The effect of taurine on kindled seizures in the rat. Recently, it has been reported that taurine, an amino acid with anticonvulsant properties, does not suppress experimental seizures generated by the "kindling" technique. This finding seems somewhat paradoxical since taurine antagonizes other sorts of experimental convulsion and since kindled seizures are easily suppressed by other anticonvulsant drugs. Further tests were therefore conducted during which taurine's anticonvulsant effects were assessed: (1) when kindling stimulation was dropped to near-threshold levels; (2) when cortical as well as limbic kindled foci were stimulated; (3) when developing as well as fully kindled seizures were involved; and (4) when taurine was introduced directly into the ventricles of the brain. Even in these tests which were specifically designed to favour the appearance of anticonvulsant effects, no taurine antagonism of kindled seizures was found.


Effects of arachidonic acid and indomethacin on the in vitro release of prostaglandins by aortic strips of spontaneously hypertensive rats. Aortic strips removed from spontaneously hypertensive (SH) rats and preincubated with arachidonic acid (1.0 X 10(-5) g/ml) for 15 min produced two times more prostaglandin (PG) like material than aortae unexposed to the precursor of PG biosynthesis. The stimulating effect of arachidonic acid was largely inhibited by indomethacin (1.0 X  10(-5) g/ml). Also, the release of PG-like material by aortic strips derived from SH rats treated with an intravenous injection of indomethacin (10 mg/kg) was inhibited by 74% compared with the control tissues. These results raised the possibility that the in vivo conversion of arachidonic acid by large arteries of SH rats may contribute to the hypotensive effect of this PG precursor in SH rats.


Inability of glucagon to increase glomerular filtration rate in dogs with experimental cirrhosis and ascites. In marked contradistinction to the normal dog, to the dog with renal hypoperfusion, or to the chronic caval dog with ascites, the intravenous infusion of glucagon at 5 microgram/min to dogs with experimental portal cirrhosis and ascites does not increase glomerular filtration rate or renal blood flow. In eight experimental dogs who did not respond to glucagon, a marked natriuresis was observed in response to furosemide and a marked renal vasodilator response was seen following the intraarterial infusion of acetylcholine. Because plasma immunoreactive glucagon levels are increased fivefold in cirrhotic dogs, it is suggested that continuous high levels of this peptide render the animals insensitive to the effects of an exogenous infusion.


Motoneuronal after-potentials and extracellular divalent cations. In cats under Dial anesthesia, microiontophoretic injections of Co2+ or Mn2+ outside lumbosacral motoneurones regularly diminish the postspike hyperpolarizing after-potential (AHP) without any clear reduction of the deplorarizing after-potential (ADP). Comparable injections of Sr2+ have the opposite effect of augmenting the AHP. These results indicate that the AHP is indeed initiated by an influx of calcium linked to the action potential, but the ADP is unlikely to be mainly a manifestation of a calcium inward current.


Dantrolene blocks intracellular calcium release in smooth muscle: competitive antagonism of thromboxane A2. Dantrolene sodium has been shown to block the release of intracellular calcium in skeletal muscle. It has been proposed that dantrolene blocks the movement and (or) action of a natural calcium ionophore. In a rat vascular preparation dantrolene was found to inhibit pressor responses to noradrenaline and angiotensin but not those to potassium with an IC50 concentration within the therapeutic levels in man. Imidazole, an inhibitor of thromboxane A2 (TXA2) synthesis, had similar actions to dantrolene. Interactions between imidazole and dantrolene suggested that dantrolene may be a competitive antagonist of TXA2 in muscle. We report the first demonstration of an effect of dantrolene sodium on smooth muscle contractility and suggest that TXA2 is an essential modulator of vascular reactivity. A similar role has been shown for TXA2 in platelets.


Antagonism of substance P induced facilitation of central neuronal activity by 2,4-dinitrophenol and depressant agents. 2,4-Dinitrophenol, pentobarbital, thiopental, methoxyflurane, and halothane more often antagonized the facilitatory effects of substance P than of acetylcholine on the activity of spinal dorsal horn neurons (of unanesthetized decerebrated and spinalized cats) as well as interpeduncular and cerebral cortical cells (of either rats anesthetized with methoxyflurane, nitrous oxide, and oxygen or 'cereveau isolé' rats). The results of the studies indicate that the excitatory effects of substance P on central neurons are extremely sensitive to anesthesia.


The effect of glucagon on intestinal lymph flow in rats. Intravenous injection of a bolus of 5 microgram of glucagon to rats with an intestinal lymph fistula produces a marked, transient rise in lymph flow and protein output from the fistula. The effect is presumably the result of brief enhancement of splanchnic blood flow.


Flow correlation of loop of Henle potassium influx. Potassium influx in short loops of Henle was assessed using end proximal to early distal perfusion with potassium-free saline. Over a wide range of perfusion rates influx was highly correlated with collected flow rates. The magnitude of the influx was comparable with the delivery rate of potassium to the early distal site seen during free flow, over a narrower range of collected flow rates.


Loss of chloramphenicol production in strains of Streptomyces species 3022alpha treated with acriflavine and ethidium bromide. An assay procedure was developed to detect chloramphenicol production in large numbers of Streptomyces species 3022alpha isolates, and was used to screen colonies from cultures exposed to acriflavine and ethidium bromide. There was a significant rise in the proportion of low- and non-producing strains in the treated cultures. Since the organism developed resistance to acriflavine but not ethidium bromide, the effects of the latter agent were examined in more detail. Loss of chloramphenicol production was not due to mutation, nor to differential sensitivity to the drug among producing and non-producing natural variants. The response of cultures varied with age, and at least three strain types--high-, low-, and non-producers could be distinguished. A study in shaken cultures of selected isolates from the screening process established the general reliability of the screening method and showed that the assay probably sometimes failed to distinguish between low- (15-20 mg/iota) and non-producers. It indicated that the non-producer class consisted of some very low (up to 4 mg/iota) producers as well as fully negative strains, and it confirmed indications from the screening results that a non-producing isolate obtained by acriflavine treatment accumulated aromatic amines and was probably blocked in the pathway for chloramphenicol biosynthesis.


The effect of growth temperature on the fatty acid composition of Thamnidium elegans Link. The fatty acid composition of a slightly psychrophilic fungus, Thamnidium elegans, has been determined and compared with other mucoraceous fungi. The growth temperature strongly influences the degree of unsaturation of lipids, as reported for other organisms, but in T. elegans both the quantitative and qualitative profiles of the fatty acids are affected. At low temperature, T. elegans contains both alpha- and gamma-isomers of linolenic acid. The alpha-isomer is reported here for the first time in a mucoraceous fungus. Besides the biosynthesis of alpha-linolenic acid at the low temperature, T. elegans shows an increase in synthesis of a relatively unknown fatty acid in fungi, i.e. octadecatetraenoic acid (18:4delta 6,9,12,15). The significance of the occurrence of both the isomers of linolenic acid as a response to temperature and in relation to fungal phylogeny is discussed.


Utilization of oleuropein by microorganisms associated with olive fermentations. Oleuropein, the bitter glucoside of olives, and its hydrolysis products can possess antibacterial action. However, there is no information on the possible utilization of this polyphenolic compound; therefore studies have been made to assess its utilization as a major source of carbon. Various microorganisms associated with fermentation of olives (both desirable lactic acid bacteria and spoilage organisms) did use oleuropein, many without a significant delay in growth resulting in the appearance of a strong visible turbidity. Although the increase in oleuropein from 0.2 to 0.4% (w/v) had little or no effect on the spoilage organisms, the additional glucoside caused a delay in development of growth with some of the lactic acid bacteria. However, all of the latter cultures tested eventually grew and developed strong visible turbidity.


Interaction between Rhizobium japonicum phage M-1 and its receptor. The receptor for phage M-1 was present in the exopolysaccharide (EPS) of Rhizobium japonicum D211. The EPS was a heteropolysaccharide consisting of glucose, galactose, glucuronic acid, and glucosamine units. These monosaccharides prevented phage-cell attachment indicating that they may mimick the receptor. Phage-cell attachment was either stimulated or inhibited by Mg2+ and Ca2+ depending upon their concentration. An enzyme which depolymerized the exopolysaccharide releasing oligosaccharides was detected in the phage-infected cell lysates. A comparison of the properties of adsorption and those of the depolymerase enzyme indicated that the latter was a component of the phage and appeared to be involved in the phage-receptor interaction.


Halobacterium vallismortis sp. nov. An amylolytic and carbohydrate-metabolizing, extremely halophilic bacterium. The extremely halophilic bacterium (formerly designated as strain J.F. 54) isolated from salt pools of the Death Valley, California, is a motile, Gram-negative, extremely pleomorphic organism, aerobe, and facultative anaerobe. A variety of carbohydrates are assimilated with or without acid production; soluble starch is hydrolyzed. The organism is not proteolytic; catalase, oxidase, and DNase reactions are positive; Tween 20 is slightly hydrolyzed, but Tweens 40, 60, and 80 are not. Nitrates are reduced to nitrites with gas production; nitrites are not reduced. Optimum growth temperature is 40 degrees C. Growth is inhibited by bacitracin and by novobiocin. The type strain J.F. 54 differs from described species of the genus Halobacterium and is assigned to a new species, Halobacterium vallismortis sp. nov.


Stable isotope fractionation by Clostridium pasteurianum. 2. Regulation of sulfite reductases by sulfur amino acids and their influence on sulfur isotope fractionation during SO32- and SO42- reduction. In addition to an assimilatory sulfite reductase, studies of cultures of Clostridium pasteurianum supplemented with methionine, cysteine, and 35SO42- provides evidence for another reductase which is induced by SO32-. This inducible reductase appears to be dissimaltory because of the copious sulfide production arising when the cells are grown on SO32-. Cysteine can repress the assimilatory sulfite reductase but does not affect the inducible reductase. During late logarithmic growth on 1 mM SO42- + 10mM cysteine, depression of the inducible reductase occurred along with increased sulfide production. The presence of 1 mM cysteine and (or) 1 mM cysteine and (or) 1 mM methionine does not affect the inverse sulfur isotope effect for evolved H2S. However, 5 and 10 mM cysteine reduce the maximum delta34S value for released H2S from +40 to 10%. A small conversion of cysteine to H2S by C. pasteurianum occurs, but only in the stationary phase.


[Ultrastructural study of the biodegradation processes. I. Beech (Fagus sylvaticus L.) leaf white rot]. An electron microscopic study of beech leaf white rot shows a certain number of characteristic developmental stages which are identical whether the material is from in vitro experimentation or from natural incubation. Endowed with a cellulolytic properly seemingly localized in the apical region only, hyphae of the white rot agent only traverse the plant cell walls. Subsequently, hyphae penetrate condensed protoplasmic residues and make them progressively transparent to electrons. During this discoloring process, a lethal factor of as yet unknown nature appears, affecting other microorganisms already present in the leaves. Phloem and xylem vascular bundles do not present notable ultrastructural modifications. Therefore, leaf discoloration is not due to an alteration of the xylem constituents but to changes having occurred in the condensed cytoplasmic residues of the dead tissues.


Light microscopy observations of tetrazolium-reducing bacteria in the endorhizosphere of maize and other grasses in Brazil. Roots of field-grown tropical maize, Panicum maximum Jacq. and Digitaria decumbens Stent., and of sorghum and wheat grown in monoxenic culture with the diazotroph Spirillum lipoferum (syn. Azospirillum spp.) were examined for tetrazolium-reducing bacteria following incubation of roots in a malate-phosphate buffer-2,3,5-triphenyltetrazolium chloride medium. Bacteria were observed between and in cells of the cortex, in intercellular spaces between the cortex and endodermis, in xylem cells, and in and between pith cells. In maize, colonization of the inner cortex and stele appears to occur in the absence of significant bacterial colonization or collapse of outerlying tissues. Bacteria in the stele remained viable after a 6-h treatment of roots with chloramine-t, indicating that the endodermis was intact. Infection of the inner cortex and stele appears to occur initially in branches, and then to spread longitudinally into main roots. Inter- and intra-cellular infections of the cortex were observed in monoxenic systems. Tetrazolium reduction and prominent crystal formation was not specific for diazotrophic bacteria, but S. lipoferum was isolated from surface-sterilized roots, and S. lipoferum-like organisms were observed in the endorhizosphere. A correlation of inner cortex and stele infections with the presence of branches appears to explain previous observations that excised roots of grasses exhibiting high nitrogenase activity are characteristically branched roots with an intact cortex.


[Physiological study and taxonomy of Alcaligenes species: A denitrificans, A. odorans and A faecalis]. We have studied 43 strains of the species Alcaligenes dentrificans, A. odorans, and A. faecalis. Twenty-five of them were isolated by enrichment culture on minimal medium containing an organic acid (L-malate, succinate, tartrate, adipate, or itaconate) and N2O as a respiratory electron acceptor. These constitute a single phenon with the A. dentrificans strain type and 9 other strains isolated from clinical specimens. However, strain 4 differs from the other 34 strains in 12 nutritional characters, in its ability to effect a meta cleavage of diphenols, and by the absence of tetrathionate reductase. The percentages of G + C are the following: strains isolated from soil, 66.4 +/- 1.1; collection strains, 67.0 +/- 1.3. The 5 strains of A. odorans differ from the 34 strains of A. denitrificans (not including strain 4) in their inability to denitrify nitrate and use D-saccharate, adipate, pimelate, suberate, beta-hydroxy-beta-methylglutarate meso-tartrate, azelate, and itaconate. Their percentage of G + C is much lower: 56.1 +/- 0.4. From the nutritional point of view the 3 strains of A. faecalis resemble A. dentrificans. However, they differ from the latter by their inability to grow anaerobically on NO3-, NO2-, N2O, and by a slightly lower percentage of G+ C: 64.3 +/- 0.0. The 43 strains synthesize poly-beta-hydroxybutyric acid. None of them is chemolithotrophic.


Denitrification in Rhizobium.

Denitrification in Rhizobium. Thirty-three strains of Rhizobium were examined for their reduction of nitrate under anoxic conditions. Three patterns of dissimilatory nitrate reduction were observed: (1) reduction to N2O and N2 (denitrification), (2) reduction to and subsequent accumulation of NO2- (nitrate respiration), (3) no reduction. Strains of R. japonicum and the cowpea miscellany displayed all three types, while strains of R. leguminosarum, R. phaseoli, and R. trifolii did not reduce nitrate by dissimilatory means. The production and subsequent metabolism of N2O was considerably different among the denitrifying strains: in some instances, N2O was a transient intermediate, while in others, it continued to accumulate during the incubation period.


The use of polyethylene glycol in radioimmunoassay of staphylococcal enterotoxins. The double-antibody radioimmunoassay of enterotoxins A, B, and C was modified by the addition of aqueous polyethylene glycol which precipitated double-antibody bound staphylococcal enterotoxins with little or no precipitation of free enterotoxin. The precipitate formed appeared as a thin coating at the bottom of the test tube and was not removed by aspiration. The procedure obviates the need for normal rabbit serum and for an additional wash of the precipitate.


Lipotropin, melanotropin and endorphin: in vivo catabolism and entry into cerebrospinal fluid. Anesthetized rabbits were given intravenous injections of either beta-lipotropin (beta-LPH), beta-melanotropin (beta-MSH) or beta-endorphin. The postinjection concentrations of these peptides in plasma and cerebrospinal fluid (CSF) were measured by radioimmunoassay (RIA). The plasma disappearance half-times were 13.7 min for beta-LPH, 5.1 min for beta-MSH, and 4.8 min for beta-endorphin. Circulating beta-LPH is cleaved to peptides tentatively identified as gamma-LPH and beta-endorphin. Each of these peptides appeared in the CSF within 2 min postinjection. The maximum CSF to plasma ratios were 0.08 for beta-LPH, 1.48 for beta-MSH,and 0.23 for beta-endorphin.


The neural hypothesis of muscular dystrophy. A review of recent experimental evidence with particular reference to the Duchenne form. Recent observations are considered to provide further evidence for an abnormality involving motoneurones in DMD. The dystrophic process appears to take place in two stages of which the first occurs during early embryonic life. This stage is thought to involve faulty inductive actions of the neural tube upon mesoderm and upon itself. The neural consequences vary among individuals and are manifested as mental retardation; EEG abnormalities and losses of functioning motor units. While the first two abnormalities are non-progressive, a further loss of motor units, associated with striking reductions in the numbers of excitable muscle fibers, takes place in trunk and large limb muscles at 9--12 years. The latter process, the cause of which is uncertain, constitutes the second stage of DMD.


The uptake of 3H(G)L leucine into single muscle fibers in Charcot-Marine-Tooth disease. In previous studies, the incorporation of 3H(G)L-leucine into muscles of patients with Charcot-Marie-Tooth (CMT) disease was shown to be increased in comparison with that observed in motor neuron disease (MND). To determine the cause of the increased uptake in CMT, studies of single fiber leucine incorporations have been undertaken. The results of this study indicate that the increased incorporation is into those muscle fibers which are undergoing regeneration following reinnervation. These results do not support the thesis that there is an associated myopathic process in CMT.


The syndrome of carnitine deficiency: morphological and metabolic correlations in two cases. Two cases of systemic carnitine deficiency are described. In both patients, carnitine concentration was lower than normal in serum and muscle tissue. In the first case, the illness began at age 35; the clinical manifestations were only muscular. In the second case, the illness began in childhood; there were intermittent episodes of hepatic enlargement and coma. An excessive lipid content was present in muscle tissue, especially in type 1 fibers, of both cases, and in the liver of the second patient. Ultrastructural studies of muscle tissue revealed important changes of mitochondria. During muscular exercise, aerobic and anaerobic metabolism were investigated. For a given relative work intensity, these patients showed abnormally high blood lactic acid concentration and lactic acid/pyruvic acid ratios. These data, together with the morphological alterations observed in mitochondria, suggest an impaired function of the respiratory chain, leading to a shift of the red/ox potential of the tissue towards a non reduced state.


Long term induction of kindled seizures in rats: interhemispheric factors. Previous research indicated that sequential alternation of stimulation of certain homologous brain areas via chronically implanted electrodes resulted in oscillation of high and low latencies for convulsions. This phenomenon suggested the establishement of interhemispheric facilitatory-inhibitory effects as a result of repeated stimulation of the two brain sites. In the present study, the latency oscillation pattern was observed in split-brain rats as well as in bilaterally stimulated controls, but not in rats stimulated on one side only. Significant differences were observed between split-brain and control rats in terms of initial kindling rates, duration of convulsions and type of oscillation. Results are discussed in the context of possible interhemispheric mechanisms involved in long term kindling.


Dominantly inherited hypertrophic neuropathy. Clinical, electrophysiological, and histopathological studies of some members of a family with dominantly inherited hypertrophic neuropathy are presented. Twenty-five members were studied. Seventeen were abnormal on clinical examination. Their ages varied from 2 1/2 to 78 years. Age at onset in 14 of the 17 varied between 2 1/2 and 56 years. Pes cavus and palpable nerve thickening were present in more than half of the affected individuals. All patients had areflexia. Fifteen of the 17 had distal motor weakness as well as mild to moderate sensory impairment. Motor weakness affecting the proximal hip and shoulder girdle muscles was seen in 13 patients. Four patients gave a history of trigeminal neuralgia. Motor nerve conduction velocities were markedly impaired in all the clinically affected members. These studies were normal in the 8 unaffected members. Motor conduction velocities of the proximal segment of the ulnar nerve were slower compared to the distal segment in almost all the affected members. There was no significant correlation between the degree of clinical disability and the extent of impairment in the motor nerve conduction velocities. Sural nerve biopsies were studied. These observations are discussed.


Hot water epilepsy.

Hot water epilepsy. A case of hot water epilepsy is presented and the literature on the subject is reviewed. The data show that hot water epilepsy is a benign form of reflex epilepsy occurring mainly in children. Males are affected more than females. The triggering stimulus is immersion in hot water (over 37 degrees C). The seizure is usually psychomotor, although generalized convulsions may occur. The EEG findings indicate that the abnormality lies in the temporal lobe.


Hydranencephaly in association with Roberts syndrome. A clinicopathological study in a case of Roberts syndrome (tetraphocomelia, cleft lip and palate, and phallic hypertrophy) is reported. This patient had hydranencephaly and impeperforate anus, two additional congenital abnormalities so far not reported in this syndrome.


Paraganglioma of the filum terminale.

Paraganglioma of the filum terminale. An unusual tumor arising in the filum terminale is described. The clinical data revealed an extensive and slowly growing lesion. The histologic picture was characterized by a proliferation of lobules and sheets of regular cells within a rich vascular network. Electron microscopic studies showed light and dark cells with sustentacular extensions. Typical neurosecretory granules were observed in both cell types, establishing the diagnosis of para-ganglioma. The glomus coccygeum could be the site of this tumor.


Charging a patient with assault of a nurse on a psychiatric unit. A patient was successfully charged with assault of a nurse on a Psychiatric Unit and was placed on probation for one year. The judge found her guilty despite the location of the incident and her 20-year history of previous psychiatric treatment, including 14 hospitalizations. Following this confrontation, the patient improved markedly in her behaviour and has continued to lead a more productive life without hysterical outbursts. It is concluded that proceeding with legal charges in such a situation is justifiable and can also be therapeutic.


Psychiatric aspects of geriatric crisis intervention. Data on 64 geriatric patients treated by the Psychiatric Crisis Team at the Jewish General Hospital were reviewed. A control group of non-geriatric patients was selected at random for comparison. The average age of the geriatric group was 69.4 years compared to 33 in the control group. Women predominated in the geriatric group. Precipitating factors were more easily delineated in the geriatric group. Physical illness, loss of a close relative and relocation were the most common precipitating events in the geriatric group. Depression, psychotic and neurotic, was the predominant diagnosis in the older group and schizophrenic psychosis in the control group. Compared to the control group, the geriatric patients were discharged sooner and were more easily managed. Only two geriatric patients required institutionalization. The study supports the value of prompt and comprehensive geriatric crisis intervention.


Sodium amytal in the diagnosis of chronic pain. The diagnosis of chronic pain cases is now an important problem for psychiatrists and many authors have presented strong evidence for the influence of psychological factors in chronic pain conditions. The author is reporting his experience with 75 consecutive out-patient consultations. Many of the patients were foreign-born and had significant language difficulties. The main diagnostic technique described is the use of sodium amytal given intravenously over a 45 minute-period while the patient is examined physically and psychologically; his responses noted during light, midrange and deeper levels of sodium amytal sedation. Most patients fell comfortably into one of the following diagnostic groups: psychogenic regional pain, organic pain, mixed group (organic plus psychogenic regional pain), and malingering. The author suggests that sodium amytal helps to overcome language barriers, reduces the time required for proper assessment and allows the patient and the examiner to appreciate more precisely, the level of pain and the limits of physical performance as well as permitting an effective exploration of important psychodynamic issues.


Brain aging and Alzheimer's disease.

Brain aging and Alzheimer's disease. The most common cause of senile dementia appears to be a pathological process indistinguishable from that found in presenile dementia of the Alzheimer type. Consideration of the neuropathological changes suggest that this disease may involve in interaction of at least three processes: a viral-like infection, a disorder in the immune system and the neurotoxic effect of an environmental agent. The evidence in support of this hypothesis is reviewed.


Encounter and psychotherapy: a look at the overlap. Human relations training has moved from the original T-group emphasis on group process, through focusing on the individual's mode of interacting in the group, to the use of the encounter situation for fostering personality change. Psychotherapy is moving out of the dyadic relationship into groups using increasing degrees of confrontation. The resulting overlap in group techniques calls for examination of the part each can play in the overlap area between the clear-cut functions of each specialty. The theoretical basis for differentiation lies in the respective models of awkward ("neurotic") behaviour: psychotherapy starts from the pathological and emphasizes intrapersonal structure, while encounter starts from full-functioning behaviour and emphasizes interpersonal interaction. Practical responsibilities can be divided between encounter and psychotherapy on the basis of the level achieved by an individual moving through a hierarchy of ascending personal achievement levels. Because of the high probability of individuals interchanging between encounter and psychotherapy, practitioners will need to have at least basic knowledge of both systems. Rapprochement could eventually come through the systematic extension of existential psychotherapy.


Diet in the management of hyperkinesis: a review of the tests of Feingold's hypotheses. Through the 1970s, Benjamin Feingold has published a series of studies in which he claimed that a diet free of salicylates, artificial food flavours and colours results in a remission of symptoms in 30 to 50 percent of children diagnosed as hyperactive. Parents of hyperactive children have responded strongly to the hypothesis and have requested that their children be placed on the diet. A series of clinical studies of the Feingold diet have produced mixed results. More recently, there have been four sets of experimental studies which have resulted in rigorous tests of the original diet and a modified diet with salicylates included but artificial additives excluded. None of the studies give unqualified support for the hypothesized diet effects, and there are reports which refute the thesis. There are findings which suggest that some hyperactive children (10 to 25 percent), particularly younger ones, respond favourably to a diet free of artificial additives. The lack of conclusive evidence dictates that additional research be conducted to test the hypothesis.


Perceptual experiences in anorexia nervosa and obesity. There is increasing evidence suggesting that the perceptual-cognitive experiences of people with anorexia nervosa and juvenile onset obesity may differ from those of people without eating disorders. The research related to several perceptual-cognitive dimensions is critically examined. These include body image perceptions; perception of hunger and satiety cues; perception of external cues; and certain personality variables which may be related to self-perception. The implications of these perceptual-cognitive variables for the treatment of anorexia nervosa and obesity are discussed. The relative efficacy of some behavioural and medical therapies may be related, in part, to their effects on perceptual-cognitive parameters. Recommendations are also made for investigations to further delineate the role of perceptual-cognitive difficulties in people with eating problems.


Pituitary fibrosarcoma secondary to radiation therapy. A patient who received postoperative radiation therapy for the treatment of a chromophobe adenoma developed a fibrosarcoma of the pituitary gland region 10 years later. A single course of irradiation was given with a total dose to the pituitary of 4092 rad in 21 fractions and 29 days using Cobalt 60 radiation at a source to skin distance of 80 cm.


Bone scintigraphy in primary tumors of the head and neck. Bones of the face and skull may be involved directly by adjacent primary tumors of the head and neck. Radiography, at present the standard method for detection of bone involvement in such tumors, is not sufficiently sensitive. Of 22 patients who showed bone involvement in scintigraphy, radiography in 15 was initially normal, in 6 the extent of the lesion was not completely shown and only in 3 was it as informative as scintigraphy. Bone scintigraphy should become a standard method for evaluation of the context of bone invasion by tumors of the head and neck.


Pretreatment radiographic evaluation of patients with malignant melanoma. During a four year period, 53 patients with malignant melanoma underwent extensive pretreatment radiographic evaluation for detection of occult extranodal metastatic disease. This included chest x-ray with tomography, upper G.I. series with small bowel follow through, barium enama, intravenous pyelogram, and radio-nuclide scans of the brain, liver and bone. All occult metastatic disease in asymptomatic patients was discovered on routine chest x-ray examination. There were three false positive examinations, which necessitated further diagnostic tests but there was no change in the final treatment decision. There was no alteration in the management of the remainder of the patients on the basis of the pretreatment radiographic evaluation.


Radiographic evaluation of metastatic melanoma. Malignant melanoma can potentially involve any organ system in the body once it metastasizes beyond the regional lymph nodes. A survey of the radiographic and associated clinical manifestations of metastatic melanoma is presented. The findings from 74 autopsies of patients who died of metastatic melanoma are included.


Effects of radiochemotherapy and splenectomy on cellular immunity in long-term survivors of Hodgkin's disease and non-Hodgkin's lymphoma. Thirty-six patients treated for Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL) who had been in complete remission and off all therapy for greater than two years were examined for evidence of immunosuppression. All patients were found to have marked depression of their lymphocyte blastogenic response to phytohemagglutinin (PHA) and of their skin test responses. No abnormalities of serum protein or immunoglobulins were found. T cells were significantly lower than normal in patients who had had Hodgkin's disease, but not in those who had had NHL. B cells, on the other hand, were significantly elevated in both groups. Splenectomy elevated the total lymphocyte count, while those who had not had a splenectomy had lower than normal lymphocyte counts. B cells were elevated while T cells tended to be lower in both splenectomy and nonsplenectomy groups, though only in the nonsplenectomized patients did this reach statistical significance. PHA response tended to be higher in patients with less advanced disease and less extensive treatment than in those with more advanced disease and more extensive treatment, although there was no statistically significant difference. Skin test response though, was shown to correlate well with both stage of disease at diagnosis and extent of treatment.


Serum clearance rates of immunologically reactive thyroglobulin. Serum thyroglobulin levels have been shown to have a role in detecting the presence of residual or recurrent disease in most patients who have undergone total thyroidectomy for thyroid cancer. It has not yet been determined at what interval postoperatively to begin following serum thyroglobulin levels in these patients to detect residual disease. Eight patients who underwent total thyroidectomy were studied to determine the clearance rate of this glycoproteint. Serial samples were obtained pre- and postoperatively and clearance rate curves were plotted for each patient. The average half-life of thyroglobulin was 14 hours, with a range of 8 to 22 hours. Based upon these results, it appears that 4 weeks is a sufficient period of time to allow for the clearance of the residual thyroglobulin in patients undergoing total thyroidectomy. Elevated levels of serum thyroglobulin after this time represent residual thyroid tissue or the presence of metastatic thyroid carcinoma.


Ultrastructural comparison between skeletal muscle and cardiac rhabdomyomas. The electron microscope features of three primary cardiac rhabdomyomas and one skeletal muscle rhabdomyoma arising from the floor of the mouth are compared, along with a review of the previously reported ultrastructural features of skeletal rhabdomyomas. Cardiac rhabdomyoma filaments appear more orderly and have features suggestive of origin from both Purkinje and myocardial fibers. Zebra bodies were seen exclusively in the cardiac rhabdomyomas. In comparison, the extracardiac rhabdomyoma filaments were more disorderly and many cases had hypertrophic Z bands corresponding to the jackstraw or matchstick structures seen with the light microscope. This finding, along with the presence of satellite cells, was not seen in the cardiac rhabdomyomas.


Elevated levels of carcinoembryonic antigen in cord plasma. 41.5% of 200 newborn infants had levels of carcinoembryonic antigen (CEA) in excess of 2.5 ng/ml in their cord plasma. There was no direct correlation with the maternal CEA level although the frequency of elevated CEA was significantly greater among infants born to mothers with CEA levels greater than 2.5 ng/ml. There was no preponderance of high CEA levels among infants with low birth weights and there was no influence of maternal smoking on a cord CEA level. There was a tendency toward an increased incidence of cancer in families with infants who had elevated CEA levels and a reverse trend was noted with respect to diabetes; however, these associations were not statistically significant. We were unable to define clearly the factors accounting for the persistent elevation of this oncofetal antigen at birth; however, the possible association with susceptibility to the development of neoplasia merits further study.


Phase I evaluation of anguidine (diacetoxyscirpenol, NSC-141537). A toxicologic evaluation of anguidine (diacetoxyscirpenol) was completed for a 5 day schedule. At 4.5 mg/M2 and 6 mg/M2 iv push CNS symptoms and hypotension were dose limiting but only mild to moderate myelosuppression was observed. At the 6 mg/M2 dose level on a 5 day schedule given by 8 hour infusion, myelosuppression was unacceptable while other toxic manifestations were minimal. An infusion of 4.5 mg/M2 over 4-8 hours appears to be an acceptable compromise between CNS, cardiovascular, and GI toxicity and myelosuppression. For patients with liver dysfunction or prior nitrosourea therapy, the starting dose should be 3.0 mg/M2.


Incidence of meningeal involvement by rhabdomyosarcoma of the head and neck in children: a report of the Intergroup Rhabdomyosarcoma Study (IRS). 141 patients with embryonal rhabdomyosarcoma (RMS) of the head and neck are reviewed. 57/141 had lesions of para-meningeal sites. 20/57 (35%) developed evidence of direct meningeal extension. 18/20 (90%) died of this complication. Radiation portals and doses were limited in 42% and 32%, respectively. All patients had chemotherapy for 6 weeks prior to radiation. The significance of the adequacy of radiation factors and the timing of chemotherapy are reviewed. Recommendations for managing these patients include earlier use of radiation and increased coverage of adjacent meninges by radiation including total craniospinal axis radiation when brain meningeal involvement exists.


Extraskeletal Ewing's sarcoma: a preliminary review of 26 cases encountered in the Intergroup Rhabdomyosarcoma Study. Twenty-six of three hundred and fourteen (26/314) patients whose tumors were reviewed by the Pathology Evaluation Committee of the Intergroup Rhabdomyosarcoma Study have histologic subtypes I and II which have morphologic characteristics similar to Ewing's sarcoma of bone. They are somewhat more common in an extremity lesion but have no relation to patient age. Disease-free survival is good; seventeen of twenty-six (17/26) or sixty-five (65%) percent thus far.


Combination chemotherapy for advanced breast cancer: two regimens containing adriamycin. Forty-eight women with advanced metastatic carcinoma of the breast were treated with one of two combination chemotherapy regimens: 1) adriamycin and cyclophosphamide or 2) adriamycin, cyclophosphamide, methotrexate and 5-fluorouracil. The response rate in the two-drug treatment group was 50% and in the four-drug treatment group, 55%. The median duration of response was ten months in both treatment groups. Dramatic responses were seen in patients with visceral metastases. Patients who responded to chemotherapy had a significantly longer survival than nonresponders (p less than 0.01). The long interval between adriamycin doses (six weeks) in the four drug regimen did not adversely effect the response rate--an important finding in view of the dose-related cardiac toxicity of this agent.


Meningeal carcinomatosis in breast cancer. Twenty-five breast cancer patients with meningeal carcinomatosis seen over a period of 16 months were reviewed. In all cases, the clinical diagnosis was made in the presence of diverse neurological manifestations by the demonstration of malignant cells in the cerebrospinal fluid. In ten patients, the clinical diagnosis was documented at autopsy. All patients were receiving systemic chemotherapy at the time the diagnosis of meningeal carcinomatosis was made. In 9 of the 25 patients, meningeal involvement was associated with progression of systemic metastases, while 5 exhibited stable or partial remission from systemic metastases and 7 were in complete remission at the time of their CNS relapse. CNS involvement was the first manifestation of recurrent disease from breast cancer in 4 of 25 patients. Meningeal involvement can, therefore, occur at any time during the course of breast cancer. With increasing diagnostic awareness and the employment of several therapeutic strategies, the prognosis of these patients, though poor, was significantly improved over that of historical control patients.


The relationship of marital status to survival from melanoma. As an indirect test of the hypothesis that prior pregnancy has a favorable influence on prognosis in melanoma, the relation of marital status to survival among melanoma patients was examined in data gathered by the Connecticut Tumor Registry, 1935--1973. Compared to women who had never been married, ever-married women with the disease had a slightly increased survival rate, but the difference was not statistically significant. If a difference between parous and nulliparous women in survival from melanoma truly exists, it is probably a small one, and could be due to differences in characteristics other than childbearing.


Incidental discovery at radical mastectomy of inapparent Hodgkin's disease in long term survivors. Two long-term survivors with nodular sclerosing Hodgkin's disease were found to have adenocarcinoma of the breast sixteen and twenty years after limited field radiotherapy. Examination of the axillary nodes at radical mastectomy showed both metastatic adenocarcinoma and clinically inapparent Hodgkin's disease. The occurrence of persistent but clinically inactive Hodgkin's disease as well as the development of secondary malignancies in this disease has important clinical ramifications. Skin testing and in vitro lymphocyte transformation studies in these two patients were also done.


Cancer of the bladder in Southern Iran.

Cancer of the bladder in Southern Iran. The sex ratio for cancer of the bladder from hospitalized cases in Southern Iran is estimated to be about nine male per female cases. Differential case ascertainment may account for some of the discrepancy; however, no other major cancer site has a sex ratio of this nature, utilizing the same data. Since industrial carcinogens and other predisposing factors, such as schistosomiasis, are rare, the role of other possible etiologic factors, such as opium addiction, which is predominantly male, were considered and discussed.


Treatment of the ameloblastoma: a controversy. Treatment of the ameloblastoma should be re-evaluated based on microscopic behavior. We suggest that conservative therapy is the initial treatment of choice. Although medullary bone is invaded by tumor cells, compact bone only is eroded. Therefore, treatment should be directed at removal of involved medullary bone, leaving as much medial and lateral cortical plates and inferior mandibular border as possible. Four patients with ameloblastoma treated conservatively are presented. Evaluation from 21 months to seven years after initial therapy revealed marked bone regeneration. Three of the four had smaller lesions remaining, requiring less radical surgery than would normally have been performed initially. No tumor was evident on rebiopsy of the fourth patient. Conservative treatment and proper follow-up were acceptable methods of initial treatment in our cases.


Lymphangiomyomatosis syndrome with hyperparathyroidism: a case report. A 48-year-old woman presented with the classical clinicopathological features of the lymphangiomyomatosis syndrome. After a three year stable period, there was the onset of a rapidly progressive downhill course unresponsive to dietary, bronchodilator and corticosteroid therapy. Pathological findings were characterized by widespread pulmonary, thoracic duct and lymph node involvement. There was a mediastinal lymphangiomyoma growing within the distal thoracic duct, and a similar lesion within the left kidney which could clinically mimic an angiomyolipoma. Comments are also made on the finding of a parathyroid adenoma. The physiopathology and possible resemblance to "formes frustes" of tuberous sclerosis are discussed.


Geographic correlates of pancreas cancer in the United States. Age-adjusted death rates for pancreas cancer during 1950--69 were correlated by sex and race with demographic and industrial data for the 3,056 counties of the contiguous United States. Only a small fraction of the county-to-county variation in mortality was explained by these variables, in contrast to their strong correlation with other common neoplasms. The only geographic cluster occurred in an area encompassing parts of Louisiana and Mississippi. Throughout the country, however, the rates for pancreas cancer were higher in urban areas, especially in males, and in counties with many residents of Scandinavian and East European (particularly Russian) descent. No associations were found with socioeconomic, industrial, or alcohol-consumption indices. The mortality patterns for pancreas and lung cancers were highly correlated in males, suggesting the influence of tobacco consumption on both tumors. In females, pancreas cancer was significantly correlated with diabetes mellitus, consistent with other evidence linking these two diseases.


Fatal pulmonary fibrosis following 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) therapy. A case is reported of a child with fatal pulmonary fibrosis following BCNU therapy. This side effect has only once previously been reported with the nitrosourea group of compounds.


Sinus histiocytosis with massive lymphadenopathy and paraparesis: remission with chemotherapy. A case report. A case of sinus histiocytosis with massive lymphadenopathy (SHML) in which cranial nerve function was impaired is described. Severe paraparesis due to an epidural block at the C2 and C5-T2 levels was also present. Treatment with cytotoxic agents resulted in a dramatic decrease in the size of the involved lymph nodes and disappearance of neurological symptomatology. A review of the literature revealed that, although the disease is benign in its clinical course, the process is not restricted to the lymph nodes. The case reported here is the second case in which the epidural space was affected.


Hepatopathy following irradiation and adriamycin. This report describes two cases of hepatopathy following irradiation and adriamycin at doses and volumes of irradiation ordinarily considered within the tolerance of hepatic function. In one case fatal hepatopathy followed 2400 rad/17 fractions/28 days to the entire liver with preceding and concurrent adriamycin. In the second case moderate clinical changes occurred after treatment in which much of the right lobe of the liver was shielded following 2500 rad/23 fractions/32 days with adriamycin administered before, during, and after irradiation. The locally enhancing effects of adriamycin on hepatic tolerance to irradiation are discussed.


Carcinogenic effects of niridazole in rats. Niridazole was administered in the diet to rats at levels of 0.1, 0.05 and 0.025%. The drug induced adenomas and adenocarcinomas of the kidneys and forestomach papillomas.


Selective induction of pancreatic ductular tumors by single doses of N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters. The selectivity of response by the Syrian hamster pancreas to the neoplastic effect of N-nitrosobis(2-oxopropyl)amine (BOP) was demonstrated by single subcutaneous injections of the compound. Only occasional tumors were induced simultaneously with those of the pancreas in the biliary ducts, kidneys and lungs of a few hamsters. In the pancreas, the ductules, especially those of an intrainsular location, were the cells primarily affected. The responded to doses as low as 1/40 of the LD50, whereas ductal lesions were found only in some hamsters treated with doses above 1/5 of the LD50. Hence it is concluded that hamster ductular cells are the most responsive to the carcinogenic action of BOP.


Toxic and transforming effects of polycyclic hydrocarbons in fetal hamster lung-cell cultures. I. Benzo(alpha)pyrene. When seeded at a low cell density in Petri dishes not pre-conditioned with feeder layers, fetal hamster lung cells at 2-4 passages grew with greatly varied plating efficiencies (PE). Addition of insulin to the serum-supplemented medium gave relatively constant PE. However, the presence of insulin in the medium enhanced the toxicity of benzo(alpha)pyrene (BP) on these cells. Cytotoxic and cell transforming effects of BP in the presence of insulin were studied.


Tumor induction by N-nitroso compounds in bivalve mollusks Unio pictorum. Diethylnitrosamine (DENA) and dimethylnitrosamine (DMNA) dissolved in tank water induced neoplasms in bivalve mollusks Unio pictorum. DENA induced tumors in 18% of the animals exposed to 200 ppm and 68% of those exposed to 400 ppm; average latent periods were 71 and 61 days, respectively. DMNA induced tumors in 8% of the animals exposed to 200 ppm for 51 days and 27% of those exposed for 152 days with average latent periods of 85 and 81 days, respectively. Neoplasms were observed in the digestive gland (basophilic cell tumors; 38 cases), the hemopoietic system (hemocytoblastosis; 12 cases) and the kidney (poorly differentiated carcinoma; 1 case). It is expedient to use mollusks, both for testing of N-nitroso compounds and as a biologic indicator of hydrospheric pollution.


Effect of dimethylnitrosamine concentration on its demethylation by liver microsomes from control and 3-methylcholanthrene pretreated rats, hamsters and guinea pigs. The effect of dimethylnitrosamine concentration on its demethylation by liver microsomes from control and 3-methylcholanthrene pretreated (100 mg/kg body wt. 24 h before sacrifice) rats, hamsters and guinea pigs was investigated. At low substrate concentration (2 mM), liver microsomes from pretreated rats and hamsters showed 30-50% lower demethylation activity than their respective controls. No such difference was found in the guinea pig. At high substrate concentration (100 mM), all 3 pretreated species showed 50-100% higher enzyme activity than their respective controls. Enzyme activities among the 3 species showed the following order of activity: hamster greater than guinea pig greater than rat.


A hydroxylapatite micromethod for measuring estrogen receptor in human breast cancer. The concentration of estrogen receptor (ER) in a human breast tumor is a critical variable predicting the response to endocrine therapy and the course of the disease. Since many tumor specimens are quite small, a reliable and simple ER assay requiring a minimum of tissue is desirable. We here describe a hydroxylapatite assay for ER that (a) requires only a single, saturating concentration of [3H]estradiol, (b) agrees with more complex multiple-concentration assays and with the standard dextran-coated charcoal assay at normal protein concentrations, (c) is far more reliable than the latter at low protein concentrations, and (d) can be adapted to an accurate and reliable ER microassay requiring less than 50 mg of tissue.


Effect of progressive neoplastic growth on the decarboxylation of DL-[1-14C]ornithine by lymphocytes from C3H/He tumor hosts. The reactivity of normal and tumor host lymphocytes incubated with normal serum or with serum or malignant ascites fluid from tumor hosts was measured by the ability of the lymphocytes to synthesize ornithine decarboxylase after phytohemagglutinin stimulation. Each of three tumors tested (a solid fibrosarcoma, an ascites mammary carcinoma, and an ascites ovarian carcinoma) caused increasing unresponsiveness in the lymphocytes of mice with progressing syngeneic neoplastic growth. The sera and particularly the malignant ascites fluids from mice given implants of the ascites cancers became progressively inhibitory to the activation of lymphocytes from tumor hosts as well as from normal mice. The serum from mice carrying s.c. implants of the fibrosarcoma enhanced the activation of lymphocytes from tumor hosts and from normal mice during early tumor growth before it also became inhibitory.


Methionine requirement and replacement by homocysteine in tissue cultures of selected rodent and human malignant and normal cells. An absolute methionine requirement for cell growth in culture was observed in four experimental rodent neoplasms, namely, P815/ara-C, L1210, lymphoma 5178Y, and Walker 256. Normal human fibroblast (F-136-35-56) and the human malignant cell lines HeLa and mammary adenocarcinoma (AlAb) cells in culture showed equal growth in 0.1 mM L-methionine or 0.1 to 0.4 mM DL-homocysteine. A human pancreas adenocarcinoma (Capan-1) had somewhat more stringent requirements for DL-homocysteine, whereas a human lung adenocarcinoma (A-549) responded poorly, and a human acute lymphoblastic leukemia (CCRF-HSB-2) responded not at all to equimolar or excess DL-homocysteine in the absence of L-methionine. These differences in requirement for methionine and the ability or inability to replace methionine by homocysteine indicate that a general discrimination between benign and malignant tissues on the grounds of their methionine requirement is not possible for human cells.


Altered growth properties of Chinese hamster cells exposed to 1-methylguanine and 7-methylguanine. Primary Chinese hamster embryo cell cultures generally yield cell lines with a finite lifetime in culture. However, if early-passage cells are exposed chronically to either of two normal degradation products of transfer RNA, 1-methylguanine or 7-methylguanine, they are converted to continuous lines with altered growth characteristics and morphology. The continuous cell lines have saturation densities 2- to 10-fold higher than did finite control cultures, and some have the ability to grow in soft agar. Certain cultures have the general appearance of fibroblasts while others are more epithelial-like. Quantitative and qualitative alterations in the transfer RNA methyltransferases are early markers for neoplastic transformation in vivo and in vitro. Transfer RNA methyltransferase activity in the continuous lines is elevated compared to that of finite Chinese hamster cells. Neoplastic transformation has been demonstrated for a 1-methylguanine-derived line, and both 1-methylguanine- and 7-methylguanine-treated cell lines exhibit characteristics similar to those of Chinese hamster cells transformed with the carcinogen 3,4-benzopyrene or the DNA tumor virus SV40.


Effects of heat on the centrosomes of Chinese hamster ovary cells. Chinese hamster ovary cells were heated either at 45.5 degrees for 15 min or at 42 degrees for 1 hr and then were either fixed immediately or allowed to recover at 37 degrees for intervals of up to 12 hr. In addition control cells and cells heated at 45.5 degrees for 15 min were immediately subjected to a cell fractionation procedure that yielded partially purified centrosome preparations. In 100% of the cells fixed and examined immediately after heating, the centrosomes were damaged. The osmiophilic cloud increased in density and became aggregated. The majority of the pericentriolar particles or virus-like particles disappeared, and in some cases the tubules of the wall of the centriole appeared disrupted. These changes were also noted in the much more abundant population of centrosomes in the partially purified cell fraction. Furthermore, in those cells heated at 45.5 degrees for 15 min, no recovery of the centrosomes or return of virus-like particles occurred even after incubation at 37 degrees for 12 hr.


Metabolic conversion of 12-O-tetradecanoylphorbol-13-acetate in adult and newborn mouse skin and mouse liver microsomes. Tritiated 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied to adult mouse skin; at specified time intervals the mice were killed, and the labeled phorbol was extracted and subjected to separation and quantitation by high-pressure liquid chromatography. After 24 hr, TPA comprised greater than 96% of the recovered label from the skin, and its apparent half-life was 17.8 hr. Pretreatment of adult skin with TPA for 4 weeks before treatment with labeled TPA resulted in an increase in the clearance rate of TPA from the skin. Skin from newborn mice was capable of converting TPA into monoesters and phorbol, but the clearance rate in the adult was about 12 times more rapid than it was in the newborn. Epidermal homogenates converted TPA into 12-O-tetradecanoylphorbol, phorbol-13-acetate, and phorbol. Hepatic homogenates were able to convert TPA to monoesters and phorbol at rates 14 to 15 times faster than were epidermal homogenates. Attempts to isolate any previously undescribed metabolites of TPA by use of liver homogenates were unsuccessful, and mixed-function oxidation did not contribute to the metabolism of TPA. From inhibitor studies it was judged that esterases were implicated in the conversion of TPA to monoesters and phorbol. The results support the hypothesis that the tumor-promoting activity of TPA is directly related to its concentration in a specific tissue and that conversion of TPA to an active metabolite probably does not occur.


Proliferation kinetics of a human breast cancer line in vitro following treatment with 17beta-estradiol and 1-beta-D-arabinofuranosylcytosine. The effect of 17beta-estradiol on an estrogen receptor-positive human breast cancer cell line (MCF-7) was studied. Low concentrations (10(-9) M) of 17beta-estradiol enhanced the rate of cell proliferation; the overall cell cycle time was shortened; and the proportion of cells in the S phase increased. Higher concentrations (10(-7) M) suppressed proliferation and slightly decreased the proportion of the cells in DNA synthesis. When combined with 1-beta-D-arabinofuranosylcytosine, an S-phase-specific chemotherapeutic agent, 10(-9) M 17beta-estradiol enhanced cell killing. This enhancement was not observed with 10(-7) M 17beta-estradiol. Kinetic changes caused by hormones have profound implications in clinical therapy, since the efficacy of cycle active agents may be altered.


Effects of phorbol-12-myristate-13-acetate on the phenotypic program of cultured chondroblasts and fibroblasts. Phorbol-12-myristate-13-acetate (PMA) has a prompt, differential, and partially reversible effect on cultured chick chondroblasts. Within 36 hr PMA transforms sessile, polygonal, epithelioid chondroblasts into motile, multilayered, fibroblastic cells. In PMA chick chondroblasts rapidly cease to synthesize two of their terminal luxury molecules, the type IV sulfated proteoglycan that characterizes the extracell matrix and a glycosylated protein with an apparent molecular weight of 180,000. This glycosylated protein constitutes approximately 5% of the total protein in normal chondroblasts. If returned to normal medium after 4 days in PMA, virtually 100% of the cells reinitiate the synthesis of their type IV sulfated proteoglycan, of the 180,000-dalton protein, and reacquire their polygonal, epithelioid morphology. If returned to normal medium after 12 days in PMA, the cells fail to synthesize their two characteristic luxury molecules, and 100% of the cells remain fibroblastic. PMA alters the morphology of chick fibroblasts but does not block synthesis of their characteristic type III sulfated proteoglycan. PMA proves to be a mitogen for chondroblasts but not for fibroblasts, in spite of the phenotypic similarities of these two cell types.


Cytotoxic and metabolic effects of adenosine and adenine on human lymphoblasts. The metabolic and growth inhibitory effects of adenosine toward the human lymphoblast line WI-L2 were potentiated by the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and coformycin. EHNA, 5 micron, or coformycin, 3.5 micron, at concentrations that inhibited adenosine deaminase activity more than 90% had little effect on cell growth or the metabolic parameters studied. Adenosine, 50 micron, plus EHNA, 5 micron, arrested cell growth in both parent and adenosine kinase-deficient lymphoblasts, implicating the nucleoside as the mediator of the cytostatic effect. Adenosine, 50 micron, in combination with the adenosine deaminase inhibitors reduced 14CO2 generation from [1-14C]glucose by 38%, depleted 5-phosphoribosyl-1-pyrophosphate by more than 90%, and reduced pyrimidine ribonucleotide concentrations. Uridine, 10 or 100 micron, reversed adenosine plus EHNA growth inhibition in WI-L2 but not in adenosine kinase mutants. Adenine, 500 micron, which may be converted to the same intracellular nucleotides as adenosine, reduced the growth rate by 50% in both parent and adenine phosphoribosyltransferase-deficient lymphoblasts. Although adenine also depleted cells of 5-phosphoribosyl-1-pyrophosphate and reduced pyrimidine ribonucleotide by 50%, the mechanisms of adenine and adenosine toxicity differ. In contrast to the ability of uridine to reverse adenosine cytostasis, growth inhibition by adenine was not reversed by uridine, indicating that pyrimidine ribonucleotide depletion is not the primary mechanisms of adenine toxicity.


Regulation of plasma-free fatty acid mobilization by dietary glucose in Ehrlich ascites tumor-bearing mice. We studied the ability of dietary glucose to cause an abrupt inhibition of free fatty acid (FFA) mobilization in mice bearing advanced Ehrlich ascites carcinoma. FFA irreversible disposal rates were estimated after i.v. injection of tracer [1-14C]palmitate complexed to mouse serum albumin. Four groups of mice were studied: 16-hr-fasted mice versus 16-hr-fasted mice refed a 58% glucose, fat-free test meal for 10 min; and control versus tumorous mice. Plasma FFA fell significantly [from 0.97 +/- 0.06 (S.E.) to 0.37 +/- 0.02 muEq/ml (n = 30 and 134, respectively)] following the ingestion of the small test meal. The lowered plasma FFA pool size remained approximately constant between t = 15 and 45 min after the mice began to eat. Tracer studies in the fasted-refed mice, carried out during that interval, showed that the plasma FFA irreversible disposal rate was reduced by 50% in both control and tumor-bearing mice. Although cancerous mice tended to have elevated plasma FFA levels in the early morning, these animals appear to have normal control mechanisms for inhibiting FFA mobilization following ingestion of carbohydrate.


Folate and pterin metabolism by cancer cells in culture. Malignant cells grown in culture excrete into their growth medium a folate catabolite that can be seen as a blue-fluorescent region on paper chromatograms of such media. This folate catabolite has now been identified by paper chromatography, thin-layer chromatography, and combined gas chromatography-mass spectrometry as 6- hydroxymethylpterin and not as pterin-6-carboxaldehyde as previously reported. Moreover, when pterin-6-carboxaldehyde was added to the growth medium of logarithmically growing malignant cells, it was primarily reduced to 6-hydroxymethylpterin. In contrast pterin-6-carboxylate was the principal product formed from added pterin-6-carboxaldehyde by normal established cell lines in culture. These results have been interpreted as indicative of a possible mechanism of folate catabolism in malignant cells. Folic acid or another folate derivative is oxidatively cleaved at the C-9-N-10 bond to yield pterin-6-carboxaldehyde as one of the products. This derivative is subsequently reduced to 6-hydroxymethylpterin, which is excreted into the growth medium.


Effects of several vasoactive drugs on the vascular resistance of MT-W9B tumors in W/Fu rats. These experiments were designed to study the effects of vasoactive drugs on normal and malignant tissue in W/Fu rats. The increase in resistance to tumor blood flow elicited by a bolus injection of 10 microgram of norepinephrine was greater than that elicited in the surrounding mammary gland tissue. A 10-fold increase in the resistance to tumor blood flow was sustained for 30 min by the infusion of norepinephrine at the rate of 1.39 microgram/min, whereas a smaller initial increase in mammary gland vascular resistance decreased with time. In contrast, the increase in resistance to tumor blood flow caused by a bolus injection of angiotensin II was less than that observed in the mammary gland tissue. A 20-fold increase in mammary gland vascular resistance could be maintained for at least 5 min by infusion of angiotensin II at the rate of 1.39 microgram/min. In comparison, such treatment caused only a 3-fold increase in the resistance to tumor blood flow. A bolus injection of 1 microgram of isoproterenol decreased the vascular resistance in all normal tissues studied, but the resistance to blood flow in the tumor remained unchanged. The results of these experiments indicate that there may be methods whereby the tumor blood flow can be manipulated for therapeutic purposes and to assist radiographic visualization of tumors.


Relative carcinogenic effectiveness of derivatives of nitrosodiethylamine in rats. The carcinogenicity of five derivatives of nitrosodiethylamine was compared with that of the parent compound by p.o. administration to rats. All were less potent than was nitrosodiethylamine. When nitrosobis(2-methoxyethyl)amine and nitrosobis(2-ethoxyethyl)amine were administered at equimolar doses in drinking water, there was a high incidence of liver tumors, but the animals died later than they did after nitrosodiethylamine treatment, which also induced esophageal tumors. Nitrosoiminodipropionitrile and nitrosobis(2,2-diethoxyethyl)amine failed to induce tumors at the same dose level. Nitrosobis(2-chloroethyl)amine was administered in oil by gavage at a dose lower than that of nitrosodiethylamine and produced a much weaker tumor response; 5 of 15 treated rats had forestomach papillomas, and 1 had olfactory adenocarcinoma and no other induced tumors.


Sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea of the EMT6 tumor in vivo as determined by both tumor volume response and in vitro plating assay. Measurements of the response of the EMT6 mouse tumor to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea by either tumor volume or the in vitro assay of the cell surviving fraction give very different results. For BCNU very little delay in tumor growth is caused by high doses of the drug, whereas the surviving fraction assayed 2 hr after drug administration may be as low as 10(-4) for comparable drug doses. Over the first 48 hr after BCNU, the measured surviving fraction in small tumors increases 50- to 100-fold; this is ascribed to the phenomenon known as "recovery from potentially lethal damage." For 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, however, this early rapid recovery in surviving fraction does not occur. Although the surviving fractions measured 24 hr after drug administration are similar for equivalent doses of the two drugs, the growth delay induced is very much longer for 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea than for BCNU. Neither of the agents appears to cause any increase in the rate of cell loss from tumors as measured by [125]iododeoxyuridine.


Resistance of resting 3T6 mouse fibroblasts to methotrexate cytotoxicity. We have compared the relative susceptibility of resting (GO) versus exponentially growing mouse fibroblasts (line 3T6) to methotrexate (MTX) cytotoxicity. Cultures of cells were exposed to different levels of MTX for various intervals. Cloning efficiencies of the cells were then determined in medium containing hypoxanthine and thymidine. We found that growing 3T6 cells exhibit time- as well as dose-dependent cytotoxicity. Greater than 95% of the cells were killed by a 24-hr exposure to 10(-6) M MTX. In contrast resting cells showed no loss of cloning efficiency even at drug concentrations of 10(-3) M and exposure times of 7 days. The resistance of resting cells is not the result of a MTX transport deficiency since extracellular MTX is taken up by both resting and growing cells. Furthermore, intracellular dihydrofolate reductase activity is abolished in both resting and growing cells at similar extracellular MTX dosages.


Steroid receptor analyses of nine human breast cancer cell lines. Nine human breast cancer cell lines in permanent tissue culture and currently available to researchers have been assayed for their content of cytoplasmic estrogen receptors, progesterone receptors, androgen receptors, and glucocorticoid receptors, as well as for the presence of unfilled or hormone-filled nuclear estrogen receptors. Receptor distribution varied considerably among the nine lines and differed from the expected distribution predicted from solid tumors. We find that estrogen receptor, when present, is usually localized in the nucleus as unfilled nuclear estrogen receptor. Progesterone receptor is correlated with presence of unfilled nuclear estrogen receptor. Glucocorticoid receptors are ubiquitous; they were found in all cell lines tested. The distribution of androgen receptor and progesterone receptor differed, suggesting that these proteins are dissimilar.


DNA cross-linking by in vivo treatment with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea of sensitive and resistant human colon carcinoma xenograms in nude mice. The DNA alkaline elution technique provides a sensitive assay for the effects of DNA-damaging drugs in mammalian cells. We have adapted this method to permit measurements of effects on DNA in solid tumors. Human colon carcinoma xenografts in nude mice were treated with a single i.p. injection of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, and the effects on the DNA were followed for 19 hr. Drug doses in the pharmacological range produced significant reductions in DNA alkaline elution rates in assays in which X-ray was used to introduce a standard frequency of single-strand breaks. These changes in alkaline elution rate were attribute to the production of both DNA interstrand and DNA-protein cross-links, which were distinguished from each other on the basis of the extent to which the effect on elution could be reversed by proteinase K. Crosslinking increased for about 8 hr after treatment with little change thereafter up to 19 hr. A drug-resistant tumor line exhibited substantially less cross-linking than did a drug-sensitive line at all time points examined.


Multicellular tumor spheroid formation by breast cancer cells isolated from different sites. Fourteen breast cancer lines (8 human, 5 rat, and 1 mouse) have been studied in terms of their ability to form multicellular tumor spheroids (MTS) with the agar-base method. Only 8 of the lines formed MTS in contrast to a 100% efficiency in a series of 11 varied tumors reported in the initial studies with this method. We have compared the lines that do and do not form MTS in terms of a variety of characteristics (e.g., estrogen receptors, time in serial passage, growth in nude mice, etc.), and only one characteristic, the source of the original tumor cells, was predictive of MTS-forming ability. All 8 of the breast cancer lines (and the original 11 lines) that formed MTS had been obtained from solid growths (primaries or metastases), while the 6 breast cancer lines that did not form MTS were all derived from pleural effusions. Similarly, artificial selection for an ascites variant of the MTS-forming rat 13762 adenocarcinoma line produced the 13762-A line, which could no longer form MTS. These results suggest that breast cancer cells derived from pleural effusions are genetically different from the bulk of the tumor cells in solid breast cancer samples, that they are unable to grow in true solid form, and that these differences persist in spite of prolonged propagation in tissue culture.


A comparison of cell cycle-related changes in postmitotic and quiescent AF8 cells as measured by cytofluorometry after acridine orange staining. AF8 cells were collected by mitotic detachment or made quiescent by serum restriction. Replated mitotic cells or serum-stimulated quiescent cells were then compared by flow cytofluorometry, when the use of acridine orange staining. Red fluorescence intensity (F greater than 600) was the same in quiescent cells and in cells immediately after mitosis. However, F greater than 600 increased very rapidly in postmitotic cells, while there was a delay in serum-stimulated quiescent cells. F greater than 600 reached a peak at 4 hr in postmitotic cells and between 16 and 19 hr in serum-stimulated quiescent cells. A similar delay in the time of entry into S phase occurred after serum stimulation of resting cell populations. The results are compatible with the hypothesis that cells after mitosis may enter a state that is different from the state of cells made quiescent by serum restriction.


Serum alkaline phosphatase isoenzymes in lymphoproliferative diseases. A new isoenzyme of alkaline phosphatase (EC 3.1.3.1) has been reported to occur in sera from patients with lymphoproliferative diseases. This enzyme is characterized by an inability to hydrolyze cysteamine S-phosphate. We find that the 5,5'-dithobis(2-nitrobenzoic acid)-coupled assay method for cysteamine S-phosphate hydrolysis is not suitable for serum, and we were unable to confirm the existence of this isoenzyme in serum by this assay method. We were unable to detect to detect this new isoenzyme by polyacrylamide gel electrophoresis with activity stains or by the reported high sensitivity of this enzyme to inhibition by cysteamine S-phosphate when p-nitrophenyl phosphate is the substrate. We were also unable to confirm reports of a unique inhibitor of normal alkaline phosphatase in the serum of patients with infectious mononucleosis.


A statistical model for predicting response of breast cancer patients to cytotoxic chemotherapy. A binary logistic model is used for predicting response to cytotoxic chemotherapy for a breast cancer patient on the basis of her tumor enzyme activity profile. The enzymes used in the model are lactate dehydrogenase, nicotinamide adenine dinucleotide phosphate-isocitrate dehydrogenase, and phosphoglucomutase, all of which were measured on primary tumor specimens from each patient. The statistical model provides an estimate of the probability that an individual will respond to treatment. Chemotherapeutic treatment consisting of combination cytotoxic drugs and subsequent evaluation of patient response followed cooperative group protocol guidelines, including outside review to confirm the patient evaluation. The model based on this study, which represents 5 years of patient follow-up, correctly predicts clinical outcome in 32 of the 37 cases available.


Metabolism of tritium-labeled 12-O-tetradecanoylphorbol-13-acetate by cells in culture. The metabolism of [20-3H]-12-O-tetradecanoylphorbol-13-acetate ([3H]TPA) was studied in human and hamster cell cultures. Within 2 to 3 days after its addition to growing or confluent cultures of hamster embryo fibroblasts, no unchanged [3H]TPA remained in the medium as determined by thin-layer chromatography of the chloroform phase obtained by extraction of the medium with chloroform:methanol:H2O. In contrast, little or no metabolism of [3H]TPA occurred under identical conditions in cultures of human fibroblasts. The major metabolite formed from [3H]TPA in hamster cell cultures was [3H]phorbol-13-acetate. with both hamster and human cells, virtually all cell-associated radioactivity was unchanged [3H]TPA.


Fluorescence study of DNA-binding metabolites of benzo(a)pyrene formed in hepatocytes isolated from 3-methylcholanthrene-treated rats. Hepatocytes and liver microsomes isolated from 3-methylcholanthrene-treated rats metabolize benzo(a)pyrene to products that bind to endogenous DNA and exogenously added calf thymus DNA, respectively. By using a sensitive fluorescence technique, it has been possible to characterize the major DNA-binding metabolite in hepatocytes as being produced by further metabolism of 9-hydroxybenzo(a)pyrene. In microsomes, two products binding to calf thymus DNA were recovered, a major species formed by activation of 9-hydroxybenzo(a)pyrene and a minor fraction formed by further metabolism of 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene. The available evidence indicates that the ultimate products responsible for binding to DNA were identical to 9-hydroxybenzo(a)pyrene 4,5-oxide and 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide, respectively. Our data further suggest that metabolic activation of 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene and 9-hydroxybenzo(a)pyrene results in quite different DNA:metabolite complexes. The former product(s) seems to be strongly associated with hydrophobic regions in DNA, whereas the latter metabolite(s) appears to be more exposed to the exterior.


Testing of known carcinogens and noncarcinogens for their ability to induce unscheduled DNA synthesis in HeLa cells. The ability of 51 compounds, of known carcinogenic potential, to induce "unscheduled DNA synthesis" in HeLa cells has been tested in the presence or absence of a rat liver mixed-function oxidase preparation. Chemicals tested included those giving erroneous results in bacterial mutagenicity assays as well as representative compounds from various classes of chemical carcinogens including nitrosamines, polycyclic aromatic hydrocarbons, aromatic amines, and mycotoxins. Of the compounds assayed, all noncarcinogens failed to induce DNA repair; of 38 compounds of demonstrated carcinogenicity, 34 were active; safrole, N-propyl-N-nitrosourea, aflatoxin B2 and N-butyl-N-nitrosourea were, however, inactive. Six compounds for which carcinogenicity data are incomplete were active, namely, 4-nitro-o-phenylenediamine, 2-nitro-p-phenylenediamine, formaldehyde, 2,2'-dichlorobenzidine, 3,3',5,5'-tetrafluorobenzidine, and 3,3',5,5'-tetrachlorobenzidine. Three carcinogens that are weakly active or inactive in bacterial mutagenicity assays, i.e., urethan, N-dimethyl-p-aminoazobenzene, and diethylstilbestrol were active in our assay. The bacterial mutagens sodium azide and 9-aminoacridine were both inactive. The use of this assay in a tier scheme for the short-term testing of potential chemical carcinogens is discussed.


Photoradiation therapy for the treatment of malignant tumors. Administration of hematoporphyrin derivative i.v. followed by local exposure to red light has resulted in complete or partial response in 111 of 113 cutaneous or s.c. malignant lesions. Tumors treated have included carcinomas of the breast, colon, prostate, squamous cell, basal cell, and endometrium; malignant melanoma; mycosis fungoides; chondrosarcoma; and angiosarcoma. No type has been found to be unresponsive. In several cases complete clearing of chest wall metastatis has been achieved in treated areas. Deep-seated and pigmented tumors required a higher dose of drug for effective treatment than did the more superficial and nonpigmented lesions. A high therapeutic ratio between tumor and skin response has been obtained by allowing at least 3 days between drug injection and exposure to the therapeutic light for 2,5-mg/kg doses and at least a 4-day interval for 5.0-mg/kg doses.


Hematology and clinical chemistry reference values for C57BL/6 X DBA/2 F1 mice. We have analyzed hematology data from 504 individual male C57BL/6 X DBA/2 (hereafter called B6D2F1) mice. Clinical chemistry data from an additional 304 individual male B6D2F1 mice have also been analyzed. The mice had served as drug-diluent controls in 24 toxicological evaluations of anticancer drugs administered singly or in combination. The studies were carried out under standardized conditions during an 18-month period between July 1975 and December 1976. Test values corresponding to 9 percentiles have been selected from an ordered ranking of values for each of 18 hematologic tests and 18 clinical chemistry tests. Since 95% of the values for a given test are found between the 2.5th and 97.5th percentiles, test values corresponding to these percentiles provide reference values ("normal" values) for these mice. The other percentiles (5th, 10th, 25th, 50th, 75th, 90th, and 95th) indicate the distribution of values between the reference limits for each test. Since values for all tests do not conform to the Gaussian distribution, this nonparametric analysis provides reference values that are more accurate than might be obtained from calculation of the mean and standard deviation of a given test. The B6D2F1 mouse, commonly referred to as BDF1, has been widely used for preclinical evaluation of anticancer drugs, and these data should be useful to investigators who are conducting qualitative and quantitative toxicity evaluations in these mice.


Invasive and noninvasive methods of assessing adriamycin cardiotoxic effects in man: superiority of histopathologic assessment using endomyocardial biopsy. Endomyocardial biopsies and cardiac catheterizations were performed in 55 patients treated with adriamycin (ADM). Eleven patients underwent serial invasive studies. In addition, most of these patients had systolic time interval determinations, echocardiograms, and electrocardiograms at the time of catheterization. The relationship of these various tests to cumulative dose of ADM and to the incidence of cardiac dysfunction was analyzed. Only pathologic assessment of ADM-induced myocardial damage showed a progressive stepwise increase in severity at successively higher doses of ADM. In addition, the incidence of myocardial dysfunction correlated well only with pathologic findings on biopsy. We conclude that standard noninvasive methods of assessing ADM cardiotoxicity are inadequate and that histopathologic assessment by means of endomyocardial biopsy is a valuable, reliable, and accurate technique.


Anthracycline cardiomyopathy monitored by morphologic changes. Seventy-six endomyocardial biopsies obtained from 60 patients receiving adriamycin (ADM) and other anthracycline analogs were studied. The biopsies were studied by light and electron microscopy. Two main types of myocyte degeneration were consistently present, the lesions were focal, and inflammatory infiltrate was absent. The severity of pathologic changes was graded on a scale from 0 (normal) to 3 (marked abnormality). Twelve patients receiving previous mediastinal irradiation (600-5700 rads) showed a mean pathology grade (2.0 +/- 0.89) that was significantly higher than in those patients receiving a comparable dose of ADM but who were not irradiated (1.18 +/- 0.23) (P less than 0.01). This study indicated that radiation, even if remote, enhances ADM-induced cardiotoxicity and evokes a "recall" phenomenon of latent acute irradiation changes. Our data suggest that a specific, progressive, subclinical injury to the heart occurs with anthracycline therapy that cannot be detected reliably by conventional tests. Anthracycline-induced cardiotoxicity in rabbits, monkeys, and dogs shows the same basic cellular lesions as in man. The analogs, adria-DNA and rubidazone, also show lesions similar to those produced by ADM in the human heart. The endomyocardial biopsy is a reliable method for monitoring cardiac damage due to anthracyclines in man.


Clinical spectrum of anthracycline antibiotic cardiotoxicity. Anthracycline derivatives may produce early or late cardiotoxic reactions in man. Early effects include: (a) pericarditis-myocarditis which can affect patients with no previous history of cardiac disease and which carries a high mortality rate ( approximately 20%); (b) left ventricular dysfunction which may lead to clinically significant heart failure in patients with limited cardiac reserve; and (c) arrhythmias, the most common of which is sinus tachycardia. Symptomatic supraventriclar tachycardia, heart block, and ventricular arrhythmias can occur, however, and may reflect primary effects on cardiac muscle or the conduction system. Late effects of anthracyclines are directly related to the degree of associated myocyte damage and include subclinical left ventricular dysfunction and overt heart failure. The implications for prognosis and further treatment are discussed for each of these entities and a common pathogenetic mechanism is proposed.


Adriamycin cardiotoxicity: early detection by systolic time interval and possible prevention by coenzyme Q10. Recent work suggests that adriamycin (ADM) cardiotoxicity results from the depletion of coenzyme 10 (CoQ10) activity in myocardial mitochondria. CoQ10 is indispensable in the bioenergetics of coupled respiration of oxidative phosphorylation. It exists naturally in mitochondria, especially in the myocardium. Bertazzoli et al have reported a decrease in ADM-induced cardiotoxicity by CoQ10 both in vivo and in the in vitro isolated rabbit heart. The systolic time interval (ATI) (pre-ejection period/left ventricular ejection time ratio) has been shown to increase (indicating cardiac dysfunction) with increasing doses of ADM. We have noted a gradual increase in the STI in eight of ten patients receiving 200-500 mg/m2 of ADM. Two of these eight patients had congestive heart failure (CHF) at doses of 200 and 350 mg/m2. The continued daily oral administration of 50 mg of CoQ10 beginning with the first dose of ADM resulted in a decreased incidence of cardiac dysfunction, and a gradual increase in STI occurred in only two of eight patients receiving 200-400 mg/m2 of ADM. CHF was observed inone patient at a dose of 350 mg/m2. It is suggested that CoQ10 was nontoxic and did not affect the antitumor activity or modify the ADM-induced bone marrow toxicity. A prospective randomized study comparing ADM with and without CoQ10 is in progress.


Systolic time intervals in monitoring for anthracycline cardiomyopathy in pediatric patients. Systolic time intervals are of value in measuring left ventricular function. The ratio of the pre-ejection period to the left ventricular ejection time (PEP/LVET) was determined serially in 60 children with cancer receiving anthracycline drugs. Measurements were examined for their predictive value in determining incipient anthracycline cardiomyopathy. An increase in the PEP/LVET ratio was not followed by clinical failure in the majority of patients. Of two patients who developed presumed anthracycline cardiomyopathy, only one demonstrated an increase in the ratio prior to going into heart failure. The value of the PEP/LVET ratio in children for predicting anthracycline cardiomyopathy appears limited, based on the results of this study.


Systolic time intervals: an effective measure of cardiac function in anthracycline-induced cardiomyopathy of rabbits. The laboratory rabbit appears to be an ideal animal model for the study of anthracycline-induced cardiomyopathy in that it exhibits a cumulative, dose-related, histologically similar lesion to that seen in man treated with the same drug. Quantification of this cardiomypathy with respect to total cumulative drug dose has been limited to histologic criteria, a cumbersome method which necessitates killing the study animal. With the intent of adapting noninvasive cardiac function studies, previously proven in man, to the rabbit, serial systolic time interval measurements in normal control and adriamycin (ADM)-treated rabbits are simple, easily performed, and readily reproducible, and accurately reflect physiologic cardiac function. In the rabbit, PEP:LVET ratios greater than 0.447 indicate significant ventricular dysfunction and are consistently seen at cumulative doses of ADM greater than 300 mg/m2.


Serial studies of cardiac function in patients receiving adriamycin. A total of 283 adult and pediatric patients treated with drug combinations which include adriamycin (ADM) had at least one cardiac evaluation; 103 patients had two or more serial studies after a baseline evaluation. Changes in systolic time intervals, echocardiographically determined ejection fractions, and electrocardiographic voltage correlated with increasing cumulative ADM dosage. However, the incidence of congestive heart failure among these patients was less than 2%. It is estimated that 22%-31% of these patients would not have completed a cumulative dose of greater than 450 mg/m2 of ADM if the drug had been discontinued on the basis of these tests, using previously published criteria for cessation of treatment. Thus far, however, no adverse effects have been observed from the completion of planned courses of therapy. The clinical significance of serial changes in noninvasive tests is therefore uncertain. While such changes may reflect subclinical anthracycline cardiotoxicity and clinical cardiotoxicity can reliably be diagnosed, the utility of routine, serial noninvasie testing in planning conventional-dose anthracycline therapy is questionable.


QRS voltage change with adriamycin administration. A decrease in the electrocardiographic limb lead QRS voltage of greater than or equal to 30% was highly correlated with the development of congestive heart failure in patients treated with adriamycin (ADM). It is felt that if a decrease in limb lead QRS voltage greater than or equal to 30% were detected in a patient receiving ADM, cardiomyopathy might be avoided or ameliorated by discontinuation of the drug.


Radionuclide angiography for the evaluation of anthracycline therapy. A sensitive and reproducible method to noninvasively monitor cardiac function in patients receiving anthracycline therapy is badly needed. The radionuclide ejection fraction (EFrn) appears to be a suitable technique to provide this hemodynamic information. This paper describes the technique for determining the left ventricular EFrn with the use of technetium99m-labeled rbcs, a gamma scintillation camera, and a dedicated computer. The comparison of radionuclide and radiographic contrast EFrn showed a high correlation ( r = 0.84) in 30 patients.


Noninvasive assessment of cardiac dysfunction in the cancer patient. The concepts of left ventricular function are reviewed with an emphasis on the pitfalls in the clinical assessment of myocardial performance. The application of noninvasive cardiac diagnostic techniques is discussed, including physical examination, systolic time intervals with external pulse recordings, echocardiography, and radionuclide cineangiography.


Time- and dose-dependent changes in ejection fraction determined by radionuclide angiography after anthracycline therapy. Twenty patients receiving anthracycline chemotherapy were studied by the technique of radionuclide ejection fraction (EFrn). This technique is capable of detecting noninvasively small changes in left ventricular function. Two patterns of anthracycline toxicity emerged: (a) an acute toxicity observable between 24 and 72 hours after administration of greater than 60 mg/m2 of anthracycline with some recovery noted by 72-96 hours (no changes were observed within the first 4 hours after administration of the drug), and (b) a chronic dose-dependent decrease in left ventricular function when studies were performed 3 weeks after the last dose of anthracycline. After anthracyclines were stopped, four of four patients showed significant  recovery in left ventricular function. We concluded that the radionuclide EFrn is a sensitive noninvasive index of left ventricular function which can be used to serially study patients receiving anthracycline therapy and can potentially be used to evaluate pharmacologic means for preventing anthracycline cardiotoxicity.


Structural investigation of Klebsiella serotype K70 polysaccharide. By using the techniques of methylation analysis, uronic acid degradation, partial hydrolysis, and periodate oxidation, th structure of the capsular polysaccharide from Klebsiella serotype K70 has been investigated. Nuclear magnetic resonance was used extensively to characterize fragments obtained as a result of the various degradation procedures. The existence of a linear, hexasaccharide repeating unit having a 1-carboxyethylidene group attached to a 2-linked alpha-L-rhamnosyl residue in every second repeating unit has been demonstrated.


Isolation of a collagen fraction from the body-wall glycoproteins of the leech (Hirudo medicinalis), and characterization of its carbohydrate--amino acid portion. Fractionation of the leech (Hirudo medicinalis) body-wall glycoproteins yielded a collagen fraction containing only D-glucose and D-galactose as its carbohydrate constituents. Digestion of the collagen with trypsin and pronase, and alkaline degradation of the resulting glycopeptides, gave a product that contained a disaccharide linked to hydroxylysine. Mild, acid hydrolysis of the N-acetylated glycopeptides yielded a disaccharide consisting of a D-glucose and a D-galactose residue. Various chemical and enzymic reactions of the disaccharide, the glycosyloxylysine, and the glycopeptide fraction indicated that the disaccharide is 2-O-alpha-D-glucopyranosyl-D-galactose, and that this is beta-glycosidically linked to O-5 of the hydroxylysine residue in the collagen.


The dextran acceptor reaction of dextransucrase from Streptococcus mutans K1-R. Soluble dextransucrase activity(ies) was eluted with a solution of clinical dextran from the insoluble dextran--cell complex produced by Streptococcus mutans K1-R grown in the presence of sucrose. Studies of the dextran acceptor-reaction of the soluble enzyme-preparation indicate that it is highly specific for dextran of high molecular weight. Increased dextran synthesis in the presence of dextran acceptor and the apparent inhibition of this stimulation by higher concentrations of dextran result from product modification rather than a direct effect on the level of enzyme activity. The results demonstrate that the potentially water-insoluble structure synthesized by dextransucrase on exogenous, soluble dextran acts as a more-efficient acceptor than the soluble dextran. The role of the acceptor reaction in the biosynthesis of complex dextrans is discussed.


Long-term management of hypertension.

Long-term management of hypertension. The ambulatory management of hypertension is relatively simple. A key factor in the success of any program is motivation of both the physician and the patient. Workup should be limited to a few simple tests as outlined; need rarely, if ever, involve hospitalization; and can be completed in one or two office or clinic visits. Treatment of hypertion over a long-term period involves the use of specific drug therapy, although some slight modification of lifestyle or diet is occasionally helpful. There are numerous drugs available, and in over 80 to 85 percent of cases, an effective combination can be found. Drug therapy must be continuous; it is rare, in our experience, that medication can be completely discontinued. Data available from the Veterans Administration study, as well as my own, clearly indicate that effective lowering of blood pressure over a long period of time is cost-effective and delays or prevents numerous complications that are frequently noted in untreated patients.


The interstitial cells in the renal medulla of rat, rabbit, and gerbil in different states of diuresis. The inner zone of the renal medulla of rats, gerbils, and rabbits was investigated to determine whether or not there are any characteristic ultrastructural differences between the interstitial cells of these species. The effects on the interstitial cells of water deprivation and water loading were also investigated. In all three species, the Type 1 interstitial cells, the lipid containing cells, were abundant and their distribution and topographical relations as well as their general ultrastructure were similar. The previously reported significantly higher frequency in desert rats could not be confirmed. Although the lipid droplets of the interstitial cells were smaller in gerbils and rabbits when compared to rats, their fine structure was similar. Their electron dense outer zone was sometimes associated with a granular material and/or a lamellar material with a periodicity of about 40 A resembling phospholipid "myelin figures". Water-loaded rats showed a considerable increase in the number of lipid droplets when compared to dehydrated or untreated animals. In contrast, the interstitial cells of waterloaded gerbils and rabbits were depleted of lipid droplets.