Hypothalamo-pituitary-thyroid function in anorexia nervosa: influence of weight gain. The functional state of the hypothalamo-pituitary-thyroid axis was assessed in 14 women and girls with anorexia nervosa when at low body weight and again in 12 cases after they had gained weight. Mean serum thyroxine concentrations were low before and after weight gain. Mean serum triiodothyronine (T3) concentrations were substantially reduced at low weight and doubled after weight gain, the absolute values being linearly correlated with body weight expressed as a percentage of the ideal. Concentrations of reverse T3 were greatly increased in some patients initially and fell with weight gain. Basal concentrations of thyroid-stimulating hormone (TSH) were unchanged after weight gain but the TSH response to thyrotrophin-releasing hormone was significantly augmented; delayed patterns of response were found in seven out of 12 patients tested before and three out of 12 patients tested after weight gain. Changes in the hypothalamo-pituitary-thyroid axis are common in anorexia nervosa and probably represent both peripheral and central adaptations to the altered nutritional state.


HBsAg-positive chronic liver disease: inhibition of DNA polymerase activity by vidarabine. Four patients who had chronic liver disease and were positive for hepatitis B surface antigen (HBsAg) were treated with vidarabine, a synthetic purine nucleoside that inhibits DNA polymerase activity in vitro and in vivo. Before treatment all had raised serum DNA polymerase concentrations. Three also had hepatitis B e (HBe) and were shown by electron microscopy to have hepatitis B virus (Dane) particles in their serum. In all patients 10 days' treatment with vidarabine resulted in an immediate loss of DNA polymerase activity. In three patients the activity returned when treatment was stopped. In those three patients Dane particles and HBe antigen persisted during and after treatment; in the fourth patient, who remained negative for DNA polymerase, HBsAg titres fell. Although vidarabine inhibited virus replication, virus particles did not disappear from the blood in these patients, presumably because the particles were cleared only slowly. Similar results with interferon suggest that the virus disappears, and HBsAg titres fall, some weeks after the fall in DNA polymerase activity. Continued treatment may therefore have a sustained effect on viral replication. Whether vidarabine can permanently clear HBsAg and so arrest chronic liver disease remains to be seen, but at the very least it could reduce the spread of infection.


Changes in antibiotic sensitivity in strains of Staphylococcus aureus, 1952-78. Two hundred strains of Staphylococcus aureus isolated from outpatients with infections of the skin and subcutaneous tissues were tested for sensitivity to penicillin, erythromycin, tetracycline, sodium fusidate, methicillin, clindamycin, chloramphenicol, and gentamicin. One hundred and sixty-three (81.5%) of the strains were resistant to penicillin and 16 (8%) resistant to tetracycline. Incidence of resistance to other antibiotics was low. No strain was resistant to chloramphenicol, gentamicin, or methicillin. When compared with results of earlier studies, there was an increase in the incidence of resistance to penicillin and tetracycline, but no appreciable increase in resistance to other antibiotics.


Ambulation in labour.

Ambulation in labour. In a randomised prospective study of 68 women in spontaneous labour half were allocated to an ambulant group and half to a recumbent group. The duration of labour was significantly shorter, the need for analgesia significantly less, and the incidence of fetal heart abnormalities significantly smaller in the ambulant group than in the recumbent group. Apgar scores at one and five minutes were also significantly greater in the ambulant group. More patients in the recumbent group required augmentations with oxytocic drugs. There was no statistically significant difference in the third stage loss in the two groups. Ambulation in labour should be encouraged: it may bring human benefits while allowing the advantages of hospital supervision.


A glucose-controlled insulin infusion system for diabetic women during labour. A glucose-controlled insulin infusion system was used to control blood glucose concentration during labour or caesarean section in six insulin-dependent diabetics. The mean blood glucose concentration during the four hours of labour immediately before delivery was 4.6-5.2 mmol/1 (82.9-93.7 mg/100 ml). Feedback control of insulin delivery by blood glucose concentration should decrease the risk of postpartum hypoglycaemia in the infant and allow normal obstetric management for the insulin-dependent diabetic in labour.


Difficulties in diagnosing and managing congenital dislocation of the hip. In a 10-year retrospective study of 25 921 consecutive deliveries in a neonatal unit in Newcastle upon Tyne 271 cases of congenital dislocation of the hips were identified. Of these, the outcome was unsatisfactory in 12: four diagnoses were missed at birth and eight children required further surgical treatment. Radiological abnormalities were detected in a further five children at long-term follow-up examination. From the results of this study and other published series it was concluded that lack of attention to detail was the main cause of inadequate diagnosis and management of congenital dislocation of the hips. More detailed instruction of junior staff, confirmation of the diagnosis by senior staff, the use of a non-removable splint early in treatment, and thorough follow-up by senior staff are all important.


Towards positive diagnosis of the irritable bowel. A questionnaire to establish the presence of 15 symptoms thought to be typical of the irritable bowel syndrome (IBS) was given to 109 unselected patients referred to gastroenterology or surgery clinics with abdominal pain or a change in bowel habit or both. Review of case records 17--26 months later established a definite diagnosis of IBS in 32 patients and of organic disease in 33. Four symptoms were significantly more common among patients with IBS--namely, distension, relief of pain with bowel movement, and looser and more frequent bowel movements with the onset of pain. Mucus and a sensation of incomplete evacuation were also common in these patients. The more of these symptoms that were present the more likely was it that the patient's pain or altered bowel habit, or both, was due to IBS. We conclude that a careful history can increase diagnostic confidence and reduce the amount of investigation in many patients with chronic abdominal pain.


Is nasogastric suction necessary in acute pancreatitis? Fifty-eight patients with mild to moderately severe acute pancreatitis were randomly allocated to treatment with or without nasogastric suction (27 and 31 patients respectively). Intravenous fluids and pethidine hydrochloride were also given. The two groups were comparable clinically at the start of the study. There were no differences between the two groups in the mean duration of the following features: abdominal pain or tenderness; absence of bowel movements; raised serum amylase concentration; time to resumption of oral feeding; and days in hospital. Prolonged hyperamylasaemia (serum amylase greater than 0.33 mU/l) occurred in one patient in the suction group and in three patients in the non-suction group. A mild recurrence of abdominal pain after resumption of oral feeding occurred in three patients in the suction group and in two patients in the non-suction group. Two patients in the suction group developed overt consumption coagulopathy and two others pulmonary complications. No patient in the non-suction group had complications. The findings suggest that most patients with mild to moderately severe acute pancreatitis do not benefit from nasogastric suction. The procedure should be elective rather than mandatory in treating this condition.


Postgraduate education in therapeutics: experience in Merseyside. A teaching programme in therapeutics for general practitioners in Merseyside, which was led by a group of clinical pharmacologists, had as its principal aim to emphasise the importance of rational drug prescribing. The course comprised 15 sessions restricted to 25 GPs, and the topics were suggested by both the organisers and the GPs. Though each session was introduced by a clinical pharmacologist, the emphasis was an open discussion and exchange of views. This programme may serve as a pattern for other centres.


Use of digitalis in general practice. Liverpool Therapeutics Group. A study, which arose out of a general-practitioner teaching programme in clinical pharmacology, was designed to assess the use of digitalis in 391 patients in general practice. Clinical, biochemical, and pharmacological data were used to assess whether digitalis treatment should be discontinued (89 patients; 22.8%); the dose kept unchanged (47; 12%); or the dose increased (47; 12%) or decreased (24; 6.1%). Serum concentrations of cardiac glycoside were below a defined therapeutic range in 159 patients (40.7%), above this range in 37 (9.7%), and within the range in 195 (49.3%). Studies of this kind may help to promote a more critical attitude to prescribing widely used drugs such as digitalis.


Sorry John--try again next year.

Sorry John--try again next year. The new legislation affecting foreign medical graduates has placed several obstacles in the path of potential visitors and immigrants to the United States. Now that there is no longer a shortage of doctors in the USA the need for these new laws is clear, but their implementation has been hasty and has allowed no time for planned transition. If further modifications are made, which may well happen, every effort should be made to disseminate information about new requirements as widely and rapidly as possible.


Sampling pure fetal blood by fetoscopy in second trimester of pregnancy. A technique for fetal blood-sampling in the second trimester of pregnancy (between 16 and 22 weeks' gestation) combining fetoscopy with real-time ultrasound was used in 48 attempts at fetal blood-sampling. Specimens containing fetal red cells with or without amniotic fluid or maternal blood, and adequate for diagnosing haemoglobinopathies, were obtained in 45 of the 48 fetoscopies. Sampling was successful in all 18 patients with a posterior placenta, and in 27 of the 30 with an anterior placenta. In 22 of the last 27 consecutive fetoscopies pure fetal blood was taken; the placenta was anterior in 16 and posterior in six. Out of 17 cases sampled between 18 and 22 weeks' gestation pure fetal blood was obtained in 16. The volume of the samples varied from 50 to 500 microliter. The ability to obtain pure fetal blood consistently even when the placenta is anterior will increase knowledge of fetal physiology and the scope of prenatal diagnosis.


Effect of stopping low-phenylalanine diet on intellectual progress of children with phenylketonuria. Forty-seven patients at the Hospital for Sick Children, London, who had phenylketonuria and were on a low-phenylalanine diet (21 early-treated--that is, treatment started before the age of 4 months--and 26 late-treated) were placed on a normal diet between the ages of 5 and 15 years. They showed significant falls in mean IQ of about six points after the diet was withdrawn. Twenty-two similar patients (five early-treated and 17 late-treated) at the Universitäts-Kinderklinik, Heidelberg, who were placed on a relaxed low-phenylalanine rather than a normal diet, showed smaller and non-significant falls in mean IQ. During the period of strict diet none of the patients in London or Heidelberg showed any consistent falls in IQ. These results suggest that complete withdrawal of the low-phenylalanine diet during childhood leads to a fall in intellectual progress in many patients.


Natural history and prognosis of recurrent breast cancer. Patterns of recurrent disease were analysed in 603 patients with breast cancer. The time of onset, frequency of recurrence, and survival after recurrence were not influenced by age or menopausal state. While survival after local recurrence was longer than survival after distant metastasis, the time to onset of local and distant disease followed an identical pattern, indicating that local recurrence should be regarded as a manifestation of systemic disease. Postoperative radiotherapy did not affect the time of onset of local recurrence. We suggest that patients with local recurrence should receive both systemic and local treatment and that controlled trials of chemotherapeutic agents in these patients might be valuable in finding the most effective drug combinations to be used as adjuvant treatment after mastectomy.


Taxonomic map of the schizophrenias, with special reference to puerperal psychosis. Data collected by a single observer on 147 schizophrenic patients were subjected to clustering analysis. The results produced the hypothesis that schizophrenic illnesses directly after childbirth are a separate disease entity. This hypothesis was not disproved by experimental testing. Several disease entities may be included in the term schizophrenia. If this is so, the methods used in generating and testing the hypothesis that puerperal schizophrenia is a separate disease may provide a systematic method of classifying the various illnesses.


Human milk bank in a district general hospital. A human milk bank was organised in the special care baby unit of a district general hospital. The staff of the unit and members of a voluntary organisation helped to contact donors and arrange collection of milk samples. Over two years 2093 samples of expressed breast milk were collected from 187 donors and examined bacteriologically. Of these samples, 1171 (56%) grew no bacteria. If the organism count exceeded 2.5 X 10(6)/1 but was less than 1 X 10(9)/1 samples were subjected to mild heat treatment. If the count exceeded 1 X 10(9)/1 the milk was not fed to babies. Sixty-five babies received milk from the bank during the second year. Although these infants were vulnerable, mortality and morbidity were not adversely affected by the banked milk they received. The cost of establishing and running a human milk bank need not be high. Extensive resources such as extra staff and laboratory and transport facilities were not needed. Enthusiastic co-operation and good will between hospital staff, voluntary helpers, and donors contributed greatly to the success of the scheme.


A clinical study of the EMI scanner: implications for provision of neuroradiological services. The records of the first 571 patients to be examined with an EMI brain scanner were assessed. The patients were divided into diagnostic categories according to their clinical presentation. The intracranial investigations that would have been performed had the scanner not been available were compared with the investigations that were actually performed. As expected, the number of contrast investigations fell, but the reduction surpassed expectation. If the full clinical impact of the scanner is to be realised the patient's illness must be defined in detail and strict attention paid to radiographic detail. By reducing the number of special contrast investigations use of the scanner enables existing contrast facilities to serve a wider population; and use of the brain scanner in district general hospitals would improve the service to patients, especially those with head injuries.


Cells of origin of subcortical afferents to the caudate nucleus: a horseradish peroxidase study in the cat. The horseradish peroxidase tracing method was used to investigate the sources of subcortical input to the caudate nucleus in the cat. Of considerable interest was the finding, not previously described, that labeled neurons were present outside of the intralaminar complex, in the ventral anterior and mediodorsal thalamic nuclei. Another new finding was that retrogradely labeled cells were present within the basolateral amygdaloid nucleus, following the caudate injections. In addition, neurons containing enzyme granules were found within all of the intralaminar thalamic nuclei, most prominently in the central lateral and centromedian nuclei. Also, HRP-positive cells were strikingly apparent within the ipsilateral pars compacta of the substantia nigra, and a few labeled cells were found in the ipsilateral pars reticularis, and the contralateral pars compacta of the substantia nigra. Cells containing peroxidase granules were also found in the ventral tegmental area and the retrorubral area. The most caudal projection to the caudate nucleus in the cat was demonstrated by labeled neurons found bilaterally in the dorsal nucleus of the mesencephalic raphe.


The cerebellar control of accommodation of the eye in the cat. The effect of cerebellar stimulation on the accommodation of the lens was examined in anesthetized cats. An infrared optometer was used to measure the refractive power of the lens during stimulation of the cerebellum. The area giving responses within latencies shorter than 160 msec and amplitudes larger than 0.15 diopters is localized in the contralateral interpositus and fastigial nuclei and the ipsilateral interpositus nucleus. No responses could be evoked by stimulating the bilateral lateral nuclei. Accommodation responses were also evoked by cerebellar cortex stimulation. Accommodation responses evoked by stimulating the cerebellar nuclei were inhibited by preceding cerebellar cortical stimulation.


Identification of a subregion within rat neostriatum for the dopaminergic modulation of lateral hypothalamic self-stimulation. Experiments were conducted to test the hypothesis that the involvement of neostriatal dopaminergic transmission in lateral hypothalamic self-stimulation might be specific to a striatal subregion. Crystalline application of dopamine or D-amphetamine increased self-stimulation rate only when made to ventral anterior striatum (VAS); more dorsal or posterior applications were ineffective. A comparison of dose-response functions for dopamine using solution injections in VAS and posterior striatum (PS) confirmed that only VAS was responsive. Injections or applications of 6-hydroxydopamine suppressed responding only when made into VAS. Haloperidol injections decreased responding only for VAS and not PS injection sites. Applications or injections of scopolamine often increased responding when made into VAS, but this effect was unreliable. Applications or injections of scopolamine to more posterior sites consistently suppressed responding. It was concluded that dopaminergic transmission in VAS, alone among the striatal sites tested, is facilitatory on hypothalamic self-stimulation. The effects of drug applications to nucleus accumbens were generally similar to VAS, and it was suggested that these areas may be functionally similar. An examination of the known afferents to VAS indicated that this area of neostriatum, like n. accumbens, may be influenced by activity in limbic structures. This anatomy may help provide an understanding of how neostriatum, traditionally considered to have a motor function, might be involved in central reward processes.


Anatomical specificity within rat striatum for the dopaminergic modulation of DRL responding and activity. The direct application of microgram quantities of crystalline dopamine, D-amphetamine, or scopolamine to the ventral anterior region of the neostriatum of rats decreased response efficiency on a 'differential reinforcement of low rate' 10 sec schedule of reinforcement. Similar applications to the dorsal globus pallidus or posterior striatum either did not alter or increased response efficiency. A comparison of dose-response functions for injections of dopamine in solution into ventral anterior, central and posterior striatum confirmed that only injections into ventral anterior striatum (VAS) decreased response efficiency on the DRL schedule. The same striatal map was found for the dopamine-induced increase in spontaneous locomotor activity in tilt boxes. It was concluded that dopaminergic transmission in ventral anterior striatum, in contrast to the other striatal and pallidal sites tested, is involved in the modulation of behavioral arousal.


On the appearance of acetylcholine receptors in denervated rat diaphragm, and its dependence on nerve stump length. Acetylcholine (ACh) sensitivity and extrajunctional receptor distribution of the rat diaphragm were closely monitored during the early period following denervation. Both contracture in response to 10 microgram/ml of ACh and extrajunctional binding of [125I]alpha-bungarotoxin ([125I]alpha-BTX)) were first detectable 30 h after cutting the phrenic nerve in the thorax. If the nerve were cut more proximally, leaving a 3.5 cm distal nerve stump, the same level of ACh contracture and [125I]alpha-BTX binding did not appear until 40 h after operation. This 10-h delay was far longer than the 3-h delay in transmission failure reportedly dependent on stump length. The earliest detectable extrajunctional [125I]alpha-BTX binding appeared throughout the entire muscle fiber, and was not localized to the endplate region as would be expected if degeneration in the nerve terminal induced new receptors. However, later significant increases in [125I]alpha-BTX binding at the endplate region could have resulted from such degeneration. All these results are consistent with neurotrophic regulation of muscle ACh receptors, working via a mechanism involving axonal transport.


Social grouping cannot account for cerebral effects of enriched environments. Several experiments were conducted to test whether, as suggested by Welch et al. in this journal, mere group living (social stimulation) can account for the significant differences in measures of brain anatomy and brain chemistry that develop between rodents housed in groups in enriched environments and rodents housed singly in restricted environments; the alternative hypothesis was that features of the inanimate environment can significantly affect brain measures of animals living in a social group. Groups of 12 male rats were assigned for 30 days to several types of environment: (a) large cage without stimulus objects, (b) large cage containing varied stimulus objects, (c) large cage containing a maze whose pattern of barriers was changed daily, and (d) a seminatural outdoor environment; in each experiment, littermates of rats in the social conditions were housed in isolation in small colony cages. At the end of the 30-day period, measures were taken of weights of brain regions, RNA and DNA contents of regions of cerebral cortex, and acetylcholinesterase activities of brain regions. Although the number of rats housed together was constant for conditions a--d and cage size was constant for conditions a--c, the magnitudes of the cerebral measures varied significantly as a function of the inanimate stimulus conditions. The differences from isola;ion-housed littermates was greatest in condition d and smallest in condition a. Thus, social grouping alone is inadequate to explain the cerebral effects of enriched environments and the inanimate stimulus conditions must be taken into account.


Presence of a pineal nerve (nervus pinealis) in the human fetus: a light and electron microscopical study of the innervation of the pineal gland. The presence of a hitherto undiscovered nerve located in the subarachnoidal space just caudal to the pineal organ, connecting this organ and the posterior commissure, was demonstrated by light and electron microscopy in a series of 18 human fetuses. This nerve is believed to be ontogenetically equivalent to the pineal nerve observed in the anuran amphibians. The nerve was present in fetuses with a CRL of 56 mm and had not disappeared in fetuses with a CRL of 169 mm. The gestational age at which this human fetal nerve degenerates could not be determined in this study. In addition to the bilateral conarian nerve a habenulopineal tract and an intrapineal ganglion were observed. The presence of the classical Pastori and Marburg ganglia was confirmed, and a new ganglion lying rostral to the pineal organ was seen too.


Electrical activation of visual pathways substitutes for tonic light input in triggering EEG correlates of food reward during conditioned behavior in cats. Cats trained to press a lever for 1 cc of milk reward normally show during the consummatory response high voltage 6--8 c/sec EEG synchronization associated with epicortical positive steady potential shift over the primary and secondary visual projections. The emergence of this postreinforcement synchronization (PRS) and Reward Contingent Positive Variation (RCPV) is known to depend upon appropriate gustatory input and presence of ambient light, although visual perception of reward and/or environment is not essential as shown in cats wearing translucent "milky" contact lenses. Training the animals in a paradigm in which a "light-off" cue signaled the availability of reward, and thus assigned positively reinforcing quality to the dark condition, also failed to restore the PRS-RCPV phenomenon in the absence of light. However, brief electrical stimuli applied to either the optic tract or the lateral geniculate nucleus substituted for unpatterned light input and fully restored the PRS-RCPV in the dark. The suprathreshold stimuli were effective only during the consummatory response. Maximum effect could be produced during a brief time period between 0.8 and 1.5 sec after the onset of consummatory response as judged by lapping activity, thus showing the specificity of the effect of visual input. Even during a relaxed wakefulness after satiation or during slow wave sleep or REM sleep the same electric stimuli were ineffective although they produced well-developed evoked potentials with all characteristic wave components. The results indicate that brain pathways utilize unpatterned i.e. noisy visual input in complex integrative processes involving gustatory input.


Regional distribution of muscarinic cholinergic receptors in rat brain. Using the tritiated ligand [3H]quinuclidinyl benzilate ([3H]QNB), a specific muscarinic cholinergic antagonist, the distribution of muscarinic receptors was determined in 75 specific brain regions and nuclei removed by microdissection as well as in large brain areas. [3H]QNB binding was highest in the caudate-putamen; other regions with high binding included the nucleus accumbens, cerebral cortex and hippocampus, certain limbic and thalamic nuclei, superior colliculus, pontine nuclei and the hypoglossal nucleus. Muscarinic cholinergic receptors may be concentrated in these regions. [3H]QNB binding generally correlated well with acetylcholinesterase staining in terminals and is consistent with certain sites as particularly enriched in cholinergic synapses.


Specific glycine uptake by identified neurons of Aplysia californica. I. Autoradiography. The identified giant neurons R3-R14 in the Aplysia parietovisceral ganglion (PVG) have a rapid, Na+-dependent and Hg2+-sensitive uptake system for glycine not found in neighboring neurons. In autoradiographs of PVG incubated in [3H]glycine (glutaraldehyde fix), the cytoplasms of R3-R14 have 3--4 times more silver grains (No./100 sq.micrometer) than other neurons. The glycine uptake system in R3-R14 is selective (alanine, serine, leucine, and proline are taken up equally by all neurons) and is unaffected by reserpine and anisomycin. Neurons R3-R14 contain 2 times less label when ganglia are fixed in formaldehyde than when glutaraldehyde is used as a fixative. Because formaldehyde fixes free amino acids poorly, much of the glycine taken up by R3-R14 is, therefore, not incorporated into protein. In autoradiographs of PVG incubated in [3H]glycine, silver grains are distributed randomly throughout the cytoplasm and nucleus of R3-R14; no association of the grains with the dense core granules characteristic of these neurons7 or other cellular components was found. In contrast, grains in the neurosecretory "bag cells" of the PVG were clustered in numerous discrete areas of the cytoplasm (Golgi complex areas) and the nucleus was only sparsely labeled. The existence of a rapid and selective glycine uptake system in R3-R14, together with their high endogenous glycine concentrations17, suggests that glycine may be a neurotransmitter in these neurons.


Specific glycine uptake by identified neurons of Aplysia californica. II. Biochemistry. Glycine is taken up twice as rapidly by neurons R3-R14 as by other identified neurons in the Aplysia parietovisceral ganglion. Earlier studies had shown that R3-R14 have much higher glycine concentrations than other Aplysia neurons. Most of the glycine taken up by R3-R14 was biochemically untransformed for at least 1 h following its uptake. Glycine is actively transported into into R3-R14 and other Aplysia neurons by carrier-mediated processes. Glycine uptake by R3-R14 was markedly reduced in the absence of Na+ and in the presence of Hg2+, while these treatments had little effect on glycine uptake by other Aplysia neurons. There appears to be a special glycine uptake system present in R3-R14 and a general glycine uptake system common to all Aplysia neurons. The elevated glycine concentrations and special glycine uptake associated with R3-R14 may indicate that glycine is utilized as a neurotransmitter by those neurons.


Activation of an inhibitory noradrenergic pathway projecting from the locus coeruleus to the cingulate cortex of the rat. Repetitive stimulation of the locus coeruleus evoked strong inhibition of the firing rate of about 50% of cells of the cingulate rat cortex. Forty per cent of the cells were not affected and 9% were excited by stimulation of the locus coeruleus. Pretreatment of the rats with reserpine and alpha-methyl-p-tyrosine drastically reduced the percentage of cells inhibited by locus coeruleus stimulation. The cells inhibited in response to stimulation of the locus coeruleus as well as those not inhibited were depressed by microiontophoretically applied norepinephrine. This inhibitory action of NE was observed in rats anesthetized either with urethane, chloral hydrate or with Nembutal. The transsynaptically elicited, as well as the norepinephrine elicited, depression of the cells' discharge rate was antagonized by the microiontophoretically applied beta-receptor blocking drug MJ 1999. These data suggest that the inhibitory action on cingulate cortical cells of locus coeruleus stimulation is mediated by the dorsal ascending noradrenergic pathway.


Tetrodotoxin sensitivity and Ca component of action potentials of mouse dorsal root ganglion cells cultured in vitro. In the mouse dorsal root ganglia cultured in vitro, neurons were classified into 3 groups according to the responses of their action potentials to tetrodotoxin (TTX) and removal of Na ions from bathing medium: (1) the neurons whose action potentials were not affected by TTX by TTX (10(-6) - 10 (-5)g/ml) and which generated Ca-dependent regenerative responses under Na-free condition, (2) the neurons whose spike potentials were resistant to TTX but failed to survive in Na-free saline and (3) the neurons whose action potentials were suppressed by TTX(10(-8)g/ml) as well as Na removal. The mean duration of spike and after-hyperpolarization was longest in the first group of the neurons and shortest in the third, probably reflecting the difference in the contribution of Ca currents to action potentials. The unresponsiveness of the neurons to TTX was shown to be due to the insensitivity of Na as well as Ca components of action potentials to the toxin. It was discussed that the occurrence of TTX-resistant action potentials to the toxin. It was discussed that the occurrence of TTX-resistant action might be related to the neuronal development.


Chick sympathetic neurons develop receptors for alpha-bungarotoxin in vitro, but the toxin does not block nicotinic receptors. Studies were carried out on the development and physiological role of receptors for alpha-bungarotoxin (alphaBT) on chick embryo sympathetic neurons maintained in dissociated cell culture. Neurons from embryos of 13 days incubation (E13) developed alphaBT receptors in vitro with a time course and to a maximum level per cell similar to that previously observed for such neurons in vivo. In vitro receptor development by E11 and E8 neurons was also present, but (in comparison with E13 neurons) reached somewhat lower maximal levels. Receptor development in vitro was not affected by exclusion of non-neuronal cells from the cultures. In the present and in previous studies, binding of alphaBT to chick sympathetic neurons was blocked by a variety of ligands of nicotinic acetylcholine receptors. However, saturating concentrations of toxin were found here to be ineffective in blocking either (a) release of [3H]norepinephrine from the cultured neurons elicited via nicotinic stimulation of acetylcholine receptors or (b) depolarizing responses of the cultured neurons elicited by iontophoretically applied acetylcholine and nicotine. Kinetic studies further revealed that, while the idssociation of alphaBT from the cultured neurons is considerably enhanced in the presence of a cholinergic ligand (100 micrometer nicotine), the rate of this dissociation (t1/2 congruent to 30 min) appears to be too slow to account for the inability of the toxin to block nicotinic responses. Such findings show that chick embryo sympathetic neurons can develop receptors for alphaBT both in vivo and in vitro, but that the toxin does not block activation of their nicotinic acetylcholine receptors. The physiologic nature of specific binding sites for alphaBT on such neurons is thus presently unclear.


Developmental changes of protein-bound radioactivity distribution in rat brain slices incubated with labelled leucine. The distribution of protein-bound labelled leucine in cortical slices prepared from young rats was investigated by autoradiography and complemented with measurements of the rate of protein synthesis in slices. During the second and third postnatal weeks the rate of protein synthesis in cortical slices from rat brain declined rapidly. The distribution of protein-bound radioactivity was fairly homogenous within the neuronal cell population of cortical slices from 7-day-old rats and was not influenced by the level of labelled leucine in the incubation medium (0.01 and 1 mM). On the contrary, the gradient-like distribution of incorporated radioactivity appeared in slices from 14-day-old rats, at both trace and 1 mM levels of the precursor. The laminar analysis of neuronal cell labelling confirmed the preponderance of incorporation into the neurones localized near the slice surface and the considerable inhibition of neuronal protein synthesis in the slice centre. Therefore, these limitations on the use of cortical slices for the study of brain protein synthesis in the rat should be respected from the beginning of the second postnatal week.


Principal component analysis of neural population response of knee joint proprioceptors in cat. (1) A means of describing the response of neural populations based on principal component analysis is presented. The analysis produces response descriptions that indicate whether two states are distinguishable and suggest how to best distinguish between states. (2) Analysis of slowly adapting joint receptor data from the cat knee joint indicates that the joint receptors are capable of signalling limb position in the range from 150 degrees to 180 degrees of extension during an extension movement. They also provide information which indicates whether the tibia is twisted inward or outward in this range of angles. (3) The first principal component in the response to a constant velocity extension of 8 simultaneously active units described 86% of the total mean square discharge displayed by all 8 units. The first principal component is qualitatively similar to the responses observed in slowly adapting thalamic joint units.


Electrical activity of hypothalamus during activation of pituitary-adrenocortical system. Multiunit activity in anterior (AHA), medial (MHA) and lateral (LHA) areas of hypothalamus during activation of the pituitary-adrenocortical system was measured in chronic experiments on rabbits. Immobilization causing blood-corticosteroid levels to rise was followed by the excitation of most pools of neurons in MHA, and by inhibition in AHA and LHA. When immobilization failed to induce stimulation of MHA (as a result of pretreatment with large doses of cortisol), it did not cause blood-corticosteroid levels to rise, either. The switching off activity in AHA and MHA is considered to be a manifestation of functional changes which are responsible for stress-induced activation of the adrenocortical system.


The genetic organization of neuron number in the granule cell layer of the area dentata in house mice. This report concerns variations in neuron number within the granule cell layer of the area dentata that occur among inbred strains of house mice. There is genetically associated variability in the total number of neurons present, with a very substantial range of estimated values. Systematic strain variations in the orientation of the granule cell layer are also present. When statistical corrections for variations in orientation are made, associations between the neuron numbers of subdivisions of the granule cell layer are consistent with the presence of common genetic determination of neuron number throughout the entire lamina.


Cupular movement and nerve impulse response in the isolated semicircular canal. The aim of the study was to record nerve impulse responses to controlled displacements of the cupula and relate these to observations of cupular motion. The preparation was the skate semicircular canal, isolated and maintained in a chamber. The canal was cut and tied tightly to an oil-filled tube driven by a 1 microliter syringe. In some experiments dye was used to make the face of the cupula visible. Small volume displacements (0.02 microliter) caused a billowing of the central portion of the cupula, whereas for repeated large displacements (0.1 microliter) the top of the cupula moved along the roof of the ampulla. Displacements of the latter amount were close to saturation in the characteristic functions (spike rate versus volume displacement) of nerve firing. It seems that the discharge rate of tonically responding units in the skate crista ampullaris rather faithfully record the force acting on the cupula. The motion of the base of the cupula rather than its tip appears to be the relevant parameter in setting the level of excitation in the sensory cells within the physiological range of stimulation. Such a mode of operation would ensure the highest sensitivity of the sense organ.


Output organization of the feline entopeduncular and subthalamic nuclei. Entopeduncular nucleus (EPN) cells which project to thalamic and non-thalamic sites were identified by antidromic discharge. Each population of cells, projecting to the ventral anterior nucleus of the thalamus (VA), centrum medianum (CM), the lateral habenula (LHB), and the pedunculopontine nucleus (PP), was distributed throughout the nucleus. While some cells projected to more than one region, particularly VA and CM, collaterals were not found in most cells. STN stimulation suppressed firing of some EPN cells for 80-120 msec in both barbiturate anesthetized and cerveau isolé cats. Suppression of activity was detected in most EPN cells projecting to LHB (73%); of all cells in which suppression of activity was detected, 84% projected to LHB and 15% to VA.


Mechanism of the dipsogenic action of tetradecapeptide renin substrate. The mechanism of the dipsogenic action of synthetic tetradecapeptide renin substrate (TDP) was studied in rats with chronically implanted lateral ventricular cannulae. All hormones and drugs were injected via the ventricular cannulae. The dipsogenic action of TDP was unaffected by the renin inhibitor pepstatin but was markedly reduced by the angiotensin converting enzyme inhibitor SQ 20881. Homogenates of rat brain readily formed angiotensin II from TDP in vitro and this was likewise unaffected by pepstatin but was reduced or abolished by SQ 20881 or by chelating agents. Natural renin substrate did not cause drinking and did not generate angiotensin II when incubated with brain homogenates. These results demonstrate that rat brain converting enzyme can generate angiotensin II from TDP and that this effect is responsible for the dipsogenic action of TDP.


Changes in the distribution of non-neuronal elements in rat median eminence and in anterior pituitary hormone secretion after activation of tuberoinfundibular dopamine neurones by brain stimulation or nicotine. In order to investigate the posssibility of acute functional changes in non-neuronal elements (mainly tanycytes) of the median eminence, the proportion of portal capillary surface covered by such elements was measured by quantitative electron microscopy in ovariectomized, oestrogen-progesterone-pretreated rats. In some of these animals, the functional state of the tuberoinfundibular dopamine (DA) neurones was assessed by histochemical microfluorimetry. Serum concentrations of luteinizing hormone (LH), growth hormone (GH) and prolactin were determined by radioimmunoassay. Two different types of treatment, i.e. systemic administration of nicotine (1 mg/kg, s.c.) or electrical stimulation in the medial amygdaloid nucleus, markedly reduced the percentage of capillary surface covered by non-neuronal profiles within 20 and 15 min, respectively. At the same time, the tuberoinfundibular DA system responded by an increase in cellular fluorescence intensity, reflecting neuronal activation. Medial preoptic stimulation had basically the same effect but with more variability in the change in capillary coverage by tanycytes. The action of nicotine was prevented by pretreatment with the DA receptor blocking agent, pimozide (5 mg/kg), which indicates (1) that a dopaminergic mechanism was involved in the nicotine effect and (2) that the tanycyte response was elicited by DA released from nerve terminals acting at some receptor site. Nicotine also lowered serum levels of GH and prolactin. Pimozide antagonized only the effect on prolactin. While the reaction of DA neurones and capillary coverage by tanycytes were correlated with each other in individual rats, no statistically significant correlation was observed between tanycyte response and hormone levels, so that no conclusions can as yet be drawn as to the neuroendocrine significance of the tanycyte reaction. These results indicate that rapid changes in the proportion or portal capillary surface covered by non-neuronal profiles can be elicited by stimulation of extrahypothalamic brain areas or by activation of cholinergic mechanisms. The tanycyte response appears to be mediated at least in part by the tuberoinfundibular DA neurones.


Hypoxic ventilatory responses during thiopentone sedation and anaesthesia in man. We have assessed the impact of thiopentone on the hypoxic ventilatory reflex, and on the responses to carbon dioxide and doxapram. Thiopentone sedation did not detectably alter any of these aspects of ventilatory control. Thiopentone anaesthesia reduced ventilation and the ventilatory responses to hypoxia, carbon dioxide and doxapram, all approximately in paralle. We conclude that, in contrast to halothane, thiopentone does not selectively reduce the ventilatory response to hypoxia. During light thiopentone anaesthesia, a reasonably brisk hypoxic response is present.


Perfusion of malignant hyperthermia susceptible and normal isolated pig livers with halothane. We have perfused malignant hyperthermia susceptible and normal isolated pig livers with halothane for one hour. The liver temperatures, oxygen and carbon dioxide tensions, the base deficits and lactate concentrations in blood entering and leaving the liver have been measured at the beginning and at the end of the perfusion. Statistical analysis has shown that there are no significant differences in these parameters between the beginning and the end of the perfusion period or between the normal and the malignant hyperthermia susceptible livers. We conclude, therefore, that the livers of malignant hyperthermia susceptible pigs are either normal or else, if abnormal, the abnormalities are sufficiently benign as to be not measurably expressed.


Blood pressure and pulse rate responses to extubation with and without prior topical tracheal anaesthesia. The results of this study demonstrate that 60 mg of lidocaine sprayed down the tracheal tube before extubation and 40 mg sprayed down the tracheal tube before extubation and 40 mg sprayed down during tracheal tube removal prevents increases in blood pressure and pulse rate during and after extubation. The data suggest that this manoeuvre should be of advantage to patients with coronary artery disease who may not be able to tolerate the increased cardiac dynamics which usually accompany extubation.


Monitoring of occupational exposure to nitrous oxide. The occupational exposure of operating room personnel to nitrous oxide was investigated by using multiple spot sampling, integrated personal sampling and end-tidal sampling in an operating room which had no ventilation system. The effect of passive scavenging on occupational exposure was determined. The study showed that all three methods to determine occupational exposure can yield representative time-weighted exposure patterns. However, the integrated personal sampling was considered the preferable method as it involved considerable saving of time and labour compared with taking and analyzing multiple end-tidal and spot samples. Passive scavenging of waste anaesthetic gases led to a three-fold to six-fold reduction of exposure of operating room personnel to nitrous oxide.


Peripheral nerve stimulator performance: the influence of output polarity and electrode placement. The median as well as the ulnar nerve may be used effectively in the evaluation of neuromuscular blockade with the peripheral nerve stimulator. Both ulnar and median nerve stimulation produce flexion of the fingers. For maximum neural stimulation either during the routine use of the peripheral nerve stimulator or when it is used as an aid to peripheral nerve block, the negative pole should be attached to the exploring needle or over the nerve to be stimulated.


A brain function monitor for use during anaesthesia. Preliminary report. This simple on-line monitor provides simultaneous noninvasive quantification of continuous processes within the brain, by measuring the augmented delta quotient (ADQ; the proportion of low frequency components in the electroencephalogram). The response of the ADQ, both during experiments in animals and in children undergoing surgery, during cardiopulmonary bypass with and without hypothermia, demonstrates that this concept may prove valuable both to monitor anaesthetic depth and to warn of impending cerebral impairment.


Hiccup and ephedrine.

Hiccup and ephedrine. Twelve patients who developed hiccup during anaesthesia and surgery were treated successfully with an intravenous injection of ephedrine 5 mg (eleven cases) or 10 mg (one case). In nine patients ephedrine was successful after traditional methods had been tried and failed, and in three patients ephedrine was the only agent given. We conclude that ephedrine is a safe and easy mode of treatment for intractable hiccup during anaesthesia and surgery.


Transient unilateral blindness following general anaesthesia: case report. A case is reported of transient unilateral blindness following general anaesthesia with a face mask. The most likely explanation for this is central retinal artery occlusion, either partial or complete, due to excessive pressure from the mask exerted on the globe. This pressure may be increased with the use of neoprene head straps as opposed to the more flexible and elastic rubber straps. Pressure from the strap over the carotid artery may be a factor in reducing the central retinal arterial pressure, thus making it more susceptible to occlusion by mask pressure.


Isozymes and allozymes: alternate forms of protein adaptation? The hypothesis is put forward that constant or predictable environments will select for multiple locus enzymes (isozymic variation) while variable or nonpredictable environments will select for multiple alleles at single loci (allozymic variation). If this hypothesis is valid, isozymes and allozymes should represent alternative forms of enzyme adaptation and the levels of the two types of variation should be negatively correlated. This prediction was tested from data reported in the literature for five groups of organisms: mammals, other vertebrates, insects, other invertebrates and plants. Single substrate enzymes showed the predicted negative relationship between allozymic and isozymic variation. Multiple substrate enzymes did not show a significant relationship. Isozymic variation was greater for insects, other invertebrates and plants, in multiple substrate enzymes compared to single substrate enzymes. For mammals and vertebrates, allozymic variation for multiple substrate enzymes was approximately double that of single substrate enzymes, while isozymic variation remained constant.


Effect of fungicide Folpet on growth and chromosomes of human lymphoid cell lines. One normal human lymphoid cell line was treated continuously with the fungicide Folpet (N-trichloromethylthio-phthalimide) at 0.5, 1, 2, and 4 microgram/ml of media and one Burkitt cell line was pulse-treated with the same compound for 15 min at 2.5, 5, 10, and 15 microgram/ml. Various times after treatment, cell viability counts and chromosomes analyses were made. Severe cell growth inhibition and an increase in chromosome aberrations were observed in both cell lines. There were two types of induced chromosome aberrations. Aberrations type A appeared in cultures treated with lower doses and were characterized by chromosome or chromatid gaps and breaks and also infrequently seen exchanges and dicentrics. In the later stages of the experiment, the rate of growth and aberrations returned to control levels. Chromosome aberrations type B appeared in early samples of cultures treated with higher doses. The whole complement of chromosomes was affected. The aberrations included chromosome stickiness, despiralization and pulverization. The cultures died off within two days.


Cell cycle and DNA synthesis in the mosquito Aedes aegypti. Chronology of the cell cycle has been determined for brain cells in Aedes aegypti (L.) larvae by autoradiography. The time of the cell cycle is approximately 10 h and 30 min. Areas of late DNA synthesis in metaphase chromosomes were localized mainly on the female determining (= m) chromosome of the sex pair. Correlations between late replication patterns and C-banding are discussed.


Lactate dehydrogenase in rabbit oocytes and eggs. It has recently been reported that the rabbit oocyte lactate dehydrogenase (LDH) isozyme pattern shifts dramatically at ovulation. We have determined that both ovarian oocytes and ovulated eggs have predominantly LDH-5 with minor amounts of LDH-4. Therefore, no change occurs at ovulation. When oocytes or eggs are not treated to remove follicle cells, all five LDH isozymes are observed. Isolated follicle cells also have five isozymes. We suggest that failure to remove follicle cells can cause altered LDH isozyme patterns and may account for conflicting results in the literature.


Pitfalls in ophthalmic genetic counselling. In Canada, half the young blind have inherited eye disease. Ophthalmic genetic counselling is a relatively new branch of preventive medicine. By informing affected families of the risk of inheriting an eye disease one hopes to reduce the frequency of such diseases. Clinical experience in ophthalmic genetics discloses many potential pitfalls. Failure to avoid them may have tragic consequences for the family advised.


Family studies of ocular manifestations in arthritis. To determine the hereditary and clinical patterns, nine patients from three families with different systemic and ocular rheumatoid diseases were examined ophthalmologically and medically. Three types of HLA-B27 associated anterior uveitis were seen. While HLA-B27 linked genes predispose the carrier to acute anterior uveitis (AAU) frequently recurring or chronic anterior uveitis may develop if an immune-complex disease such as Rheumatoid arthritis coexists. Hereditary factors may dispose patients to rheumatoid episcleritis, scleritis and keratitis.


Talc retinopathy.

Talc retinopathy. We observed talc particles in the retinal vessels of nine out of 17 addicts to intravenous methadone. The retinopathy was found in patients who had injected more than 9,000 tablets. In seven the chest roentgenograms showed a diffuse micronodular pattern which progresses to resemble massive pulmonary fibrosis and is associated with severe disability. The ophthalmologist must recognize this entity since he may be the first to identify drug abusers who inject oral medications containing talc. Early detection and counselling may prevent the severe pulmonary complications.


Retinal detachment in renal insufficiency a report of 3 cases. Three cases of retinal detachment associated with renal insufficiency are presented. The authors feel that dilutional hyponatremia and hypervolemia were not significant in the genesis of the detachments and that control of the blood pressure was the key factor in their cure. The importance of hypertensive retinochoroidopathy in the pathogenesis of the detachment is emphasized.


Ocular findings in homozygous sickle cell disease in Nigeria. We report the ocular findings in 124 Nigerians with homozygous sickle cell disease. None had ocular symptoms. In order of frequency conjunctival vessel anomalies, tortuosity of the major retinal vessels and chorioretinal scars were found. The resemblance of sickle cell chorioretinal scars to toxoplasmic choroiditis is remarkable and should lead to the exclusion of sickle cell disease whenever such lesions are encountered. Angioid streaks, retinitis proliferans, retinal detachment and arteriovenous fans were not observed.


Globular bodies: a primary cause of the opacity in senile and diabetic posterior cortical subcapsular cataracts? We examined 9 cataracts from maturity onset diabetics and 4 senile posterior subcapsular cataracts by scanning electron microscopy, transmission electron microscopy, immunofluorescence for crystallin proteins and actin, histochemical methods and x-ray diffraction. The cataractous regions contained spherical globules up to 20 mu in diameter, often in a fibrous matrix. Some were extracellular Morgagnian globules, apparently formed by blebbing from the cell surface; others appeared to have been formed intracellularly. The area of globular degeneration was usually 300 mu deep, but had deeper fusiform extensions. Morphological changes in the cell cytoplasm varied according to their depth in the cataract. Electron microscopy showed intracellular and extracellular globules, many of them were bounded by lipid bilayer membranes. Immunofluorescent staining showed that all the globules contained gamma-crystallin; some contained alpha- and beta-crystallins and actin. All the globules contained higher concentrations of cysteine or cystine than the surrounding lens tissue but they did not react to stains for carbohydrate or calcium. X-ray diffraction studies showed that crystalline calcium salts were absent. Globules and cavities averaged 45% of the total area in cross section. Assuming an area of cataract to be 300 micron thick and that globules 1 mu in diameter scattered, while 2--20 mu in diameter reflected light, we calculated that light passing through such a thickness would be reduced by 65%. Thus the globules could account for most of the opacity of the cataractous area. Presumably the fibrous degeneration of the cells causes enough light scattering to account for the remainder of the reduction. Cataract patients complain of decreased visual acuity, a golden halo around objects, and difficulties when driving while facing oncoming traffic at night. These probably result from light scattering. In our previous experiments, globular bodies containing gamma-crystallin were found in cells grown in tissue culture, and blebs with increased acitn content similar to Morgagnian globules were formed in tissue culture by treating differentiated rat lens cells of stage 2 by cytochalasin D (which impaired microfilament function). These results suggest the possibility of simulating in tissue culture the morphological alterations seen in the cataractous cell.


Specificity of tumor-associated antibodies in sera of patients with uveal melanoma. We have identified antibodies against cytoplasmic components of allogeneic uveal melanoma cells in the sera of 16 of 31 patients with proven intraocular melanoma. Similar antibodies were found in 27% of controls and in 24% of patients with uveal nevi. The antibodies in these 3 groups of subjects were absorbed by components of uveal and cutaneous melanoma cells but not by those of normal choroidal melanocytes, normal uvea and retinal pigment epithelium, dermal nevus, pigmented skin or fetal cells. We found that specificity of the antibodies was also demonstrated by absence of reactivity with normal choroidal melanocytes, loss of reactivity after immune blocking, and absence of reactivity of melanoma antigen with conjugated antihuman immunoglobulin alone. Attempted absorption of the conjugated antihuman immunoglobulin by components of uveal melanoma cells did not alter the reactivity of the conjugated antihuman immunoglobulin.


Computed axial tomography localization of intra-orbital foreign body. Conventional radiographs in a patient with an intra-orbital foreign body showed that it was close to the back of the globe. Computed axial tomography showed that it lay beside a swollen and probably lacerated optic nerve. The advantages of CT scanning in the investigation of intra-orbital foreign bodies are outlined.


Strokes and head injury.

Strokes and head injury. This is a report of a series of patients who suffered major cerebral hemorrhage or infarction complicating industrial head injuries. The variable importance of trauma and of pre-existing vascular disease is exemplified. Accuracy of assessment of such complex problems is facilitated by modern applied neuroscientific techniques.


Regional cerebral blood flow in patients with aneurysms: estimation by Xenon 133 inhalation. Seventy six regional cerebral blood flow (rCBF) studies were conducted on 32 patients who had a total of 39 aneurysms. Twenty three of these patients were studied pre- and post-operatively. Normal values were obtained from a control group of 33 subjects, each of whom underwent one rCBF study. Flow was reduced following subarachnoid hemorrhage (SAH); it increased significantly post-operatively. Lower flows were associated with poorer clinical grades. There was a greater variation in regional distribution of flow immediately following SAH than in normals or in patients who had recovered from the acute phase. rCBF studies correlated with CT scans demonstrated that a progressive increase in ventricular size was accompanied by a progressive reduction in flow. In addition, intraventricular hemorrhage (IVH) was associated with a significant reduction in cerebral blood flow (CBF). No significant correlation between CBF and spasm was demonstrable.


Serial radionuclide scans in multiple sclerosis. A 28 year old woman with multiple sclerosis has been followed for 10 months with serial brain scans on 5 admissions. The correlation between the clinical picture and the brain scans was clearly demonstrated.


The significance of mediastinal involvement in early stage Hodgkin's disease. Between April 1969, and December 1974, 111 consecutive surgically staged I A and II A patients with supradiaphragmatic Hodgkin's disease were treated at the Joint Center for Radiation Therapy. Patients received 3600--4400 rad to mantle and para-aortic--splenic pedicle regions. Median follow-up was 56 months (30--96). Fourteen patients developed relapsing Hodgkin's disease and three patients died of possible treatment-related causes, two with acute myocardial infarctions and one with radiation pneumonitis. Patients with mediastinal enlargement greater than one third of the chest diameter have a significantly higher risk (p less than 0.01) of developing relapse (9 of 18) than patients with lesser or no mediastinal disease (5 of 93). Of the 18 patients with large mediastinal disease, six relapsed in the mediastinum and two in the lung. There continue to be no pelvic extensions in the entire group. There is a 92% relapse-free and 97% overall survival in the 93 patients without extensive mediastinal disease. We continue to recommend mantle and para-aortic--splenic pedicle irradiation for these patients. In view of the large number of relapses in patients with extensive mediastinal disease, we are now treating this subgroup of patients with MOPP chemotherapy in addition to mantle and para-aortic irradiation.


Treatment of rectal carcinomas by means of endocavity irradiation. Direct contact irradiation may be used in the curative treatment of patients with carefully selected early rectal lesions. With earlier diagnosis, a large number of patients may present with suitable lesions. The treatments last three minutes and are administered every two weeks to a total dose of 9,000 rad to 12,500 rad. The patients require no general anesthesia or hospitalization and may continue working during this treatment. There appears to be no risk of morbidity or mortality. The rectum is preserved. Most beneficial of all to the patient, a colostomy is avoided, although later surgery is not precluded for local failures. It has been found that recurrence, should it occur, appears within the 18 months immediately following treatment. Good palliation can be achieved in some cases for patients with metastatic disease, for their local symptoms. We believe that the endocavity method of irradiation contributes an important advance in the management of patients with cancer of the rectum and feel it should be available universally.


Carcinoma of the vocal cord: results of treatment and time-dose relationships. A retrospective analysis has been done of 173 patients with epidermoid carcinoma of the vocal cord treated with radiation therapy at Rush-Presbyterian-St. Luke's Medical Center between January 1970 and December )974. one hundred fifty-eight patients (91.3%) were early (T1, T2) glottic lesion and 10 were advanced (T3, T4) lesion. Five (2.9%) were presented with positive cervical lymph nodes initially. Of 158 patients who had T1, T2N0M0 glottic tumor, 146 had definitive radiation therapy and 12 had preoperative radiation therapy. An analysis of frequency of local recurrence versus total dose (NSD) has been done for 146 patients and a dose response curve has been generated. Local failure rates were 22.2% for 1,800 +/- 50 rets, 11.1% for 1,900 +/- 50 rets, and 3.2% for 2,000 +/- 50 rets. For the early glottic cancer, local control rates were increased with increasing total dose without significant complications. In patients with advanced primary tumors, a greater number of the patients were treated with preoperative radiation therapy and this group had slightly better results.


Cutaneous Hodgkin's disease: indolent course and control with chemotherapy. A case of nodulat sclerosing Hodgkin's disease in an elderly woman is presented. Following radiotherapy, widespread lymphomatous skin lesions developed anatomically unrelated to her nodal disease. These lesions have been controlled, but not eliminated by chemotherapy. Cutaneous manifestations of Hodgkin's disease are discussed including the possible pathologic mechanism in the present case. Skin involvement by Hodgkin's disease may follow a relatively benign course, provided disease elsewhere is treated appropriately.


Adriamycin, 1,3-bis (2-chloroethyl) 1 nitrosourea (BCNU, NSC No. 409962), cyclophosphamide plus prednisone (ABC-P) in melphalanresistant multiple myeloma. Fourteen patients with multiple myeloma resistant to melphalan plus prednisone were treated with BCNU 50 mg/m2 plus cyclophosphamide 200 mg/m2 on day 1, adriamycin 20 mg/m2 on day 2 and prednisone 60 mg orally, daily for days 1 through 5. Therapy was repeated every four weeks. Depending upon criteria used, objective antitumor responses were achieved in five to nine of the 14 patients. Mean survival was 9.5 months and actuarial median survival was 7.0 months. Six patients are alive, four to 35 months after initiation of therapy. This preliminary report indicates that this combination may be a useful treatment program in the management of patients with advanced multiple myeloma. A review of studies employing adriamycin plus BCNU suggests that these regimens currently offer the most effective treatment of melphalan-resistant patients.


Sequential studies of development of gastric carcinoma in dogs induced by N-methyl-N-nitro-N-nitrosoguanidine. Fifteen male Beagle dogs received N-methyl-N-nitro-N-nitrosoguanidine (MNNG), 50 or 83 microgram/ml, in drinking water for 35 to 63 weeks. Broad superficial erosion and ulceration were observed in the angulus of the antrum and the anterior or posterior wall of the fundus during MNNG administration. After the discontinuation of MNNG administration, the erosions and ulcers healed rapidly, resulting in mucosal atrophy and scarring of the ulcer. In two dogs new depressions with atypical glands were observed by endoscopy and biopsy of the ulcer scars of the angulus, which became carcinomatous lesions at about the 100th week. Necropsy revealed 5 other carcinomas in the fundus of 5 additional dogs. One lesion was located in the ulcer scar and the other 4 in the areas of the mucosal atrophy. The possible relationship between carcinoma and the associated lesions was discussed.


Ultrastructure of fallopian tube carcinoma. Fallopian tube carcinoma is one of the rarest of primary gynecologic malignancies. Normal tubal epithelium is composed of secretory, ciliated, and intercalary cells. To determine the cellular composition and ultrastructural details of this rare neoplasm, a moderately well-differentiated tubal carcinoma was studied with the electron microscope. A prominent feature was the formation of numerous ultramicro alveolar spaces lined by cell surface microvilli. The nuclei of the neoplastic cells demonstrated a variety of fine structural abnormalities. Based on cell size and shape criteria, a possible dual tumor cell population was suggested. However, no cilia were seen in any of the tumor cells and almost all were devoid of secretory granules. These latter observations suggest that this tumor was primarily a proliferation of intercalary cells.


Carcinoembryonic antigen in patients with breast cancer: an adjunctive tool to monitor response and therapy. Plasma carcinoembryonic antigen (CEA) levels were performed by radioimmunoassay in 234 patients with histologically proved breast cancer: 181 with advanced metastatic disease and 53 without distant metastases but nodal involvement at time of mastectomy. Four hundred and thirty-four assays were done and correlated with the clinical status of the patients. Values above 2.5 ng/ml were taken as abnormal. Active disease was associated with elevated plasma CEA levels. Very high values were not recorded in 109 patients when they were considered to be in complete remission, while only 22 patients out of 63 patients with progressive disease had normal values. In 16 of these values remained normal despite progression of disease. In 6 patients clinical relapse preceded CEA elevation by 2--5 months. Tumor burden and abnormal serial CEA values showed positive correlation in 38 patients. In 30 patients, change in clinical status and CEA values occurred simultaneously. In only 2 patients an increase in CEA value occurred 2--3 months before clinical documentation of relapse.


Benign and low grade variants of mixed mesodermal tumor (adenosarcoma) of the ovary and adnexal region. Eleven examples of a rare group of neoplasms composed of both epithelial and mesenchymal components are reported. Ten arose from the ovary and one arose separately in the para-ovarian region. The neoplasms are distinctive in that the stoma is more cellular than that of adenofibromas, but epithelial component is not malignant, as in carcinosarcoma and mixed mesodermal tumors, and the stoma is not sarcomatous in the low grade varieties. The 11 cases were highly variable in the cellularity and atypism of the stromal cells. The term, adenosarcoma, for these tumors is not acceptable because some were too low a grade to be regarded as sarcomas, and reports of the uterine counterpart disclose that some contain heterologous elements. For that reason, a term that will embrace the full spectrum of changes in the stroma--benign through sarcomatous--is needed. We propose that they be regarded as variants of mixed mesodermal tumor so that both the benign neoplasms and low grade sarcomas can be accommodated under one designation. Of the 11 cases, five lowest grade examples were all confined to the ovary and did not recur after surgical excision, but some of these were borderline in malignancy and probably would have progressed if untreated. Two of the 3 intermediate grade neoplasms extended beyond the ovary but were arrested by surgical excision. The 3 highest grade neoplasms were overly sarcomatous. One of these extended beyond the ovary but was arrested by combination chemotherapy. The para-ovarian adenosarcoma (also high grade) metastasized and proved fatal.


Clinical bladder cancer in sponge matrix tissue culture: procedures for collection, cultivation, and assessment of viability. We studied the growth of surgically resected human bladder cancer in three dimensional tissue culture, Observations were made in the living cultures and after the sponge matrix cultures were fixed and prepared as histologic sections. We compared the histologic appearance of each tumor immediately after removal and after a week in culture. In a few instances the donor tumor was kept in medium at room temperature for one day before being inoculated into the matrix. This delay had only slight deleterious effect on the growth in culture. Over 85 consecutive cases have been placed in culture and the first 47 have been evaluated in histologic preparations. Tumors grew into the matrix with distinctly different patterns even when the zero time specimens were of similar histopathology. We also studied several antibiotics to idenify conditions that would suppress the usual urinary bacterial contaminants without producing cytotoxicity to tumor cells by microscopic evaluation. A combination of gentamicin and kanamycin, each at a concentration of 50 microgram/ml was effective.


Mental disorders in cancer patients: a study of 100 psychiatric referrals. Records of 100 consecutive hospitalized cancer patients referred for psychiatric consultation were reviewed. These patients constituted only 5% of those seen by the Psychiatry Consultation Service during the study period. Fifty-six percent of the referred patients were diagnosed as depressed and 40% as having organic brain disease. Twenty-six of the 100 patients were misdiagnosed by the referring physician as depressed but were classified by the staff psychiatrist as suffering from organic brain syndrome. When referral was studied by primary site of cancer, only patients with breast cancer were referred at a significantly higher than expected rate (p less than .001). The importance of the mental status examination as a routine procedure in all cancer patients is stressed so that an organic brain syndrome will not be missed. Suggestions for patient management are given.


Dormancy and spontaneous recurrence of human breast cancer in vitro. Monolayer cultures of the human breast cancer cell line MDA-361 require insulin for growth and for maintenance of viability, as is evidenced by rapid and complete degeneration of the cells after the removal of insulin from the medium. Detachment from the plastic surface occurs within 24 to 48 hr, and the rare (less than 0.1%) cell that remains attached doubles every 3 to 4 weeks. Multicellular tumor spheroids, derived from this same tumor cell line, enter a dormant phase which lasts approximately 6 weeks, when insulin is removed from the medium. During this dormant period the multicellular tumor spheroids appear healthy and gradually become less dependent on and more responsive to insulin. This dormant period culminates in spontaneous regrowth in the absence of insulin after the sixth week, and this growth continues at least through 3 months. In this respect these multicellular tumor spheroids parallel the behavior of residual tumors in vivo; the residual tumor remains viable but nongrowing for a prolonged period only to resume growth following escape from the growth-limiting mechanism.


In vitro analysis of the response of multicellular tumor spheroids exposed to chemotherapeutic agents in vitro or in vivo. Multicellular tumor spheroids (MTS) have been exposed to chemotherapeutic agents in vitro (nitrogen mustard) or in vivo (cyclophosphamide) and analyzed in vitro in terms of altered growth patterns. Whether the MTS were exposed in vitro or in vivo, the major effect of the drugs was to induce a dose-dependent lag period before the normal MTS growth rate resumed. Exposure of MTS in the peritoneal cavity to i.v. injection cyclophosphamide results in patterns similar to the in vitro exposure system, except that a host anti-MTS reaction was detected. In combination, these two methods allow the study of the responses of these complex tumor forms to chemotherapy.


Binding characteristics of zearalenone analogs to estrogen receptors. The estrogenic effect of zearalenone derivatives was investigated for their binding characteristics to cytosol and nuclear receptors in the uterus. Competition with 17beta-estradiol at the cytosol receptor sites was observed in four of the six derivatives tested, namely trans- and cis-zearalenone, zearalenol, and zearalanol. The other two, 8'-hydroxyzearalenone and 6'-aminozearalene, lacked the binding ability to receptors and were biologically inactive. trans-Zearalenone, like 17beta-estradiol, could elicit an immediate translocation of cytosol-receptor complexes into the uterine nuclei. However, it differs from either 17beta-estradiol or antiestrogens (tamoxifen) in three aspects: (a) a second wave of translocation occurred 6 to 12 hr following zearalenone injection; (b) there was a much longer nuclear retention (over 24 hr) than in the case of 17beta-estradiol; and (c) following a depletion of cytosol receptors, trans-zearalenone induced an overreplenishment by 24 hr, whereas tamoxifen is reported to suppress the replenishment.


Effect of adriamycin and analogs on the nuclear fluorescence of propidium iodide-stained cells. Adriamycin (ADR) and N-trifluoroacetyladriamycin-14-valerate, respectively, inhibit and enhance the nuclear fluorescence of cells stained with propidium iodide for DNA per cell estimation by flow cytometry. In cells incubated with ADR, the reduction in fluorescence is gradually manifested due to the slow intracellular drug transport. In contrast the effect of N-trifluoroacetyladriamycin-14-valerate on propidium iodide nuclear fluorescence is seen within 5 min of incubation. The effect of ADR on propidium iodide nuclear fluorescence could be detected in vivo even after 24 hr of ADR administration.


Increased tyrosine phenol-lyase activity in mice following pyridoxal phosphate administration. A limiting factor in the depletion of plasma tyrosine following tyrosine phenol-lyase injection into normal mice was found to be the availability of an essential cofactor, pyridoxal phosphate. Because of the extremely short half-life of this cofactor, adequate elevation of circulating cofactor levels for prolonged periods by injection of a pyridoxal phosphate solution was not practical. Similarly, long-term diets enriched with pyridoxine and pyridoxal phosphate did not significantly improve the efficiency of the injected holoenzyme. A repository dosage form was devised that consisted of an s.c. implant of pyridoxal phosphate suspended in a spermaceti and peanut oil mixture. Under these conditions a sustained increase in holoenzyme activity levels and a significant resulting decrease in plasma tyrosine levels were obtained.


Increased tumor immunity in mice inoculated with muconomycin A-treated B16 melanoma cells. B16 melanoma cells were treated in vitro with muconomycin A, a long-lasting inhibitor of protein and glycoprotein synthesis, to reduce cellular sialic acid. Two i.p. inoculations of 10(7) muconomycin-treated cells into female C57BL/6 mice, followed by challenge with homologous live cells, resulted in a significant decrease in tumor incidence when compared to the results of inoculation with untreated cells (p less than 0.01). Inoculation of mice with cells treated with neuraminidase resulted in little or no decrease in tumor incidence. Effective immunity was dependent on the number of cells injected and was found only with the i.p. route of inoculation into female mice.


Effect of estrogen on tumor-associated immunity in patients with adenocarcinoma of the prostate. Tumor-associated antigen-induced leukocyte adherence inhibition has been used as an in vitro criterion for evaluating the effect of estrogen on cell-mediated antitumor-associated immunity in patients with adenocarcinoma of the prostate. Significant (p less than 0.05) suppression from the reactivity obtained with untreated patients' leukocytes to allogeneic extracts of malignant prostatic tissue ranging from 19 to 80% was observed in all patients following preincubation of their leukocytes with diethylstilbesterol diphosphate. The observed suppression of tumor-associated immunity in the presence of exogenous estrogen provides further evidence to earlier studies that demonstrated estrogenic suppression of nonspecific cellular responsiveness as evaluated by phytohemagglutinin-induced lymphocytic blastogenesis of normal and prostatic cancer patients' lymphocytes and for the initially suggested concern over the efficacy of estrogenic therapy and its adverse effect on host cell-mediated immunological responsiveness.


Human lymphoblastoid cell lines as effector cells in mitogen-dependent and antibody-dependent cell-mediated lysis. Based on reports that both human and murine lymphoblastoid cell lines can effect lysis in antibody-dependent (ADCC) and mitogen-induced (MICC) cell-mediated cytotoxicity, 10 human lymphoblastoid cell lines were investigated for their ability to act as effector cells in these lytic reactions. Four cell lines promoted MICC and ADCC of chicken erythrocytes. MICC was inhibited by subjecting the effector cells to gamma-irradiation, and ADCC was partially inhibited by treating antibody-coated target cells with Protein A from Staphylococcus aureus. The latter finding suggests that antibody plays a role in the cytotoxic reaction. The lytic activity of cultured human lymphoid cells in both MICC and ADCC reactions was, however, quite variable for unknown reasons. Because of this instability human lymphoblastoid cell lines are not a suitable source of effector cells for studying the biological and molecular properties of structures responsible for the lytic reaction.


Induction of neoplasms in hamster tracheal grafts with 3-methylcholanthrene-coated Lycra fibers. Synthetic Lycra spandex fibers were coated with 3-methylcholanthrene (3MC) and inserted into the lumina of 104 tracheas removed from young adult inbred Syrian hamsters. Tumors appeared 3 to 21 months after implantation of these tracheal grafts in syngeneic animals. 3MC in amounts ranging from 9 to 75 microgram/fiber induced a diversity of neoplasms in tracheal epithelium, the majority of which were classified histologically as carcinomas. Tumors failed to develop when smaller amounts of 3MC were used and in control tracheal grafts containing fibers without carcinogen. The use of tracer quantities of [14C]-3MC allowed quantitation of the carcinogen dosage to the mucosa before and at intervals after grafting. These studies demonstrate the dosage-dependent sensitivity of the hamster tracheal epithelium to relatively small quantities of 3MC. The direct application of carcinogens coated on synthetic fibers provides a useful tool for assaying water-insoluble carcinogens.


Long-term organ culture of human uterine endocervix. Explants of human endocervix have been maintained in organ culture for 24 weeks. The epithelium was viable for the entire duration of culture, as demonstrated by ultrastructural morphology and mitotic activity. The epithelium of the explants retained a near normal morphology for 2 to 4 weeks. The only changes observed were decreased mucus secretion in columnar cells, focal epidermoid metaplasia, and an increase in autophagic vacuoles. Subsequently, a slowly progressive transformation of the columnar epithelium into a metaplastic epithelium was observed, with loss of mucus-secreting columnar cells and ciliated cells and the appearance of cuboidal and flattened epidermoid cells, forming often two to three layers. Metaplasia began at the top of the papillae and ridges and extended progressively downwards into the clefts. Nevertheless, in a few areas deep in the clefts, columnar cells retained evidence of mucus secretion during the entire duration of culture. Epidermoid metaplasia appeared to develop in the explants by transformation of columnar mucous cells into cuboidal and flattened cells with epidermoid characteristics. This hypothesis is supported by ultrastructural observations that showed mucus secretion and early keratinization in the metaplastic cells. Mitotic figures were observed with transmission electron microscopy for up to 24 weeks, and all dividing cells contained mucous granules.


Direct study of alkylating agent--RNA interaction by 13C nuclear magnetic resonance spectroscopy. The interactions of Torula yeast RNA with four biologically important methylating agents (methyl methanesulfonate, dimethyl sulfate, 1-methyl-1-nitrosourea, and 1-methyl-3-nitro-1-nitrosoguanidine) have been studied by 13C nuclear magnetic resonance spectroscopy. This direct stable isotope method eliminated all tedious and questionable degradation processes for determining the reactive sites and product distribution. Based on the integration curves, two types of product distribution can be distinctly observed according to the biological potency of the methylating agents [(a) weakly mutagenic and carcinogenic, methyl methanesulfonate and dimethyl sulfate and (b) strongly mutagenic and carcinogenic, 1-methyl-1-nitrosourea and 1-methyl-3-nitro-1-nitrosoguanidine]. With 90% 13C-enriched methylating agent, it significantly increases the specificity and sensitivity and provides better quantitative results.


Antiproliferative agents and differential survival between normal and cancer cells. A basic difference in response between normal cells (primate fibroblasts) and colonic cancer cells (human and rodent) to the antiproliferative action of both N-(phosphonacetyl)-L-aspartate and thymidine is described in this report. Both normal and colonic cancer cells, when cultured in the presence of these agents, cease to increase their cell numbers. Evidence is presented to show that the normal cells respond to deprivation of pyrimidine nucleotide induced by these agents by simple growth arrest, in which a quiescent state may be maintained for prolonged periods without cell death. Cancer cells are shown to respond in a characteristically different manner in which cell division continues accompanied by limited cell survival, with the surviving population representing a balance of these opposing processes. The extent to which these in vitro findings, based on a limited number of comparisons under restrictive artificial conditions, relate to the in vivo state remains to be established.


Heterogeneity in drug sensitivity among tumor cell subpopulations of a single mammary tumor. Three distinct subpopulations of tumor cells derived from a single parent strain BALB/cfC3H mammary adenocarcinoma were tested in vivo for sensitivity to cyclophosphamide, methotrexate, and 5-fluorouracil. Treatment was begun either 2 days after s.c. tumor cell injection or at the time when the tumors became palpable. It was given on a weekly basis for 4 weeks. The mice were observed for growth of the primary implant and for development of spontaneous metastases. The three subpopulations differed markedly in their sensitivity to the drugs. The effects of the drugs ranged from induction of regression of the "primary" to enhancement of metastases. The effect on primary growth was independent of that on metastasis. The effect of the time of administration of the drugs also varied among the subpopulations. The sublines were also tested in vitro with methotrexate and 5-fluorouracil. Again there were marked differences in sensitivity to inhibition of cell division by the drugs. The relative sensitivities in vitro did not correlate with observations in vivo. The existence of subpopulations of tumor cells, differing in sensitivity to therapeutic agents, within a single neoplasm, presents a challenge to development of assays capable of predicting drug response and to the selection of combination therapies.


Induction of alkaline phosphatase activity in HeLa cells by choline chloride. Choline chloride produced a dose-dependent induction of alkaline phosphatase activity in HeLa cells. At the highest concentration tested, 40 mM, there was a 5- to 7-fold increase in alkaline phosphatase activity, a significantly greater induction than that produced by equiosmolar additions of either NaCl or sucrose. Enzyme activity was higher than control values by 24 hr after the addition of the salt, although the largest increases in activity occurred between 36 and 72 hr. The induction of alkaline phosphatase activity by choline chloride could be inhibited in a dose-dependent manner by the simultaneous addition of either caffeine or theophylline. At comparable concentrations of inhibitor, the magnitude of the inhibition of the induction produced by choline chloride was greater than that observed when the xanthines were used to inhibit the induction by either 5-iodo-2'-deoxyuridine or NaCl. Choline chloride, like NaCl, produced a proportionately greater increase in the heat-stable rather than the heat-labile form of alkaline phosphatase activity.


Erythropoietin responsiveness in vivo of Friend virus target cells for transformation and virus replication. Techniques that allow the selective stimulation of the erythropoietin-responsive cell population in mice with suppressed multipotential hemopoietic stem cells were used to identify (1) the in vivo target cell transformed by Friend virus (FV) into a tumor colony-forming unit and (2) a target cell for FV replication in vivo. Plethoric mice with busulphan-induced reductions in stem cell populations (characterized as colony-forming units) and stimulated erythropoietin-responsive cell compartments were given FV; control groups, not receiving erythropoietin, also received FV. A comparison of the number of target cells transformed in each group provided evidence identifying the ERC as the in vivo compartment in which the target cell detected by tumor colony formation resides. Differences in plasma virus titers revealed that the erythropoietin-responsive cell is also predominantly responsible for the production of FV as measured by focus-forming activity.


High pressure liquid chromatographic assay for alpha hydroxylation of N-nitrosopyrrolidine by isolated rat liver microsomes. A high-pressure liquid chromatographic assay for alpha hydroxylation of N-nitrosopyrrolidine by isolated hepatic microsomes was developed. Mixtures consisting of N-nitrosopyrrolidine, microsomes, and an NADPH-generating system were incubated at 37 degrees. The major product of alpha hydroxylation of N-nitrosopyrrolidine, 2-hydroxytetrahydrofuran, was trapped by the addition of 2,4-dinitrophenylhydrazine reagent to form 4-hydroxybutyraldehyde-2,4-dinitrophenylhydrazone. The latter was quantified by reverse-phase high-pressure liquid chromatography. Under optimal conditions, as determined by varying protein and substrate concentrations, the alpha hydroxylation of N-nitrosopyrrolidine was linear for at least 90 min and showed characteristics typical of the microsomal mixed-function oxidase system, such as inhibition by CO and induction by pretreatment of male F-344 rats with Aroclor. N-Nitrosopyrrolidine exhibited type II spectral changes upon interaction with isolated hepatic microsomes. A close correspondence between binding affinity and alpha hydroxylation of N-nitrosopyrrolidine was observed.


Effect of tumor promoters on the response of cultured embryonic chick ganglia to nerve growth factor. The tumor-promoting plant diterpene 12-O-tetradecanoyl-phorbol-13-acetate (TPA) inhibits nerve growth factor (NGF)-provoked neurite outgrowth in cultured embryonic chick sensory and sympathetic ganglia. Other plant diterpenes that are tumor promoters on the mouse skin carcinogenesis system also inhibit ganglia response to NGF, but structurally related nonpromoting compounds are inactive. There is no evidence that the inhibitory effect of TPA is due to cytotoxicity. In fact, it appears that TPA can enhance the survival of neuronal and nonneuronal cells in culture. Although neurite outgrowth is prevented, established neurites do not retract in the presence of TPA. After 24 hr, ganglia can slowly overcome the block, even in the presence of fresh TPA; thus, inhibition is transient. The concentration of NGF that does induce a half-maximal neurite outgrowth response in sensory ganglia is approximately 0.6 X 10(-11) M. The antagonism of NGF by TPA is dose dependent and apparently noncompetitive. TPA concentrations that extensively inhibit neurite outgrowth do not affect the amount of 125I-labeled NGF bound to specific sites on dissociated dorsal root ganglion cells, which supports the contention that TPA acts at a stage beyond the initial interaction of the factor with its receptive site.


Olfactory neuroepithelioma in a domestic carp (Cyprinus carpio). A well-differentiated olfactory neuroepithelioma was found protruding from the left olfactory fossa of a 6-year-old domestic multicolored carp, Cyprinus carpio. Following diagnostic biopsy the neoplasm continued to grow. At necropsy, the tumor was found to extend beyond the olfactory chamber into the intracranial portion of the olfactory bulb, but no distant metastases could be detected. Histologically, the neoplasm had a remarkably organoid appearance, being composed of imperfect reproductions of the normal olfactory organ including olfactory membrane, axonal bundles, and glial tissue. Electron microscopy demonstrated the presence of numerous ciliated olfactory sensory cells as well as sustentacular, mucous, and basal cells within the neoplastic simulations of olfactory membrane. These observations, together with those from two previous case reports of olfactory neuroepitheliomas in teleosts, suggest that this type of tumor tends to be more highly differentiated than are neoplasms of similar origin in mammals.


Differential effects of lectins on the in vitro growth of normal mouse lung cells and low- and high-cancer-derived cell lines. The comparative aspects of cell growth, i.e., [3H]thymidine and [14C]leucine uptake of low-cancer (P4Bis) and high-cancer (P4BisT) cell lines and of their normal counterparts, have been studied in the presence and absence of concanavalin and Robinia lectins. These lectins have similar effects on cell growth, on thymidine and leucine uptake, and on incorporation of these precursors. The growth of normal cells is stimulated by both lectins, whereas the growth of transformed cells is inhibited. In all cases the uptake of both leucine and thymidine by cells is increased by the lectins, but the percentage of incorporation of the precursors is affected in a different manner. The percentage of thymidine incorporated by normal and transformed cells increases or decreases in direct proportion to cell growth; leucine incorporation is not affected significantly. The reversibility of these lectin effects by specific inhibitors shows that cell membranes are implicated in these phenomena. Our study with normal and transformed cells suggests that cell surface may play a role in the process of malignant transformation and that P4Bis cells are "transitory" between PB1 normal cells and P4BisT high-cancer cells.


Menstrual cycle patterns and breast cancer risk factors. Using a data set of women who longitudinally recorded menstrual and reproductive events, we examined menstrual cycle characteristics in relationship to early and late menarche, early and late menopause, and deferred parity, three variables epidemiologically related to breast cancer incidence. Women with late onset of menarche had longer and more variable cycles in the 10 years after menarche than did those with early onset. Women with late onset of menopause had longer and more variable cycles in the premenopausal interval than did those with early onset. Cumulative fertility in women after marriage did not differ according to cycle length and variance. Late menopause may be a breast cancer risk factor due to relative estrogen excess and progesterone lack as reflected in longer, more varied cycle patterns. Observed cycle differences between women with early and late menarche await further study of the endocrine physiology of the menstrual cycle in those groups.


Plasma hormone profiles of young women at risk for familial breast cancer. The plasma hormone concentrations of 30 young women, who were judged by genetic analysis to be at high risk for familial breast cancer, were compared with those of 30 matched controls identified as at low risk for the disease. The hormone measurements were obtained every second day throughout the menstrual cycle, and the results were analyzed in terms of follicular, luteal, and full-cycle mean concentrations. Comparison was carried out in a paired fashion with each high-risk and low-risk pair matched closely for height, weight, age, and reproductive history. No statistically significant differences were found in prolactin, gonadotropin, estrone, estradiol, or estriol plasma concentrations although the high-risk group displayed consistently lower values in all of the above except estriol.


Relationship between urine and plasma estrogen ratios. Normal young and postmenopausal women were placed into groups according to the ratio of the estrogens in their urine. Women whose ratio was greater than 1.3 if young and greater than 3.2 if postmenopausal were compared to women whose ratio was less than 0.7 and less than 2.1 for young and postmenopausal, respectively. Between the respective high- and low-ratio groups, there were no significant differences for circulating levels of estriol, metabolic clearance rates of estriol, or blood production rates of estriol, estrone, or estradiol. Women who had had breast cancer were compared to a group of normal controls and were also found to have similar blood production rates for estriol, estrone, and estradiol. The ratios of the blood production rates of estriol to estrone and estradiol were similar for the high and low groups for young and postmenopausal women and also between the breast cancer women and their controls. It appears, therefore, that the difference in urinary estrogen ratios is primarily due to different pathways of metabolism of the free circulating estrogens and not to differences in the production rates of the estrogens. Estriol is produced at only 10% the rate of estrone and estradiol.


Proposed coupling of chromatin replication, hormone action, and cell differentiation. DNA replication in isolated nuclei is highly dependent on the availability of soluble proteins from the cell cytoplasm. Activity is distributed nonrandomly among the different proteins, and the range of proteins that are required for optimal DNA replication varies with the fractions of DNA being replicated. Support of DNA replication has been correlated with the uptake of these proteins by nuclei and their integration into an immature form of the newly replicated chromatin; the latter has been shown by density analysis to be richer in protein content than the bulk of nonreplicating chromatin. Pulse labeling of DNA in living cells has revealed that a similar protein-rich chromatin is formed as an intermediate in chromatin replication in vivo; however, this form rapidly matures by the exclusion of proteins. The dependency of DNA replication on the presence of soluble cytoplasmic proteins and the physical association of these entities with newly replicated chromatin prompt the proposal that availability of specific proteins may play an important role in determining the ultimate genetic expressability of the matured chromatin and thus the cell phenotype. The finding that dexamethasone, a steroid that regulates the expression of several genes and directs the differentiation of certain cells, can modify the uptake of proteins in isolated nuclei is in accord with this hypothesis.


Role of hormones in mammary neoplasia.

Role of hormones in mammary neoplasia. A testable hypothesis for the role of hormones in mammary carcinogenesis with implications for other endocrine-related carcinogenesis is presented. The hypothesis is based on these observations: (a) hormones are involved, directly or indirectly, in regulating cell division in normal mammary cells: (b) emergence of overt mammary tumors requires hormonal stimulation of cells receiving carcinogenic stimulus; (c) normal mammary cells are of finite divisional capabilities, whereas neoplastic cells appear to have infinite divisional life; and (d) normal cells, when present in large quantities relative to the neoplastic cells, inhibit the growth of the latter cells. According to the hypothesis hormones play at least two roles in mammary carcinogenesis induced by diverse agents, such as viruses, chemicals, and radiation. First, hormones are necessary for DNA synthesis and mitosis of initial transformed cells for their conversion into fixed transformed cells with heritable characteristics. Second, hormones, by increasing the rate of cell division, shorten the reproductive life span of normal cells, eventually causing a reduction in the normal to transformed cell ratio in the population--a condition that allows the emergence of tumor cells by overriding the inhibitory influence of normal cells.