Acute hepatitis is often transmitted in hospitals. Infective routes are discussed and means are described, by which is attempted, to reduce the incidence of hospital-acquired hepatitis.


Chronic cadmium poisoning.

Chronic cadmium poisoning. Chronic cadmium poisoning occurs after prolonged exposure to the dust or fumes of cadmium-containing compounds. This paper describes the case of a pigment worker exposed to cadmium carbonate dust who exhibited many of the characteristic features of chronic cadmium poisoning.


Genetic and enzymatic analysis of a glycerol kinase deficient mutant in Neurospora crassa. Genetic analysis showed that the glycerol non-utilizing isolate gly-u(234) of Neurospora crassa is derived by mutation in a nuclear gene situated in the right arm of linkage group I, about 2.2 cross-over units distal to ad-9 and 11 units proximal to nit-1. Enzymatic testings using a radiochemical method indicate that the mutant is deficient for the enzyme glycerol kinase. The radiochemical testings further indicate that the mutation has inactivated an inducible glycerol kinase, while a low residual activity may be due to a second, basal and non-inducible glycerol kinase, in accordance with a proposal by North (1973, 1974) that Neurospora has two glycerol kinases with these properties.


Protein-liposome interactions and their relevance to the structure and function of cell membranes. Recent studies on the interactions of soluble proteins, membrane proteins and enzymes with phospholipid model membranes are reviewed. Similarities between the properties of such systems and the behavior of biomembranes, such as alterations in the redox potential of cytochrome c after binding to membranes and effects of phospholipid fluidity on (Na+K) ATPase activity, are emphasized. The degree of correspondence between the behavior of model systems and natural membranes encourages the continuing use of model membranes in studies on protein-lipid interactions. However, some of the data on the increase of surface pressure of phospholipid monolayers by proteins and increases in the permeability of liposomes indicate that many soluble proteins also have a capability to interact hydrophobically with phospholipids. Thus a sharp distinction between both peripheral and integral membrane proteins and non-membrane proteins are not seen by these techniques. Cautious use of such studies, however, should lead to greater understanding of the molecular basis of cell membrane structure and function in normal and pathological states. Studies implicating protein-lipid interactions and (Na+K) ATPase activity in membrane alterations in disease states are also briefly discussed.


On the histoenzymology of the human stomach. By means of histochemical methods, the stomach in the man was studied for some oxidoreducing enzymes and hydrolases. The surface epithelium displays in the fundic area a mean activity which grows intense in the pyloric area. The parietal cells show a very high mitochondrial dehydrogenase activity, while the chief ones display a moderate oxidative activity. The pyloric glands exhibit a positive reaction for oxidoreducing enzymes with great differences of intensity from one cell to another. Around each principal and pyloric gland one can see an intense ATP-ase reaction in the endothelium of vessels and a very intense acid phosphate activity in the histiocytes. The submucosa, muscularis externa and serosa are very active for oxidoreduction and ATP-ase.


Pleomorphous macrocellular pulmonary carcinomas. An anatomoclinical study on 193 cases. A pathomorphologic study was carried out by the conventional histologic methods in 193 cases of pleomorphous macrocellular pulmonary carcinoma, of a total of 1,637 cases of lung cancer diagnosed histologically between January 1, 1961 and December 31, 1974. In comparison to other histologic types, the incidence of macrocellular carcinomas was of 11.8%, 62.6% belonged to the 40-60 years age-group, with male predominance. The results showed this carcinoma to be an autonomous type of neoplastic proliferation. The pathomorphologic particularities observed in the 193 cases and their evolution are conclusive arguments for considering pleomorphous macrocellular carcinomas as a separate histologic type in the classification of lung cancers. The term of pleomorphous macrocellular carcinoma appears to be the most comprehensive and in keeping with the histologic structure of these tumours. Cellular pleomorphism is an important diagnostic feature. Zones of specific differentiation observed in some cases may be included in the pleomorphism of these carcinomas. Notions of histogenesis are likewise discussed. It is increasingly assumed that these carcinomas are morphologically the expression of a cellular proliferation, differentiation and maturization response to the action of complex factors. The reduced stroma of these carcinomas indicate a more rapid increase of the tumoural parenchyma.


[Bacterial resistance factors as vectors for gene manipulation and gene therapy (author's transl)]. Bacterial resistance factors are extrachromosomal elements, consisting of circular closed, double stranded DNA. They may contain genes which make the host bacterium resistant to certain antibiotics. Such resistance factors have become important vectors for selective replication of specific segments of all kinds of DNA. Suitable DNA segments are obtained by treating DNA with restriction endonucleases of defined cutting properties. They can then be linked to the respective vector. It was thus possible to anneal DNA segments originating from the same, but also from different bacterial resistance factors. They gave biologically functional units. The annealed products can be propagated in bacteria. The relevant experiments are described. Their potential dangers for man, and efforts to agree on suitable safety regulations are discussed.


[Conception of programmed and standardized after-care of mammary carcinoma (author's transl)]. Optimal after-care of mammary carcinoma begins with the end of the primary therapy and lasts practically for a lifetime. The after-care consists of several inpatient follow-ups in specially equipped follow-up clinics, of outpatient after-care by the general practitioner and of care by appointment at the treatment center. Standardized diagnostic methods combined with programmed appointments form the basis of an effective after-care for mammary carcinoma. The essence of a programmed and standardized after-care for mammary carcinoma lies in the fact that all participants are forced into a uniform and scheduled procedure by which the observance of a minimum program is guaranteed.


[Effect of clofibrate on glucose tolerance and insulin secretion in patients with endogenous hypertriglyceridemia (author's transl)]. In 22 patients with endogenous hypertriglyceridemia, oral and intravenous glucose tolerance showed significant improvement under clofibrate treatment which was in no way correlated to the fall in triglycerides. Basal and stimulated insulin, cholesterol and fasting blood sugar did not change, body weight remained constant and was not correlated to the degree of hypertriglyceridemia. On the other hand a positive correlation between body weight and insulin concentrations was found. Improvement of glucose tolerance independently of body weight and insulin may be due to a direct effect of clofibrate on glucose metabolism without any correlation to its triglyceride-lowering.


The mutability of the minute loci of Drosophila melanogaster with ethyl methanesulfonate. It has been suggested that the Minute loci of Drosophila melanogaster are the redundant structural loci for the transfer RNA's [31]. To inquire whether the Minute loci differed from other loci in their genetic organization we have determined the dose response curves for the induction of Minutes and sex-linked recessive lethals with ethyl methanesulfonate (EMS). There are approx. 67.75 +/- 9.35 Minute mutants induced for every 5000 recessive lethals induced in the genome and this relationship is independent of EMS dosage. This is in good agreement with the relative numbers of Minute and lethal loci in the genome. Because the target size of the average Minute locus is the same as that of the average locus capable of mutating to a lethal, these data do not support the view that the Minute loci are special in their genetic organization. Since Minute mutants can be scored in the F1 of mutagenized flies it is suggested that the induction of Minute mutants may provide a more rapid and economical means of assessing mutagenicity than do traditional screens for the induction of recessive lethals.


Mutagenesis studies on cultured mammalian cells. The sensitivity of the asparagine-requiring phenotype to several chemical agents. The effect of several chemical agents on the mutation frequency from asparagine dependence to asparagine independence has been studied in Jensen sarcoma cells. It was found that ethylmethanesulfonate brought about a dramatic exponential increase, while nitrosoguanidine was not lighly effective as a mutagen, causing only a modest increase in mutation frequency, and quinacrine HCl was ineffective. The results presented here are compared with those obtained in other systems and with our previous work on the effects of UV on mutation induction in the asparagine system. They suggest that the basis of the asparagine requirement of mammalian cell lines resides in a specific genetic alteration in nuclear DNA which is corrected by the mutagenic action of the agents tested here.


Adenine arabinoside therapy of herpes zoster in the immunosuppressed. NIAID collaborative antiviral study. We evaluated adenine arabinoside treatment of herpes zoster in immunodeficient patients in a randomized, controlled crossover study. The two study groups had similar characteristics. In spite of rapid natural healing, those receiving adenine arabinoside over the first five days had accelerated clearance of virus from vesicles (P = 0.01), and cessation of new vesicle formation (P = 0.004), and a shorter time to total pustulation (P = 0.001). Factors modifying the response to therapy included age, underlying disease, and the duration of zoster prior to therapy. Clinical toxicity was minimal. Laboratory assessment of bone-marrow, liver and renal function showed insignificant alterations as a result of therapy. These studies show that adenine arabinoside is a drug with promise for therapy of systemic herpes zoster in immunocompromised patients. It is most efficacious when administered during the first six days of disease (P = 0.001) to those who have reticuloendothelial neoplasia (P = 0.001) and are less than 38 years of age (P = 0.001).


Myocardial infarction and estrogen therapy in post-menopausal women. Data obtained from two multipurpose surveys of hospitalized patients were examined to determine the risk of nonfatal acute myocardial infarction in post-menopausal women 40 to 75 years of age in relation to use of estrogen-containing drugs. Eight (2.4 per cent) of 336 myocardial infarction patients and 330 (4.9 per cent) of 6730 reference patients were regular estrogen users (crude rate ratio, 0.47) at the time of hospitalization. After control for confounding variables -- among them, age, past history of myocardial in farction, angina, diabetes, and hypertension (alone or in combination) and cigarette smoking -- the summary point estimate of rate ratio was 0.97 with 95 per cent confidence limits of 0.48 and 1.95. Thus, there was no evidence of a statistically significant association between current regular use of estrogens and nonfatal acute myocardial infarction.


Estrogens and endometrial cancer in a retirement community. All cases of endometrial cancer occurring among the residents of an affluent retirement community were compared with controls chosen from a roster of all women in the same community. Evidence of estrogen and other drug use and of selected medical conditions was obtained from three sources: medical records of the principal care facility, interviews, and the records of the local pharmacy. The risk ratio for any estrogen use was estimated from all available evidence to be 8.0 (95 per cent confidence interval, 3.5 to 18.1). and the for conjugated estrogen use to be 5.6 (95 per cent confidence interval, 2.8 to 11.1). Increased risk from estrogens was shown for invasive as well as noninvasive cancer, and a dose-response effect was demonstrated. For an estrogen user, the risk from endometrial cancer appeared to exceed by far the base-line risk from any other single cancer.


Infectious mononucleosis. Epstein-Barr-virus shedding in saliva and the oropharynx. In an examination of excretion patterns of Epstein-Barr virus in 104 throat washings from 20 patients with infectious mononucleosis we found that three persons regularly shed virus from the second week through the third month after onset; 15 demonstrated intermittent excretion over three months, and in two cases, no virus was detected. In oral secretions, the virus appeared to be located extracellularly. Transforming activity was demonstrated in aliquots after centrifugation and filtration, in a sample in which cells were disrupted before filtration, and in specimens after two years' storage. Multiple oropharyngeal sites were examined for presence of the virus. In one patient, virus was regularly demonstrated in throat washings and saliva; swabs from Stensen's duct orifices yielded virus in three of four cases. Demonstration of virus in these oropharyngeal specimens explains increased transmissibility in age groups in which salivary exchange is high.


Radiation and high-dose metronidazole in supratentorial glioblastomas. We used "high-dose" metronidazole, an "in vitro" and "in vivo" specific radiosensitizer of hypoxic cells, in a controlled trial to evaluate possible enhancement of radiation effect in patients with supratentorial glioblastomas. Thirty-six patients were stratified according to functional level and randomly allocated within two weeks of operation to one of two therapeutic groups: Group 1, radiation alone; and Group 2, radiation as in Group 1 but with high-dose metronidazole. We examined survival with the Kaplan-Meier probability plot and non-parametric tests. Patients in Group 2 had a 4 1/2-month delay between relapse and subsequent death (P = 0.02). This shift of the survival curves suggests a delay in the time of tumor regrowth consistent with the ability of metronidazole to make the hypoxic tumor cells less radioresistant. Nitroimidazole derivatives may be useful radiosensitizers in human solid tumors.


Susceptibility of chickens to avian encephalomyelitis virus. II. Behavior of the virus in day-old chicks. The VR strain of avian encephalomyelitis virus, which had been adapted to embryonated hen's eggs, was inoculated into 2-day-old chicks by the subcutaneous route (10(2.5) approximately 10(3.0) EID50) or by the oral route (10(4.8) EID50). The chicks were examined chronologically for the distribution of the virus in the body. As a result, minute amounts of the virus were detected from the liver, spleen, pancreas, and muscle at the site of inoculation one day after inoculation and various amounts from almost all the organs 3 days and more after inoculation. The virus titer could nearly reach a maximum 7 to 9 days after inoculation. Above all, such high virus titers as ranging from 10(4.3) to 10(5.8) EID50/0.1 g were demonstrated in the brain, heart, liver, spleen, and pancreas. After that, there was a tendency for virus titer to decrease in most organs and for virus to multiply persistently in the pancreas, brain, and eyeball. Virus titer was maintained at a level of 10(2.3) approximately 10(2.8) EID50/0.1 g in these three organs even 21 days after inoculation. In the group of subcutaneous inoculation, all the chicks manifested clinical signs of infection 5 to 10 days after inoculation. On the other hand, no chicks were involved in clinical infection in the group of oral inoculation. Multiplication of the virus was delayed in the body of these chicks. Small amounts of the virus were detected from the spleen and pancreas 11 days after inoculation. Low titers (10(2.7) EID50/0.1 g at the highest) of the virus were only detected from the brain, spinal cord, spleen, pancreas, esophagus, and other organs 14 and 21 days after inoculation.


Pathogenicity for chicks of line cells from lymphoma of Marek's disease. Pathogenicity for chicks of the MSB-1 line, a cell line derived from the tumorous tissue of a chick with Marek's disease (MD) and established by Akiyama & Kato, was studied. Five groups, including a control one, of 20 chicks each were inoculated with 1 X 10(3), 1 X 10(4), 1 X 10(5), 1 X 10(6) and no cells of a 180-day culture of the cell line at one day of age. They were housed all together in an isolation unit. An attempt was first made successfully to isolate MD virus (MDV) directly in culture of kidney cells 3 weeks after inoculation. Horizontal infection was first detected 4 weeks after inoculation. From 3 weeks after inoculation on, the disease with almost the same clinical and pathological pictures as the infection with a virulent strain of MDV showed a high incidence. Morbidity was closely related to the number of MSB-1 line cells inoculated. Parenchymal destruction was conspicuous in the central lymphoid organs of four chicks given the largest number of MSB-1 line cells and sacrificed in extremis about 4 weeks after inoculation. Establishment of MD in chicks inoculated with MSB-1 line cells carrying MDV genome seemed to be initiated under the circumstances where the line cells which had come into contact with susceptible cells in the peritoneal cavity released virulent MDV per se. Then host chicks might be infected with MDV and suffer from MD at a high rate. There was no great difference in oncogenic potential between MSB-1 line cells cultivated in vitro for 180 days and virulent MDV serially passaged through one-day-old chicks.


Recrudescence of equine infectious anemia by treatment with immunosuppressive drugs. Horses which had passed a few months to a few years asymptomatically after the last recurrence of equine infectious anemia (EIA) showed a typical febrile response after treatment with the immunosuppressive agent, dexamethasone (DM) or cyclophosphamide (CY). In horses showing a febrile response, EIA virus which had not been neutralized by neutralizing antibody previously produced was propagated. In DM-treated horses it disappeared from the blood soon after pyretolysis and antibody against the virus was produced promptly. In contrast, detectable viremia persisted in CY-treated horses for 10 to 84 days after pyretolysis. Antibody against the virus was barely produced for 42 to 126 days after treatment. After drug treatment, there was no decrease in neutralizing antibody previously produced. Then, it was inferred that this febrile response was due to propagation of an immunologically variant virus which might have been produced as a result of decline in cell-mediated immunity. The role of cellular mechanisms in the development of immunity to EIA was also discussed.


[Transmission of impulse trains by nerve fibers upon near-threshold stimulation]. Impulse trains evoked by stimulation of the hindlimb nerves were studied in group A fibres at the lumbar level of spinal cord in anesthetized cats. Random (Poissonian) trains fo stimuli and trains with modified structure were used. With suprathreshold stimulation the impulse trains in the nerve fibres differed from the stimulus trains only by the absence of the shortest (less than 1.0 divided by 1.5 ms) intervals caused by refracteriness. Substantial differencies between the impulse and stimulus trains occurred when the stimulus intensity was decreased to a near-threshold level and mean frequency of stimulation was higher than 10 per second. Differences were found in interval histograms, intensity functions, correlation coefficients for successive intervals. Afterdischarge processes in the nerve fibres are supposed to be the main reason of changes in the impulse train structure.


Growth potential and skeletal maturity in children with chronic renal insufficiency. The growth potential of 27 boys with varying degrees of chronic renal insufficiency has been determined from their present height centile for both bone age and chronological age. With increasing age their growth potential diminishes. The delay in bone age is greatest in those children whose disease dates from infancy, but does not correlate with their present state of renal function. Bone age continues to advance in the presence of severe osteodystrophy and growth arrest. Knowledge of the growth potential of children with chronic renal failure is of relevance in interpreting the height increments observed following renal transplantation. Serial determination of bone age is therefore an important aspect of their clinical management.


Effects of an intraventricular injection of synthetic ACTH on plasma testosterone, progesterone and LH levels and on sexual behavior in male and female rabbits. Sexual behavior and elevation of gonadal steroids were induced in both male and female New Zealand white rabbits following injection of synthetic beta (1-24) ACTH into the lateral cerebral ventricle. In blood assays collected by cardiac puncture, testosterone, progesterone and corticosterone were all increased above both resting levels and samples were taken after a control intraventricular injection of physiological saline. Parallel increases of plasma LH were also demonstrated. The results were interpreted to indicate that intraventricular ACTH, through LH release, influences sex hormone levels and sexual behavior by 'centrally', probably within the hypothalamus.


Rapid eye movement sleep alterations in myasthenia gravis. The nocturnal sleep patterns of 10 patients with myasthenia gravis and five controls were recorded in the conventional manner for 7 hours on two consecutive nights. One patient was retested 4 weeks after institution of prednisone therapy. All the myasthenics had a significant disturbance in rapid eye movement (REM) sleep cycles. In the patient who was retested after clinically successful prednisone therapy, the REM sleep pattern had become normal. Since acetylcholine is the putative brain stem transmitter substance involved in the maintenance of REM sleep, our findings suggest a disturbed central mechanism of acetylcholine in myasthenia gravis.


Electrophysiologic diagnosis of myasthenia gravis and the regional curare test. Two hundred and fifty consecutive patients were evaluated for myasthenia gravis with repetitive supramaximal stimulation of peripheral nerves and regional curare administration when necessary. Among patients with definite generalized myasthenia gravis, 72 percent had abnormal responses to repetitive supramaximal stimulation alone and another 17 percent had abnormal responses after regional curare administration. Among those with possible generalized myasthenia gravis, 15 percent had abnormal responses to repetitive supramaximal stimulation and another 12 percent had abnormal responses after regional curare administration. Of those with only ocular symptoms, 46 percent had abnormal responses to repetitive supramaximal stimulation before or after regional curare administration, suggesting generalized involvement. Myasthenia gravis has not developed subsequently in any of the equivocal patients with negative electric tests. We have found these electric procedures to be simple, safe, and at least as effective as other methods in diagnosing myasthenia gravis.


[Importance of early hormonal treatment of salaam seizures for the further course of epilepsy in children]. The authors analysed 13 cases of West's syndrome (8 females and 5 males observed in a period of 30 months. In only one case there was history of perinatal trauma. In 7 children the psychomotor development was very good until the time of development of seizures, in 2 children hyperexcitability was present, 1 was obese, 2 had various infections. In 7 cases the seizures developed within 1 to 20 days after DiPerTe or poliomyelitis vaccination. The time from the onset of seizures to beginning of hormonal treatment ranged from 4 weeks to 5 months. Corticosteroids or ACTH were administered for 2 months at least, and benzodiazepine drugs and/or phenobarbital were given additionally. It was found that the effects of treatment were much better in children referred for treatment early after onset of seizures. In cases with delayed hormonal treatment mental retardation was considerable and seizures were frequent.


Pain in peripheral neuropathy related to rate and kind of fiber degeneration. In a series of 72 patients with disease of peripheral neurons, neuropathic painfulness of the foot was found to be related to the rate and kind of nerve fiber degeneration. Patients with acute breakdown of myelinated fibers (either by wallerian or axonal degeneration) tend to have pain more often and to a greater degree than do patients with more chronic forms of nerve fiber degeneration. Neuropathic painfulness was not found to be related simply to the ratio of remaining large and small fibers after nerve fiber degeneration. These studies do not fit the expectation of the proponents of the gate theory of pain.


The acetylcholine receptor in normal and pathologic states. Immunoperoxidase visualization of alpha-bungarotoxin binding at a light and electron-microscopic level. Acetylcholine receptor now can be visualized in the muscle sarcolemmal membrane with the use of an immunoperoxidase staining of alpha-bungarotoxin (alpha BT), a substance that binds specifically to the acetylcholine receptor. This technique has allowed new observations in various neuromuscular diseases in which the acetylcholine receptor is affected. In normal muscle, the acetylcholine receptor is confined to the neuromuscular junction. In both experimental denervation and human denervating illnesses, the acetylcholine receptor becomes present diffusely along the muscle sarcolemmal membrane in denervated fibers. In myasthenia gravis, a circulating factor that blocks alpha BT binding to the acetylcholine receptor of either normal neuromuscular junctions or denervated sarcolemmal membranes is present in 68 percent of serums tested.


Koilocytotic atypia of the cervix.

Koilocytotic atypia of the cervix. Koilocytotic atypia was found in 217 of 858 cervical biopsies obtained during a 26-month period. Koilocytotic change was more common in younger women. Nuclear atypia in the koilocytotic cells was associated with cervical dysplasia in a high proportion of cases. There was a significant difference in the incidence of dysplasia in koilocytosis with marked nuclear atypia when compared to koilocytosis without nuclear atypia. In some cases koilocytosis was associated with vesicular changes in the cervical epithelium. The significance of this change and its association with other abnormalities of the cervix is discussed.


Cytomegalic virus disease in pregnancy.

Cytomegalic virus disease in pregnancy. A case report is presented in which cytomegalic virus inclusion bodies were demonstrated in twin placentas and in both infants. This is the fourth such report in the English language literature. The case also demonstrated interlocking of the fetal heads requiring decapitation of the dead twin in order to deliver the surviving twin. The survivor showed gross stigmas of cytomegalic viral disease.