Relapsing polychondritis with crescentic glomerulonephritis. Relapsing polychondritis is rare and its cause is unknown. The tissues affected are those with a high glycosaminoglycan content, such as cartilage, the aorta, the sclera and cornea, and parts of the ear. Symptoms can usually be controlled with oral steroids, but when there is coexistent progressive crescentic glomerulonephritis quadruple chemotherapy may be used. Three cases of the clinical syndrome of relapsing polychondritis were studied in which rapidly progressive cresentic glomerulonephritis developed. In two the patients appeared to respond to aggressive treatment with immunosuppressive agents and anticoagulants. The multisystemic nature of the disease, the renal lesions, and the response to treatment all suggested that the condition might be related to periarteritis nodosa.


Growth hormone, prolactin, and corticosteroid responses to insulin hypoglycaemia in alcoholics. Plasma growth hormone (GH), prolactin, and corticosteroid responses to insulin-induced hypoglycaemia were studied in 24 men with progressive alcoholism who had been abstinent for two to seven days. Ten normal healthy subjects (five men, five women) served as controls for comparing GH and prolactin responses, while cortisol responses were studied in a further six male controls. Blood samples were taken at intervals after an injection of soluble insulin (0.1 U/kg body weight). All patients developed adequate hypoglycaemia (blood glucose <2.2 mmol/l (<39.6 mg/100 ml)) and nine had impaired GH responses (peak concentration <10 mU/1). Prolactin concentrations fell or remained unchanged in nine patients, eight of whom also had impaired GH responses. In seven patients corticosteroid concentrations decreased from basal concentrations, and six of these patients had impaired GH responses. All three hormone responses were impaired in several patients, and significant correlations were found between the GH and prolactin responses at 45 and 60 minutes. GH response was not correlated with age, duration of drinking, duration of alcoholism, or admitted alcohol intake. GH responses were significantly lower in patients who had the most severe withdrawal symptoms. Our observations of impaired stress responses in some recently abstinent alcoholics may have important implications for the management of alcohol withdrawal syndrome.


Epidemiology and clinical significance of cervical erosion in women attending a family planning clinic. Women attending a family planning clinic were studied to determine the relation between cervical erosion and clinical and social characteristics. The appearance of the cervix was recorded without knowledge of the women's symptoms. The prevalence of erosion increased with parity but, when the effects of other factors were controlled, decreased in women aged 35 and over. Erosion was significantly more common in women taking the "pill" and less common in women using barrier methods of contraception than in others. There was considerable variation between doctors in the reporting of erosion. No association was found between erosion and postcoital bleeding, dyspareunia, backache, or dysuria. There was a significant but modest association between erosion and vaginal discharge and a suggestion that erosion may sometimes be associated with nocturia and frequency of micturition. Vaginal flora was similar in women with and without erosion. Cervical erosion should not be regarded as pathological in asymptomatic women, nor should it be assumed necessarily to be the cause of symptoms in women with genitourinary complaints.


Scabies in Sheffield: a family infestation. From June 1972 to May 1973 the medical officer of health and general practitioners in Sheffield referred all suspected cases of scabies to the Hallamshire Hospital skin department. Contact tracing, similar to that in VD departments, was carried out by a specially trained state registered nurse. In all, 1482 cases were found in 609 households. This was ten times the number referred to the skin department in 1971. Infestation was introduced to households mainly by schoolchildren and teenagers, especially by girls. The commonest sources were friends and relatives outside the home. Schools did not play an appreciable part in spread. The secondary attack rate in households was 38%. Notification of cases, adequate treatment within the home, and contact tracing are recommended to halt the present epidemic of scabies.


Intended place of delivery and perinatal outcome. Data from the "1958 Perinatal Mortality Survey" have been analysed to assess differences in stillbirth and neonatal death rates according to the arrangements made for delivery. Only women aged 20-34 delivering at term, with no pregnancy abnormalities, were selected from three groups of women (normotensive primiparae, hypertensive primiparae, and normotensive women of parity 1, 2, or 3). Despite the fact that within each group the women booked for NHS consultant units were heavily weighted with adverse factors, the death rate of their infants was no more than 70% of that found among the women booked for either domiciliary, general practitioner unit, or private consultant delivery. Care and delivery in a NHS consultant unit carries least risk of death for the infant.


The regional drug information service: a factor in health care? Most regional health authorities throughout the United Kingdom have established drug information units to provide health service staff with a wide range of information about drugs and drug use. The units, which are staffed by drug information pharmacists, provide their service mainly by answering inquiries, although some disseminate information more positively through lectures and bulletins.An analysis of inquiries received by regional information units during 1976 showed that most were submitted by hospital doctors or pharmacists; comparatively few were received from general practitioners. Topics of inquiry included adverse effects of drugs, source of supply and identification, current treatment, dosage, route, precautions, and pharmaceutical problems such as stability or formulation of drug preparations. A more detailed analysis of the inquiries received by the North-western Regional Drug Information Service at Manchester over three years showed that the number of inquiries gradually increased and that more were received from general practitioners after a programme of lectures had been introduced to tell them about the service. The North-western service also received more requests from hospital pharmacists than other units, though many originated from clinicians.The regional drug information units consulted widely with clinical and other specialists in answering questions, but about a quarter of all inquiries were pharmaceutical, relating to stability and incompatibility. A multidisciplinary approach therefore seems necessary to provide a comprehensive and advisory drug information service.


Encephalization in vertebrates. A new mode of calculation for allometry coefficients and isoponderal indices. The conventional allometric power function, with its slope near 2/3, works well for interspecific scaling of brain vs. body weight in all groups of vertebrates. It fails, however, in extrapolation to vertebrates of the largest size within their groups: these have smaller brains than the equation would predict. We propose a correction, the hyperbolic tangent, to linearize the data over all sizes, and we discuss evolutionary reasons for the relatively small brain size of the largest vertebrates.


The vestibular nuclei in the domestic hen (Gallus domesticus). IV. The projection to the spinal cord. Horseradish peroxidase was injected at various levels of the spinal cord of the hen and the cells in the brain stem, labeled due to retrograde transport of the tracer enzyme, were mapped with particular reference to the vestibular nuclear complex. The Deiters' nuclei project ipsilaterally to the spinal cord. The projection from the nucleus Deiters ventralis reaches down to the lumbosacral spinal cord. The spinal projection from the nucleus Deiters dorsalis is somatotopically organized. Cells localized rostrally within the nucleus project to upper parts of the spinal cord cells localized caudally project to the lumbosacral spinal cord. The medial and the descending nucleus contain labeled cells in two compartments of the nuclei. In each of them a rostral one projects to the upper cervical cord, a caudal one projects to the thoracical spinal cord. In addition, labeled cells are observed in the reticular formation, mainly in the pons and the medulla oblongata, in the red nucleus, in the raphe nuclei and in the periaqueductal grey. Very few labeled cells are observed in the locus ceruleus, the nucleus intercalatus and in the nucleus of the solitary tract. In some cases, the number of labeled cells in the various nuclei in the brain stem projecting to the spinal cord was counted to get an impression of the quantitative importance of the vestibulospinal projection relative to afferents to the spinal cord from the other nuclei. The findings are discussed in the light of what is known of the vestibulospinal projection in mammals.


Topography of visual and somatosensory projections to the superior colliculus of the golden hamster. The topography of visual and somatosensory projections to the superior colliculus in the Syrian hamster was studied using electrophysiological techniques. The visual projection to the superficial layers of the colliculus is similar in general topography to that described for other rodents. The magnification of the visual field on the colliculus surface was greatest for nasal visual field. The magnification factor paralleled retinal ganglion cell density for corresponding visual field sectors. In the deep layers of the colliculus, a somatosensory projection is found in register with the visual projection such that the anterior somatosensory field and nasalmost visual field are both represented in rostral colliculus; posterior somatosensory fields and temporal visual fields are found in caudal colliculus. Likewise, upper visual and somatosensory fields are found in medial colliculus, and lower visual and somatosensory fields are found in lateral colliculus. Large receptive fields make the somatosensory topography less precise than the visual topography, but this lack of precision could serve to keep the two maps generally in register during eye and body movements.


The location of spinal projection neurons in the cerebellar nuclei (cerebellospinal tract neurons) of the cat. A study with the horseradish peroxidase technique. The distribution of spinal projection neurons was studied in the cerebellar nuclei of the cat following injections of horseradish peroxidase (HRP) into the cervical, thoracic and lumbar cord. HRP-positive (labeled) neurons were found in the medial (fastigial) and the posterior interpositus nuclei on the side contralateral to the cervical injection, being most numberous in cases with injections between the C2 and the C3 segments. In the medial nucleus (M) labeled neurons were distributed in the central to the caudal portions, and there was a conspicuous group of labeled small neurons extending from the ventrolateral part to the intermediate zone between the M and the anterior interpositus nucleus. With an increasing number of medium-sized neurons, this neuronal group persisted caudally in a similar position, ventromedial to the posterior interpositus nucleus (IP). Labeled large neurons were seen in the medial third of the IP. In the two cases labeled neurons of medium and small sizes were equal in number, and the neurons of the IP constituted about 10% of the total number of the spinal projection neurons. The present study suggests that the neurons of the M and the IP, including those of the intermediate group located between the two, project the bulk of the crossed descending fibers as far caudally as the C2 and the C3 segments.


Postnatal development of rat cerebellum: massive and transient accumulation of concanavalin A binding glycoproteins in parallel fiber axolemma. Modifications of protein-bound sugars during postnatal development of rat cerebellum were studied. Glycoprotein-bound mannose accumulates, in the particulate fractions, at an earlier age than the bulk of glycoprotein sugar. This corresponds to a transient and massive accumulation of glycoproteins which bind to Concanavalin A (Con A). These glycoproteins were localized by using fluorescent Con A and the horseradish peroxidase-Con A method. Cerebellar white matter and the molecular layer bind massive amounts of Con A. The binding in the molecular layer is transient. It follows the same time course as the Con A-binding glycoproteins of particulate fractions, and it is largely confined to the axolemma of parallel fibers. Only growing or newly formed parallel fibers bind Con A. The disappearance of the binding is simultaneous with the maturation of parallel fibers and their synapse formation. These phenomena can be related to fiber growth and maturation and, also, to synapse formation. The possibility of a specific role of Con A-binding glycoproteins is discussed.


Chemical relationship of the paired helical filaments of Alzheimer's dementia to normal human neurofilaments and neurotubules. Intraneuronal fibrillary tangles are prominent features of several neurological diseases, including especially Alzheimer presenile and senile dementia, and to a much lesser degree in the normal aged human brain. These tangles are made up of abnormal fibrillar elements each about 22 nm at its widest, periodically reduced to 10 nm at about every 80 nm. Each abnormal fiber seems to be a pair of 10 nm filaments helically wound around each other. In this study the protein subunit of these paired helical filaments isolated from cases of Alzheimer's dementia was compared with the major protein subunits of normal neurofilaments and neurotubules by two-dimensional peptide maps of the tryptic or chymotryptic digests of these proteins labelled with 125I. The paired helical filament protein is very similar in its peptide maps to identically treated major neurofilament protein and to the beta monomer of neurotubule, while it is not so similar to the alpha tubulin. These data suggest that the paired helical filament protein subunit is closely related chemically to the normal neurofilament protein subunit, and the beta tubulin.


Junctional complexes and variations in gap junctions between spinal cord ependymal cells of a teleost. Sternarchus albifrons (Gymnotoidei). Junctions between ependymal cells lining the central canal in the spinal cord of the weakly electric teleost, Sternarchus albifrons, were investigated by means of thin-section and freeze-fracture electron microscopy. Junctional complexes representing the 'terminal bar' consist of a zonula occludens, followed by intermediate junctions and desmosomes. This pattern is common in many types of epithelia but uncommon in ependyma. Three types of gap junctions were found below the level of the terminal bar and intermixed with desmosomes: (1) gap junctions at least partially enclosed by a single strand of apparent tight junction, (2) ordinary gap junctions, partially surrounded by a particle-free halo and (3) segmented gap junctions, in which linear arrays several particles wide are separated by fairly regular linear particle-free regions. Some of the observations may have implications for the mechanism of formation of gap junctions.


An electron microscopic study of rubrospinal projections to the lumbar spinal cord of the opossum. The rubrospinal system is a major suprasegmental input to the important interneuronal pool at the base of the lumbar dorsal horn in the North American opossum. After appropriate lesions, rubral axons and their synaptic terminals were found in electron micrographs of lamina IV, V and VI as well as within the dorsal extreme of lamina VII. Degenerating terminals contact small diameter dendrites in the lateral terminal zone and large dendritic profiles in the medial terminal zone. Correlating these data with the dendritic arborizations of interneurons in Golgi preparations and with existing physiologic studies, it appears that interneurons in the intermediate and medial aspects of lamina V, VI and VII receive rubral input on both their proximal and distal dendrites.


Conduction of nervous impulses in spinal roots and peripheral nerves of dystrophic mice. Conduction was studied in the sacral ventral roots and ventral tail nerves of dystrophic mice (dy/dy) and phenotypically normal littermates. In myelinated ventral root fibers of normal mice, conduction velocity was uniform with internodal conduction time 45 +/- 5 musec (26 degrees C). In ventral root fibers of dystrophic mice, conduction velocity was decreased and strikingly non-uniform; both saltatory and continuous conduction were observed in different portions of the same nerve fiber. Continuous conduction with velocity less than 2 m/sec (26 degrees C) was characteristically observed in mid-root where the axons are bare; conduction was saltatory close to the exit from the spinal canal and near the spinal cord where the axons are myelinated. Maximum conduction velocity in ventral tail nerves was 21 +/- 3 m/sec for dystrophic mice and 31 +/- 4 m/sec for littermate controls (37 degrees C). Internodal lengths were somewhat decreased in the dystrophic peripheral nerves but there was no significant difference in maximum fiber diameters, myelin thickness or nodal morphology between dystrophic and normal nerves.


Histological studies of trophic dependencies in crayfish giant axons. Medial giant (MGA) and lateral giant (LGA) axons of crayfish were doubly cut in order to selectively isolate axonal segments from perikaryal and transsynaptic sources of trophic input. Isolated MGA segments remained morphologically intact for over 43 days, whereas isolated LGA segments usually degenerated within one week. The glial sheaths around isolated MGA segments had significantly increased in thickness within one week, but severed LGA segments showed no increase in sheath thickness at any time after lesioning. These data suggest that cells of the surrounding glial sheath can provide trophic support to isolated MGA segments but not to isolated LGA segments. Extent of glial hypertrophy seems dependent upon specific spatiotemporal parameters. The diameters of isolated MGA segments decreased more rapidly than the diameters of singly cut MGA segments. These data suggest that the MGA also receives some trophic support from pre- or postsynaptic sources. Conversely, some singly cut LGA segments completely degenerated within one week, whereas other singly cut LGA segments remained intact for at least 43 days after lesioning. Such results suggest that the LGA receives a significant trophic input from pre- or postsynaptic structures.


Properties of central vestibular neurons fired by stimulation of the saccular nerve. In 4 cats all vestibular afferents in one labyrinth except those innervating the saccular macula were transected and allowed to degenerate. 23--53 days after the initial surgery the central connections of the remaining saccular nerve were studied under chloralose anesthesia. Stimulation of the saccular nerve evoked N1 field potentials in the ipsilateral lateral and descending vestibular nuclei; little or no field potential activity was seen in the superior nucleus. The distribution of field potentials overlapped with that of neurons of origin of the vestibulospinal tracts. Forty-two neurons in the ipsilateral vestibular nuclei, many in the lateral nucleus, responded, often monosynaptically, to stimulation of the saccular nerve with single or double shocks; some of the neurons projected to the spinal cord. All saccular-fired neurons were tested for commissural actions by stimulation of the contralateral vestibular nerve. Many were facilitated, almost none were inhibited. In agreement with earlier work, we conclude that commissural inhibition may be a property of the canal system only.


The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats. One or two bottle preference tests, i.e., relative fluid consumption, constitute the primary methodology for determining acceptance or rejection of tastes in animals other than humans. These tests require organisms to initiate and maintain drinking behavior, and, therefore, can not be applied to preparations which do not eat or drink spontaneously. The taste reactivity test, a new method for assessing responses to gustatory stimuli, circumvents this shortcoming. A 50 microliter taste stimulus is injected directly into the oral cavity of a freely moving rat and the immediate response videotaped for frame by frame analysis. Each of the sapid stimuli used (4 concentrations of sucrose, NaCl, HCl, and quinine HCl) generated a stereotyped response derived from a lexicon of 4 mimetic (movements of lingual, masticatory, and facial musculature) and 5 body response components. Responses to taste stimuli were highly consistent within and between rats. For example, sapid sucrose, NaCl and HCl stimuli elicited a response sequence beginning with low amplitude, rhythmic mouth movements, followed by rhythmic tongue protrusions, and then lateral tongue movements. No body movements accompanied these mimetic responses. In contrast, quinine in concentrations at and above 3 X 10(-5) M (1/2 log step above the absolute behavioral threshold for quinine) elicited a response pattern beginning with gaping and proceeding through as many as 5 body responses. These normative data for the intact rat can be directly compared to the taste reactivity of neurally ablated preparations which do not spontaneously feed or drink. Such comparisons can be utlized in determining the neural substrates necessary for the execution and regulation of ingestive behavior.


The taste reactivity test. II. Mimetic responses to gustatory stimuli in chronic thalamic and chronic decerebrate rats. The taste reactivity test described in the preceding paper was used to begin determining the capacity of brain stem structures to execute and regulate ingestive behavior. Both chronic thalamic and chronic decerebrate rat preparations were examined repeatedly, and their gustatory mimetic responses compared through frame-by-frame videotape analysis with the responses of neurologically normal controls. In response to orally injected taste stimuli, chronic decerebrate rats executed the same mimetic response components, and very similar response sequences observed in intact rats. In contrast, all taste stimuli elicited a quinine-like rejection sequence from chronic thalamic rats. In thalamic rats mimetic responses associated with ingestion were completely absent. Based on the similarities in the ingestion and rejection responses of decerebrate and intact rats, it appears that discriminative responses to taste result from integrative mechanisms complete within, or caudal to, the midbrain. Since decerebrate rats have the capacity to execute both ingestion and rejection response sequences, neural mechanisms rostral to the midbrain in some way suppress ingestion and/or releaser ejection responses in the thalamic preparation.


Neurological tests and behavioral deficits in chronic thalamic and chronic decerebrate rats. The taste reactivity of chronic decerebrate rats is very similar to intact rats although chronic thalamic rats display only the quinine-like rejection sequence. The performance of intact (n = 12), decerebrate (n = 10) and thalamic (n = 10) preparations was further compared across a set of simple behavior tests to more broadly assess the behavioral capacities of the rodent brain stem. Decerebrate rats were immobile. They exhibited no spontaneous activity other than grooming, but often overreacted with well-coordinated movements (i.e., running, jumping and climbing) to seemingly inappropriate activating stimuli such as tail pinch, handling or water squirted on the fur. Decebrates had lower thresholds for elicited attack and grooming behaviors than thalamic or intact rats. The thalamic preparation exhibited a wider range of intact neurological responses than the decerebrate. Cage climbing, resistance to gravity, suspension and muscle tone reactions, rhythmic vibrissae movements and examination of objects with snout and mandible were difficult to distinguish from controls. Decerebrates either did not perform these responses or did so in a clearly different manner. In contrast, grooming behavior in thalamics was much less effective than in decerebrates. Thalamic rats spontaneously executed grooming sequences, but the responses were misdirected and ineffective. Desite their relative immobility, decerebrates coordinated grooming sequences and maintained their fur. No single mechanism appears to account for the constellation of deficits and capacities observed in either chronic thalamic or chronic decerebrate rats.


Differential effects of lateral and ventromedial hypothalamic lesions on gastrointestinal transit in the rat. Lateral hypothalamic lesions that produce aphagia reduce gastric retention and increase intestinal transit of a 10 ml liquid load in anesthetized rats. Ventromedial hypothalamic lesions which produce hyperphagia and obesity have the opposite effects. These results are apparent within minutes after lesioning as well as after postoperative stabilization of body weight (26--41 days). These data suggest that changes in gastrointestinal motor function(s) may contribute to the changes in food intake which follow hypothalamic damage.


Responses of neurones of the pontine nuclei to stimulation of the sensorimotor, visual and auditory cortex of rats. The aim of this study was to investigate the degree of convergence of corticofugal neurones from various cortical areas onto single neurones of the pontine nuclei (PN). Eighty-five% of the PN neurones responded to electrical stimulation of at least one of the following cortical areas: sensorimotor, visual, auditory. Slightly less than half of these neurones displayed a convergent input from two or three of functionally different cortical areas. The sensorimotor cortex, particularly the face areas, provided the most important input to the PN; stimulation of the visual cortex was less effective and stimulation of the auditory cortex rarely excited PN neurones. The electrophysiological results suggest that considerable cross-link exists between the anatomically defined cortico-pontine projection columns.


Reset of hippocampal rhythmical activities by afferent stimulation. Physostigmine induced theta rhythm and unit activity were recorded from the dorsal hippocampus in immobilized locally anesthetized rats. Correlations between theta and rhythmical unit activity and their modifications by hippocampal afferent stimulation were studied. The principal finding was that electrical stimulation of afferents reset theta and rhythmical unit activity in phase. Poststimulus theta displayed a variable frequency which depended upon the structure stimulated. Lower frequencies were evoked by septal, higher frequencies by entorhinal and reticular formation stimulations. When theta rhythms were absent either by spontaneous disappearance or as a consequence of lesions in the fornix superior of septum, the reset was not observed. The reset of the theta rhythms and unit activity by afferent stimulation, suggests that the hippocampus may participate in timing mechanisms.


Recovery of function after brain damage: the extrinsic stimulus specificity of spared neural traces. Previous research has demonstrated that while primary visual cortex lesions in rats will disrupt performance of a learned brightness discrimination, the neural traces associated with this discrimination are spared. Moreover, the spared neural traces may, in certain instances, influence the postoperative reinstatement of a brightness discrimination. The present research was designed to determine the generality of this postoperative influence. The results indicate that while the normal rat and the visual decorticate rat may readily transfer learning between discriminations involving different discriminative cues, a visual lesion between two discriminations prevents this transfer. These data are interpreted as indicating that the postoperative influence of a spared neural trace is dependent upon the reoccurrence of specific extrinsic stimulus cues.


Sodium pump activity, amino acid transport and long-term memory. Long-term protein synthesis-dependent memory formation is shown to be inhibited by the non-metabolizable amino acid alpha-amino-isobutyrate (AIB) possibly through a process related to competition for uptake with amino acids necessary for protein synthesis specific to long-term memory. Unlike cycloheximide (CXM) which inhibits long-term memory by inhibiting ribosomal protein synthesis, AIB is non-effective when administered 10 min or more after learning, and its effect is overcome by the sodium pump stimulator diphenylhydantoin if the latter is administered 10 min or more after learning. Within the model of memory formation adopted in this paper it is postulated that the amino acids necessary for long-term memory protein synthesis are taken up by sodium pump activity in the first 10 min following learning, when formation of the preceding labile memory phase is occurring.


Spatio-temporal pattern discrimination in cats with insular-temporal lesions. Previous studies have demonstrated that cats with bilateral insular-temporal lesions are impaired in their ability to perform temporal pattern discriminations of the general form A--B--A vs B--A--B. This deficit has been seen to occur when A and B are made up of two different auditory, visual, or vibrotractile stimuli. These data suggest that insular-temporal cortex is a multimodal area concerned with the perception of temporal sequences of stimuli. The present study extends these earlier observations by testing insular-temporal lesioned cats on a spatio-temporal pattern discrimination. A spatio-temporal pattern is defined as one in which the same stimulus is presented to the animal sequentially from different spatial locations. The data indicate that insular-temporal lesions disrupt a spatio-temporal pattern discrimination just as they do auditory, visual, or vibrotactile temporal pattern discriminations. Insular-temporal cortex appears to be critical for certain higher order perceptual abilities in the cat.


Meal patterns in rats with nigrostriatal dopamine-depleting lesions, subdiaphragmatic vagotomy, and their combination. Rats which had sustained 97% bilateral striatal dopamine depletions after intranigral 6-hydroxydopamine recovered feeding and drinking to show normal meal patterns on both solid and liquid food. The motor acts of eating were somewhat slow but, in contrast to lateral hypothalamic lesioned animals, there were no interruptions for other activities. Vagotomy produced the expected decrease in liquid meal size, and an identical change was observed when the dopamine-depleted rats were similarly vagotomized. The fragmented meal patterns seen after far-lateral hypothalamic lesions do not arise from damage to either of the systems here investigated.


Precursor role of 15alpha-hydroxyestradiol and 15alpha-hydroxyandrostenedione in the formation of estetrol. Studies were designed to elucidate the origin of estetrol (15alpha-hydroxyestriol (estra-1,3,5(10)triene-3,15alpha,17beta-tetrol) or E4) during late human pregnancy. 3H-Labelled 15alpha-hydroxyestradiol (3,15alpha-dihydroxyestra-1,3,5(10)-trien-17-one or 15E2) and 14C-labelled 17beta-estradiol (estra-1,3,5(10)-triene-3,17beta-diol or E2) were infused into the fetus during transfusion in utero for erythroblastosis fetalis, and in another study the same substrates were injected intravenously into the maternal circulation. In a third study, 3H-labelled 15alpha-hydroxyandrostenedion (15alpha-hydroxyandrost-4-ene-3,17-dione or 15delta4) and 14C-labelled E2 were infused into the fetus. Maternal urine was collected for 5--6 days, and after Glusulase hydrolysis, the following metabolites were isolated: estriol (estra-1,3,5(10)-triene-3,16alpha,17beta-triol or E3) containing 14C only and 15alpha-hydroxyestrone (3,15alpha-dihydroxyestra-1,3,5(10)-trien-17-one or 15E1), 15E2, and E4, all containing both labels. From the isotope content of these metabolites, it was concluded that E4 was derived from both fetal E2 and 15delta4 and only partially via 15E2. When administered to the fetus E2 and 15delta4 contributed approximately equal amounts to urinary E4. The yield of 15alpha-hydroxylated estrogens from E2 injected into the mother was very low indicating the predominantly fetal origin of the 15alpha-hydroxylase. 15delta4 was a better precursor than E2 for urinary 15E2.


Uncoupling activity of endogenous free fatty acids in rat liver mitochondria. Changes in the respiratory control index (RCI) and ADP:O ratio were found to be related to alterations in the free fatty acids levels of rat liver mitochondria aging in 0.25 M sucrose- Tris buffer at 0 degrees C. Free fatty acid levels increased with time after isolation of mitochondria while a concomitant decrease in the RCI and ADP:O ratio occurred. The changes in free fatty acid levels corresponded with the reported increasing levels of phospholipase A activity in aged mitochondrial preparations. Washing these mitochondria with sucrose buffer containing 1% defatted bovine serum albumin (BSA) counteracted the aging effect on the RCI (E.G., 2.5 to 3.5) and reduced the free fatty acid levels (e.g., 50 to 16 nmol/mg protein). This reversible phenomenon could be repeated several times during the in vitro aging at 0 degrees C. Use of 125I-iodinated BSA showed that approximately 5 microgram BSA/mg mitochondria was adsorbed by the mitochondrial membranes during washing. These results indicate a direct correlation between the level of endogenous fatty acids and the uncoupling of mitochondrial oxidative phosphorylation. The mechanism of counteracting the aging effect by BSA involves the removal of some of the free fatty acids.


[Rapid technic for preparation of thyroid ribonucleic acids without phenol]. Thyroid tissue was homogenized in 2 M LiCl. The homogenate was alloued to stand 1 h 30 min at 2 degrees C and then centrifuged. The pellet was suspended in 5% triisopropylnaphthalene sulfonic acid (the sodium salt), 0.05 M Tris--HCl, and 0.1 M NaCl (pH 8). After stirring and centrifuging, the supernatant containing the crude RNA was purified by filtration on Ultrogel AcA 22 (LKB, Sweden). Before adding the sample of crude RNA to the column, pronase was placed on the column. When pronase had entered the gel, we added the sample. The first peak contained pure RNA plus some DNA. The former was precipitated with 2 M LiCl. The RNA species obtained by this technique were undegraded and the yield was 30% better than that of the phenol technique.


Synthesis of peptides by the solid-phase method. III. Bradykinin: fragments and analogs. The natural sequence of bradykinin (BK) and 55 fragments or analogs of this peptide were perpared via the solid-phase method. The peptides were purified using ion-exchange (O-carboxymethyl(CM) and partition (Sephadex G-25) chromatography. The purity of each peptide was established by paper and thin-layer chromatography, paper electrophoresis, amino acid analysis, and biological assays. The compounds were tested in anesthetized rats (tested in vivo) and in two smooth-muscle preparations (rabbit aorta strip, cat ileum strip) in which BK produces contraction by stimulating specific receptors of different types. Some of the new peptides are interesting in that they either resist pulmonary inactivation, or are more potent than BK itself, or antagonize the myotropic effect of BK in rabbit aorta strips.


Profundoplasty for limb salvage.

Profundoplasty for limb salvage. Profundoplasty was performed in 26 legs because of rest pain or gangrene; previous arterial reconstruction had been done in 12 of them. In 16 limbs the popliteotibial segment was patent; profundoplasty was successful in each case. In 10 limbs the popliteotibial segment was occluded, and profundoplasty failed in one instance. One patient died. The authors believe that re-establishing blood flow and pressure to the deep femoral artery, especially to the descending branch of the lateral circumflex artery and the distal part of the deep femoral artery can effectively improve the condition of ischemic legs.


Myocardial protection during aortic valve replacement: normothermia versus hypothermia. The operative results in 32 patients who underwent aortic valve replacement with aortic occlusion and normothermic myocardium (group 1) were compared with 54 similar patients in whom the myocardium was protected by hypothermic coronary perfusion through the aortic root (group 2). The operative mortality and the incidence of heart failure, subendocardial ischemia and myocardial infarction were the same in the two groups. The maximal concentrations of cardiac enzymes after operation in group 2 patients were significantly lower than those in group 1. The postoperative cardiac performance was significantly different in that only 5.6% of group 2 patients required inotropic agents after operation compared with 25% of group 1 patients. The patients in group 2 were easier to defibrillate after cardiopulmonary bypass.


Femorofemoral bypass: a valuable procedure. Twenty-seven femorofemoral bypasses were performed in 25 patients with severe arteriosclerosis obliterans affecting the iliofemoral arteries. The series comprised 16 men and 9 women, aged 51 to 80 years. Nineteen patients were poor-risk cases with severe cardiorespiratory disease. Twenty-one patients had undergone vascular procedures previously without success. The operation was carried out: (a) as the primary procedure for very poor-risk patients in an attempt to salvage a limb, (b) to deal with unilateral limb occlusion of an aortoiliac--femoral prosthesis, or (c) as management of infected prosthetic grafts. Fourteen Dacron grafts and 13 saphenous veins were used for the bypasses. There were no operative deaths. Twenty-two patients were clinically improved, two required amputation later and one patient was lost to follow-up. Four patients, including three with preexisting graft infection, had wound infections that cleared with drainage and antibiotics. No other major complications occurred in this group of poor-risk patients. Femorofemoral bypass is safe and provides the surgeon with a useful method of revascularizing the limbs of selected patients.


Acute cardiac failure: the relation between coronary flow and oxygen consumption. In an initial study with dog hearts functioning in situ on total coronary bypass, we demonstrated that predetermined levels of reduced cardiac pump function could be achieved by reducing total coronary flow through changes in the perfusing pressure. In subsequent experiments, oxygen values were measured so that changes in myocardial aerobic consumption in response to brief (3 minute) alterations in coronary perfusing pressure could be determined as well. As a result significant linear correlations were found between coronary flow and myocardial oxygen availability (r = 0.98), oxygen extraction (r = 0.49) and oxygen consumption (r = 0.92). These changes in oxygen values paralleled those in cardiac function (stroke work, r = 0.84).


Clinical evaluation of porcine heterograft cardiac valves in 200 patients. Of 200 patients who received porcine heterograft cardiac valves, the first 100 did not receive postoperative anticoagulant therapy. In the second 100 patients anticoagulant measures were used when thrombogenic factors not related to the prosthesis were evident. Anticoagulation should be employed following mitral valve replacement while factors contributing to thromboembolism prevail. The conditions that tend to induce vascular stasis in the left atrium followed by embolism are chronic atrial fibrillation, a large dilated left atrium and a calcified left atrial wall. The results of our study provide assurance of the continued use of the porcine bioprosthesis.


Permanent transvenous atrial pacing.

Permanent transvenous atrial pacing. Atrial pacing has electrophysiologic and hemodynamic advantages for patients with symptomatic bradyarrhythmias and intact atrioventricular conduction or with certain refractory tachyarrhythmias. Permanent atrial pacing has been achieved in 29 patients followed up for periods of up to 7 years at two institutions. At Sunnybrook Medical Centre, Toronto, 16 patients have had coronary sinus electrodes introduced pervenously using standard bipolar or special unipolar catheters. Initial pacing thresholds were acceptably low (mean, 2.0 mA); chronic thresholds in three patients were similar. At the Toronto General Hospital, 13 patients had endocardial J-electrodes, bipolar or tined unipolar, inserted in the right atrial appendage. Initial thresholds were low (mean, 1.3 mA) and P-wave voltage was adequate (3.4 mV) for pacemakers with standard sensitivity. In both series, conventional R-inhibited, asynchronous or rate-programmable units have been employed. Radiofrequency self-conversion pacemakers were used in three patients. Preliminary His bundle studies were done in 10 patients; the others were tested by rapid atrial pacing during insertion of electrodes. Early and late electrode stability in both series was excellent; one electrode became dislodged from the coronary sinus position and one from the right atrial appendage.


Clinical application of Doppler ultrasonography in the thoracic outlet syndrome. Difficulties in diagnosing the thoracic outlet syndrome prompted a pilot study of noninvasive Doppler ultrasonography in 160 thoracic outlets of healthy volunteers. Encouraged by the results we applied the technique to the clinical evaluation of flow disturbances during various provocative maneuvers. Ninety-four thoracic outlets were examined; of these, 32 were operated upon. Severe flow occlusion which was detected by Doppler ultrasonography reproduced symptoms of which the patients had originally complained. All patients were relieved of their symptoms, and only five had minor flow disturbances after resection of the first rib and scalenotomy. Resection of cervical ribs was carried out in seven of nine patients with this anomaly. Doppler ultrasonography was found to be a most valuable diagnostic modality and its wider application in this field is recommended.


Alterations in red cell metabolism during and following cardiac bypass surgery. Reduced concentrations of red cell organic phosphates and increased hemoglobin--oxygen affinity have been reported during and following cardiac bypass surgery. Some have related these changes to low concentrations of ATP and 2,3-diphosphoglycerate (DPG) in stored blood while others have related them to use of the pump oxygenator. There was a 10% decrease in DPG concentration in seven dogs on cardiac bypass although the animals received no transfusions. In 16 patients who received 0 to 7 units of blood during cardiac bypass there was a decrease of 10% in the red cell DPG concentration from the preoperative value, but it did not relate to the concentration of DPG in the transfused blood bags. The magnitude of the decrease was not sufficient to impair oxygen delivery severely. The results suggest that a re-evaluation of indications for the use of fresh red cells in cardiac surgery is necessary.


Medical litigation in Canada.

Medical litigation in Canada. It is impossible to predict the future of medical malpractice litigation in Canada. However, the statistics indicate that medical malpractice claims are steadily increasing. Action whould be taken now to ensure that the problem does not reach crisis proportions. In so far as the medical profession itself is concerned, it should ensure that the competence of medical practitioners remains on the highest possible level.


Review of function in bilateral lower limb amputees. A review of the results of bilateral lower limb amputation in 53 individuals indicates that the physician can now be more optimistic when considering the use of prostheses and the value of rehabilitation in patients with bilateral amputation. Many patients continue to use a prosthesis after the second amputation, irrespective of the site of the first. Associated disease and lack of motivation delay successful rehabilitation. About half of the amputees used a wheelchair as a principal aid to mobility. A number of patients found that amputation of the second limb necessitated a change of accommodation, reduced their degree of independence and decreased their social activities. Individuals with bilateral lower limb amputation prefer to retain the knee joint, even if they already have unilateral above-knee amputation.


Aneurysmal bone cyst of the vertebra with paraplegia. Aneurysmal bone cyst, a benign lesion, is difficult to diagnose radiologically, particularly in the spine, but has a characteristic microscopic appearance. Treatment of spinal lesions consists of curettage, with or without bone grafting, together with irradiation at low doses (1000 to 2000 rads). The author reports a case of aneurysmal bone cyst of the neural arch associated with neurologic complication, which illustrates some typical features of such cysts of the spine. The condition should always be considered in patients with lytic lesions of the spine, and prompt surgical intervention is recommended.


Recurrent psychiatric hospitalization.

Recurrent psychiatric hospitalization. Undue emphasis has been placed on rising rates of readmission to psychiatric facilities. After a decade of preoccupation with discharge rates, readmission statistics have been singled out in the last 15 years as the key factor for assessing hospital effectiveness. A study of a group of patients at high risk for recurrent hospitalization revealed that these patients were characterized more by features relating to environmental supports than by diagnosis. The operational definition for recurrent hospitalization (five or more admissions during the 2-year period preceding the latest admission) was effective in identifying this group; this is the first reported instance in which the definition has specified a certain number of admissions within a time-limited period. The findings of this study, as well as of an analysis of case histories and consumer opinion, led to the design of a pilot program for persons undergoing recurrent hospitalization. Readmission statistics are useless or misleading as measures of hospital effectiveness and efficiency; what matters is the way the former patients function in the community after discharge. Rather than simply trying to reduce the readmission rate psychiatric facilities should be examining the types of persons who are hospitalized recurrently to develop programs aimed at improving the functioning of these people in the community.


Hepatic function following portoenterostomy for extrahepatic biliary atresia. Liver structure and function in 10 patients with extrahepatic biliary atresia were studied after portoenteric anastomosis (Kasai operation). Bile flow adequate to reduce the serum bilirubin concentration was established in five patients (improved group), three of whom became anicteric. The serum bilirubin concentration did not decrease in the remaining five patients (unimproved group). Hepatic effluent collected postoperatively from both groups contained small amounts of cholesterol and bilirubin; bile salts, however, were present in the hepatic effluent of only the improved patients. Liver biopsy specimens obtained postoperatively from the five improved patients showed partial (in two) or complete (in three) relief of cholestasis; hepatic fibrosis, however, was unchanged (in one) or worse (in four). The serum concentrations of bile salts were markedly elevated, despite normal excretion of sodium sulfobromophthalein and rose bengal, in two anicteric patients studied 14 and 24 months postoperatively. It is concluded that neither structure nor function of the liver is normalized by portoenterostomy even in clinically well, anicteric patients.


[Health monitoring in a nursery school]. In contrast to the traditional program of health assessment of schoolchildren based on periodic physical examination, the program described in this paper is based on the integration of information and data obtained by observation through the school year from parents, teachers and the school nurse, who coordinates the program. The numbers and the types of problems and the date on which they were identified are compared in an experimental group of 557 kindergarten children and a matched control group of 498 children in whom the traditional program was maintained. For problems of hearing, enuresis, learning and behaviour the number of cases detected was significantly greater in the experimental group than in the control group. Each element of the proposed program is analysed and the advantages of an integrated approach to health assessment of schoolchildren are underlined.


The young physician: types of practice.

The young physician: types of practice. An inquiry was conducted into the type of practice (whether solo, group or salaried) entered by young physicians graduating from Canadian medical schools in 1970. Twenty-one percent entered solo practice, 57% joined a group practice or partnership, and 22% became salaried physicians in a number of different categories. Surgeons and psychiatrists, more than other types of specialist, were inclined to select solo practice. Group practice was more popular in the western provinces and in rural than in urban areas. More than half of the physicians recently established in urban solo practice complained of having too few patients. Lack of patients was a lesser problem in smaller towns and rural areas.


Myocardial perfusion imaging with thallium-201: correlation with coronary arteriography and electrocardiography. Myocardial perfusion imaging with thallium-201 and electrocardiography with the subject at rest and undergoing submaximal treadmill exercise were performed in 19 men and 3 women. Selective coronary arteriography and left ventriculography showed that 7 had normal coronary arteries and 15 had coronary artery disease.The 11 persons with electrocardiographic evidence of an old myocardial infarct (q waves) had a perfusion defect at rest in the area of the infarct and a segmental abnormality of wall motion apparent on the left ventriculogram corresponding to the perfusion defect.MYOCARDIAL PERFUSION IMAGING AND ELECTROCARDIOGRAPHY WERE EQUALLY SENSITIVE IN DETECTING CORONARY ARTERY DISEASE IN EXERCISING INDIVIDUALS: perfusion defects were noted in 7 of the 15 persons with coronary artery disease, and diagnostic ST-segment depression was present in 8 of the 15. Combination of the results of the two tests with exercise permitted the identification of 11 of the 15 persons and improved the sensitivity. Combination of the results of rest and exercise imaging and electrocardiography permitted the identification of 94% of the patients with coronary artery disease.Myocardial perfusion imaging with (201)TI in the subject at rest is a sensitive indicator of previous myocardial infarction. Imaging after the subject has exercised is a useful adjunct to conventional exercise electrocardiography, especially in those whose exercise electrocardiogram is non-interpretable.


Labour: when to worry.

Labour: when to worry. To ensure an optimum result in pregnancy it is essential that the physician be alert in the antenatal period to recognize those women and their babies who are at risk during labour. Premature labour, with its attendant risk of respiratory distress syndrome in the newborn, continues to be an important factor in perinatal morbidity and mortality. Early recognition of predisposing factors and the judicious use of myometrial inhibiting agents have helped to reduce the incidence of fetal prematurity in these cases. A long interval between rupture of the membranes and delivery continues to be a danger to both mother and fetus. Delivery is recommended when gestation is beyond 36 weeks or when there are signs of incipient infection, and once labour has begun antibiotics should be used prophylactically. Failure of labour to progress should be recognized and managed aggressively in its early stages. Amniotomy and oxytocin infusion have reduced considerably the incidence of prolonged labour and its risks to both mother and fetus. The role of intrapartum monitoring of the fetal heart rate, measurement of the pH in the fetus's scalp blood and assessment of amniotic fluid is discussed, as is the monitoring of maternal well-being.


Eye injuries in squash: a preventable disease. As more Canadians are taking up squash the incidence of eye injuries is increasing dramatically. Over 2-1/2 years, 23 cases from one urban practice were examined. Almost half of the group required inhospital treatment. Five patients sustained a permanent decrease in vision; these cases involved three corneal scars, one cataract and one macular cyst. Patients wearing glasses or hard contact lenses appear to be more susceptible to serious eye injury. Experience does not appear to reduce the likelihood of eye injuries; the patients in this study had played squash for 5.6 years on the average. Consequently the medical profession must take the lead by encouraging squash players to use protective equipment now available to reduce the incidence of these injuries that pose so much personal hazard.


Noncompliance in an exercise rehabilitation program for men who have suffered a myocardial infarction. A group of 163 men in the Hamilton, Ont. region who had suffered a myocardial infarction were enrolled in a rehabilitation program of physical activity. These men constituted one cohort of a multicentre collaborative study designed to determine the effects of regular exercise of differing intensity on morbidity and mortality over a 4-year period.The noncompliance rate was 43% for the men who could have participated for 1 year, 46% of whom were classified as noncompliers within 1 month of entry into the program. There was no difference in overall compliance between the men exercising at high intensity and those exercising at low intensity; lack of motivation or interest was the most common reason for their leaving the program. Those leaving the program early tended to have a type A behaviour pattern (they were aggressive, ambitious and competitive, with a chronic sense of time urgency), were inactive during their leisure time, had had at least two previous infarctions and smoked. These characteristics suggest that the men leaving the program early may have been those at greatest risk for a further myocardial infarction.


Contribution of twin pregnancy to perinatal mortality and fetal growth retardation; reversal of growth retardation after birth. A survey of factors associated with perinatal mortality in 511 twins and fetal growth retardation and its reversal in 262 twins is presented. The incidence of stillbirth was almost 50% higher in twins than in singletons and the neonatal mortality was six times as high. Eighty percent of the neonatal deaths occurred in infants born prior to or at 30 weeks of gestation; 93% of the deaths were in infants weighing less than 1500 g and 75% occurred within 48 hours of birth. Fetal malnutrition was the main cause of stillbirth, and respiratory distress syndrome and asphyxia neonatorum were the main causes of neonatal death. One quarter of the twins had fetal growth retardation, a prevalence 10 times that in singletons. In almost all, the growth retardation was reversed by high-energy feedings. Although twins represented only 1% of all pregnancies and 2% of live births, they composed 12% of infants with early neonatal death and 17% of growth-retarded infants. A program is suggested for reduction of twin mortality and morbidity.


Nonvisualization of the gallbladder by 99mTc-HIDA cholescintigraphy as evidence of cholecystitis. Cholescintigraphy with N-substituted iminodiacetic acid (HIDA) labelled with technetium-99m is a new noninvasive technique for evaluation of the hepatobiliary system. The significance of nonvisualization of the gallbladder by this method in comparison with standard radiologic examinations was studied. In 43 healthy subjects the gallbladder was visualized by the two methods. By contrast, all 27 patients in whom the gallbladder was not visualized by cholescintigraphy had cholecystitis. When visualization failed to occur, a repeat cholescintigraphic study after an injection of cholecystokinin demonstrated the status of the cystic duct. Visualization excludes cystic duct obstruction and acute cholecystitis, whereas persistent nonvisualization indicates cystic duct obstruction.


Globus and headache: common symptoms of the irritable bowel syndrome. Persons with the irritable bowel syndrome (IBS) have a significantly higher prevalence of globus and migraine-like headache than age-matched control subjects. On the other hand, persons with organic disease of the esophagus or colon may have a reduced prevalence of functional symptoms involving the opposite end of the gastrointestinal tract. The dispersed pattern of symptoms in IBS suggests that some agent, such as a hormone, may be acting systemically.


Disseminated coccidioidomycosis: clinical, immunologic and therapeutic aspects. A patient with disseminated coccidioidomycosis initially had pulmonary and skin manifestations and survived for 14 years before dying of meningitis due to Coccidioides immitis. In addition to several courses of amphotericin B therapy the patient received injections of transfer factor derived from appropriate donors and miconazole nitrate therapy. The immunologic defence mechanisms of the patient during the course of his disease were studied and the possibility of a cell-mediated immunologic defect, potentially reversible by transfer factor, was demonstrated.


The Canadian general internist: education and future role. Available manpower data indicate that for the forseeable future there will be a continuing requirement in Canada for specialists in general internal medicine. While these specialists will be located predominantly in community hospitals, they will also be needed in university medical centres. The major roles of the general internist will be (a) to provide consultative service to primary care physicians and to other specialists, (b) to provide continuing care to patients with complex serious illness and (c) to participate in intensive care, particularly in community hospitals. Therefore training programs in this specialty must provide adequate experience in consultative medicine in both university and community hospitals, an opportunity to follow up patients with chronic serious illness over long periods, and experience in a variety of intensive care settings including surgical intensive care units. In some university departments the organization and supervision of training programs in this discipline have been carried out by a division of internal medicine that has equal status with other specialty divisions within the department. This seems to have been a salutory development.


Myotonia dystrophica: unusual features in a Labrador family. A large family with myotonia dystrophica has been recognized in an isolated area of Labrador. The complete family tree showed 29 of 108 members to be affected, including an infant with the congenital form of the disease. The propositus presented with epiphora and reduced frequency of blinking, with incomplete closure--features that have not previously been stressed. Ten of the younger affected persons had no lens opacities, although most had systemic muscle signs. Slit-lamp examination was therefore not a valuable method of early detection of the disease in the family. Many of the women affected by myotonia dystrophica had obstetric complications, particularly hydramnios, premature onset of labour, necessity for cesarean section, postpartum hemorrhage and neonatal death. Hydramnios was associated in each instances with perinatal death. The fetus in each case of hydramnios may have had the gene for myotonia dystrophica. Immunoglobulin A concentrations were reduced significantly in 27 affected persons in comparison with 77 unaffected family members. There were no such differences for the other immunoglobulin classes.


An improved rebreathing method for measuring mixed venous carbon dioxide tension and its clinical application. The mixed venous carbon dioxide tension (PVCO2) can be measured at the bedside by a rebreathing equilibrium technique that is quick, simple and noninvasive. Only one brief period of rebreathing is required. The technique is accurate even when the lungs are not normal, and gives a graphic record that allows verification of the accuracy of the estimate. The PVCO2 is affected mainly by changes in alveolar ventilation and cardiac output. It can be measured instead of the arterial carbon dioxide tension (PACO2) to follow changes in alveolar ventilation when the cardiac output is normal (PaCO2 = 0.8 PVCO2). When the cardiac output is abnormal, measurement of both PaCO2 and PvCO2 is useful in determining how much the cardiac output is reduced. Consideration of the relation between oxygen consumption and carbon dioxide production suggests that the equation PaCO2 = 0.8 PVCO2 - 12 indicates a reduction in cardiac output that may impair the oxygen supply to tissues. Simple corrections can be applied to allow for variations in arterial oxygen saturation and hemoglobin concentration that will affect this relationship.


Influence of age and previous use of diazepam dosage required for endoscopy. In 19 patients (10 men and 9 women) a 22-fold variation was observed in the intravenous dose of diazepam necessary as preparation for endoscopy (median dose, 20 mg; range, 5 to 110 mg). Analysis of plasma samples for diazepam and N-desmethyldiazepam revealed that the clinical response did not relate to the rate or character of initial drug distribution. There was a high correlation (r = 0.96) between the dose and the plasma concentration 10 minutes after administration. Users of diazepam displayed tolerance to its pharmacologic effects, requiring a significantly larger (P less than 0.05) dose than nonusers (median doses, 35.0 mg and 14.5 mg respectively). Older patients required less than younger patients (r = -0.54, P less than 0.05). The variation between individuals in the dose of diazepam required as preparation for endoscopy cannot be explained by variation in drug disposition but instead reflects previous diazepam use, age and probably differences in sensitivity at the site or sites of drug action.


Auger injuries in children.

Auger injuries in children. A 6-year review of auger injuries in Manitoba children revealed that 23 children sustained major injuries resulting in amputation of 17 limbs. Auger injuries are the main cause of traumatic amputation in children in Manitoba. Improved safety education for the entire farm family as well as better design of safety shields would decrease this carnage.


Dermatologic problems in amputees.

Dermatologic problems in amputees. Improvements in surgical techniques and prosthetic devices and the establishment of prosthetic clinics have altered the outlook for the amputee. A cooperative effect on the part of professionals looking after amputee patients, as carried out in these clinics, offers the best means of recognition and treatment of difficulties as they arise. Until the "bionic man" becomes a reality, amputees will continue to have skin problems. In describing a number of illustrative cases, we have attempted to: (a) renew interest in these problems; (b) demonstrate the value of the group approach; and (c) encourage the participation of interested dermatologists in the prosthetic clinic team to facilitate earlier recognition and treatment of troublesome skin disorders in the amputee.


Mitomycin-C and megestrol acetate in treatment of breast cancer refractory to hormonal and combination chemotherapy. Fifty patients with breast cancer refractory to endocrine manipulation and/or combination chemotherapy were treated with mitomycin-C 20 mg/m2 I.V. every 4-6 weeks and megestrol acetate 160 mg daily. Of 48 evaluable patients, 4% achieved complete remission (CR), 23% had partial remission (PR). Median duration of response for CR and PR was 7 months. Non-responders had a median survival of 2 months. The difference in survival of responders (both CR and PR) and non-responders was statistically significant at p less than 0.01 level. Attenuated doses of mitomycin-C were administered at increasing intervals due to cumulative myelosuppressive toxicity.


Combination chemotherapy of metastatic breast cancer with vincristine adriamycin and prednisolone. Fifty patients with metastatic breast cancer were treated with a combination of vincristine, Adriamycin and prednisolone (VAP) at four weekly intervals. Response rates of 78% for soft tissue disease, 66% for parenchymal lung disease, 67% for liver disease, and 64% for pleural effusions were seen. Only 26% of patients with bone metastases showed an objective response. These figures are as good as any previously reported for chemotherapy of breast cancer.


Effect of 5-fluorouracil on liver regeneration and metabolism after partial hepatectomy in the rat. The effects of 5-fluorouracil (5-FU) on regenerating liver were studied after two thirds hepatectomy in rats. In Group I, 68% hepatectomy was performed. In Group II, 5-FU in a dose of 20 mg/kg was administered intravenously immediately after, 24 and 48 hours after the same hepatectomy. In Group III, the same amount of 5-FU was given after sham-operation. The mortality rates were 4.5% in Group I, 28.0% in Group II, and 0% in Group III. The treatment with 5-FU following hepatectomy caused not only suppression but delay of liver cell division. Histologic changes such as cellular degeneration, liver steatosis and dilatation of the sinusoidal space were marked and prolonged in the hepatectomy-5-FU group. The metabolic abnormalities in albumin, cholesterol, triglycedides, and phospholipids were further more profound in Group II compared to those in Group I. In Group III, moderate derangements in albumin, triglycerides and phospholipids were observed. The results may indicate that adjuvant chemotherapy with 5-FU or similar drugs immediately after partial hepatectomy in hepatoma patients should be performed with great care if necessary. Otherwise, it should not be carried out until hepatic regneration is almost completed.


Pulmonary disease with chlorambucil therapy. A 73-year-old female developed pulmonary disease during treatment with chlorambucil for polycythemia vera. Cough and dyspnea were prominent symptoms. A chest roentgenogram revealed interstitial fibrosis. The diffusing capacity was markedly reduced. Pathologic findings included alveolar lining cell dysplasia, interstitial round cell infiltrates and interstitial fibrosis. Resolution of the pulmonary symptoms and partial clearing of the fibrosis on chest roentgenogram followed discontinuation of the chlorambucil and institution of steroid treatment. Chlorambucil may cause pulmonary fibrosis similar to busulfan and cyclophosphamide and this may be a potential complication of all alkylating agents.


Computed tomographic scanning in patients with lymphoma. Computed tomography (CT) of the chest and abdomen was performed in 40 patients with lymphoma and the results compared to conventional diagnostic techniques. Overall 34 (85%) of 40 CT scans correctly reflected the presence or absence of lymphoma. Close agreement between the findings of lymphography and CT was noted in 26 of 27 cases. CT has particular utility for assessment of lymphomatous involvement of mesenteric lymph nodes, high retroperitoneal lymph nodes, and extranodal abdominal sites other than the spleen or liver (e.g., pancreas, kidney). Abdominal CT is a useful noninvasive diagnostic technique for the initial staging and subsequent evaluation of selected patients with lymphoma.


Primary leptomeningeal melanoma: an ultrastructural study. A primary leptomeningeal melanoma in a 19-year-old white women has been shown by electron microscopy to contain light and dark cells. The light cells fill the subarachnoid space, contain mature melanosomes and exhibit intracytoplasmic fine fibrils. The dark cells are found within the collagen network of pia-arachnoid. They possess a small rim of ribosomal-rich cytoplasms, occasional premelanosomes and no intracytoplasmic fibrils. The tumor cells appear to arise from these dark activated melanoblasts in the pia-arachnoid and proliferate into more differentiated light cells. A similar pattern of two types of cells has not been described in primary CNS melanomas. The possibility of differentiation from cutaneous melanoma is discussed.


Triiodothyronine-secreting (toxic) adenoma of the thyroid gland: light and electron microscopic characteristics. A patient with thyrotoxicosis due to a triiodothyronine (T3)-secreting autonomous adenoma is described. The histmorphology of the neoplasms was similar to other neoplasms previously reported. Ultrastructural features of the adenoma are compatible with a very actively secreting follicular cell and are best compared with the ultrastructure of a diffuse toxic goiter. Distinctive features that separate toxic adenomas from various thyroid carcinomas and normal thyroid parenchyma are discussed.


Anaplastic seminoma of the testis: ultrastructural analysis of three cases. Three anaplastic seminomas of the testis were examined by transmission electron microscopy, and the ultrastructural features are described for comparison with those reported in other seminomas and related neoplasms. It is concluded that anaplastic seminomas are similar ultrastructurally to classic testicular seminomas, extragondal seminomas, and ovarian dysgerminomas, all of which are less differentiated than spermatocytic seminomas.


Ceruminous gland adenocarcinoma: a light and electron microscopic study. Tumors of ceruminous gland origin in the external auditory canal are rare in man. A case is described in which such a tumor presented as an invasive vascular temporal bone neoplasm, mimicking a glomus jugulare tumor. Light and electron microscopic study of this tumor confirmed a diagnosis of ceruminous gland adenocarcinoma. Tumors of ceruminous gland origin appear to have a distinctive clinical behavior by virtue of their unique anatomical location in the external auditory canal. Our experience with this case establishes another clinical picture characterizing the histologic type of ceruminoma designated as a ceruminous gland adenocarcinoma. We feel that the generic term "ceruminoma," with its implied histologic subgroups, is useful to the clinician when he encounters a tumor arising from the modified sweat glands of the external auditory canal.


Epithelioid granulomas associated with Hodgkin's disease: clinical correlations in 55 previously untreated patients. Non-caseating sarcoid-like epithelioid granulomas associated with Hodgkin's disease have been found in 55 patients initially staged and treated at the Stanford University School of Medicine. These patients are compared to 553 concurrent patients not having granulomas associated with their Hodgkin's disease. Pre-treatment parameters of the two groups are presented and found not to be different. Patterns of relapse in granuloma patients are presented and no relationship between location of granulomas and subsequent relapse is found. Survival and relapse-free survival curves are significantly different in favor of the granuloma group (p = 0.005 and p = 0.03, respectively). Correlation with skin test data has been attempted using a matched control analysis and no difference is found in reaction to intradermal antigens between the two groups.


Proximal tubulare dysfunction associated with Burkitt's lymphoma. Generalized aminoaciduria, uricosuria, glycosuria and phosphaturia were discovered in a patient with advanced Burkitt's lymphoma with renal infiltration. The literature is reviewed and three pathogenetic mechanisms are discussed. It is presumed that proximal tubular dysfunction in this case was related to the marked peritubular infiltrate causing cell mediated immunological injury or direct tubular destruction by tumor.


Congenital solitary fibromatosis of the skeleton: case report of a variant of congenital generalized fibromatosis. A study of a 3-month-old boy with a solitary form of congenital generalized fibromatosis of the skeleton is presented. Radiographic examination revealed a shortening of the right ulna and an osteolytic lesion in the distal metaphysis extending to the epiphysis. The histological appearance seems to be consistent with previously described cases of generalized congenital fibromatosis of soft tissues and skeleton. Ultrastructurally, the tumor cells resembled primitive fibroblasts. The lesion was curetted 3 times and filled with bone transplants before it finally healed. At follow-up of the boy at age 13, there were no signs of the tumor.


Biochemical markers in advanced testicular tumors: serum lactate dehydrogenase, urinary chorionic gonadotropin and total urinary estrogens. Twenty-seven patients with advanced testicular tumors were screened for serum lactate dehydrogenase (LDH) concentration, and 24-hour urinary excretion of human chorionic gonadotropin (hCG) and total estrogens. The investigation indicates an overall correlation between serum LDH concentration and cancer burden and an overall correlation between the maximum serum LDH and prognosis. It indicates an overall ocrrelation between the hCG determined within 2.5 months after the orchiectomy and prognosis. The relation between total estrogens and cancer burden or prognosis does not support the hypothesis that total urinary estrogens are a biochemical marker in testicular tumors.


The bone marrow examination in breast cancer: diagnostic considerations and clinical usefulness. Bone marrow examinations were performed on 116 women with primary and metastatic breast cancer and were correlated with the clinical status of the patient and other specific diagnostic modalities. The relative diagnostic efficacy of the marrow biopsy, aspirate smear and clot section was examined, as was the value of serial marrow examinations. A marrow positive for tumor was found in 40% of those with metastatic disease, 55% with positive x-rays, 56% with positive bone scans, but only 4% (1/24) with both scan and x-ray normal. Routine hematologic parameters were of limited usefulness in predicting the finding of a positive marrow. The biopsy was superior to the smear and clot section but aspirated material also had to be analyzed to maximize diagnostic yield. When analyzed qualitatively, i.e., positive or negative for tumor, serial marrow examinations were not useful in assessing the efficacy of antitumor treatment. The potential usefulness of bone marrow examination in patients with breast cancer is discussed.


Pulmonary resection for metastatic renal adenocarcinoma: pathologic findings and therapeutic value. Forty-four cases of metastatic renal adenocarcinoma to the lung were studied to assess the efficacy of surgical management and to review the histological criteria for diagnosis. Our data support the role of surgical resection in patients with unilateral pulmonary metastasis. Adverse prognostic features include radiographically multiple lesions and involvement of tracheobronchial lymph nodes. A better survival was associated with extensive tumor necrosis. In patients presenting initially with pulmonary metastases, nephrectomy is indicated only when the metastases are unilateral. The various histological patterns of the neoplasm, and features helpful in differential diagnosis are discussed. An intravenous pyelogram (IVP) is indicated for all patients presenting with clear cell tumors of the lung. In certain cases a renal arteriogram may be necessary to exclude the possibility of a renal primary.


Prospective evaluation of periodic breast examination programs: interval cases. A mathematical model is developed and used to obtain estimates of the expected proportion of breast cancer cases which will be detected at scheduled examinations and between them in various periodic examination programs; the latter are called interval cases. Another model is used to get estimates of the proportion of women in such programs who get cancer and are expected to have axillary node metastases at the time of first treatment. Programs with or without patient self-examinations are also evaluated. The purpose of both models is to enable evaluations of different periodic schedules. Although interval cases have been reported to have poorer prognostic characteristics than those found at scheduled examinations, calculations indicate that large reductions in these cases do no imply an equivalent reduction in positive axillary node cases. Thus, interval case counts are a relatively weak measure of the success of a periodic program. However, they may still be valuable since programs which can be expected to have low porportions of interval cases are less dependent on efficient patient self-examinations. Cost-benefit calculations show how the relative costs of mammographic and physical examinations can be considered in the development of mass screening programs. For example, if a mammographic examinations cost three times as much as a physical, then a physical examination program may be preferred to one involving both modalities.


Liver disease complicating the management of acute leukemia during remission. Eight adults who developed persisting liver function abnormalities during remission from acute leukemia (6 acute nonlymphoblastic leukemia and 2 acute lymphoblastic leukemia) are reported. These patients constituted 20% of the adults with acute leukemia attaining remission over the time period studied. Although we were unable to be absolutely certain of the etiology of the liver dysfunction, the following findings characterize the problem: 1) onset following red blood cell and platelet transfusions in all cases; 2) minimal symptoms and signs except for transient episodes of jaundice; 3) fluctuating, but often marked, increases in liver transaminases; 4) no other consistent laboratory abnormalities; 5) liver biopsies showing varying degrees of inflammation; 6) a consistent decrease in transaminase levels following pulse chemotherapy; 7) absence of progression of abnormalities during the observation period. This group of patients did not have a worse prognosis than patients with normal liver function. We feel that it is important to recognize this entity and to not withhold antileukemic therapy.


Reproductive history and risk of breast cancer: a case-control study in an unselected Swedish population. Variables in reproductive histories were studied in 179 consecutively detected, unselected breast cancer patients and age-matched controls selected from a computerized population register. The comparison between patients and controls showed no significant difference in age at meanarche, age at first birth, age at menopause or number of children. A subdivision into pre- and post-menopausal women yielded no further information. These results are at variance with most earlier reports, possible because the controls here were selected from the whole female population instead of hospitalized patients. Our data do not support the view that it is possible to define groups at high risk for breast cancer on the basis of productive histories.


Reserpine and breast cancer.

Reserpine and breast cancer. After a series of studies on the linkage of reserpine with breast cancer, both evidence and interpretation appeared to be in conflict. Our case-control survey of long-term, comprehensive records from the Kaiser Foundation Medical Care Program, on 108 hypertensive breast cancer cases and 324 hypertensive controls, matched by year of birth and by race, produces a significant positive association between reserpine use and breast cancer. However, the association vanishes upon further matching with respect to the year of the first hypertension diagnosis and the subsequent length of follow-up. We thus fail to support suspicions of causality.


Central nervous system involvement by ovarian carcinoma: a complication of prolonged survivial with metastatic disease. Six patients with epithelial ovarian cancer had clinical diagnoses of central nervous system (CNS) metastases during a four-year period. A thorough review of the literature shows that involvement of the CNS by ovarian cancer is a rare phenomenon. Four of the six patients developed parenchymal brain metastases whereas carcinomatous meningitis was detected in the other two. These patients were younger and survived longer from initial diagnosis than the majority of women with ovarian cancer. Five of the six patients had previously received chemotherapy and had developed metastatic spread to extraperitoneal sites. Following extensive surgical resection, chemotherapy may provide intraperitoneal and systemic control, thereby extending survival and permitting occult CNS metastases to become apparent.


Development of haematopoietic colonies on the macrophage layer formed in the peritoneal cavity of S1/S1d mice. The colony-forming ability of haematopoietic cells was examined on the macrophage layer formed in the peritoneal cavity of S1/S1d mice. The bone marrow cells of the congenic +/+ mice formed many macroscopic colonies on the macrophage layer of the S1/S1d mice although they did not form macroscopic colonies in the spleens of the same S1/S1d recipients. The size and the differentiation pattern of colonies on the macrophage layer of the S1/S1d mice were comparable to those of the colonies on the macrophage layer of the +/+ mice. There are two possible explanations for these results: (a) The microenvironmental defect of the S1/S1d mice has a more prominent effect on the development of spleen colonies than that of macrophage-layer colonies because 'Steel' locus may not be expressed significantly in the peritoneal macrophages or (b) because the cells that make colonies on the macrophage layer may be more differentiated cells than the multipotential stem cells that make colonies in the spleen.


Changes in stem cell compartments in mice after hydroxyurea. Hydroxyurea injection kills only approximately 10% of CFUs which are in the S phase of the cell cycle. In mice given a single injection of hydroxyurea CFUs in the femur decreased only about 50% in 2--4 days after hydroxyurea, and then started to return to normal levels with an overshoot evident after the eighth day after hydroxyurea. CFUs in spleens of mice given a single injection of hydroxyurea show an evident overshoot as early as 3 days after the drug, reaching levels which are about 300% of normal. CFUs from blood disappear rapidly, but equally rapidly return to normal values followed by a significant overshoot. The radioresistance of mice increased up to 4 days after hydroxyurea.


Differential radiation response amongst proliferating epithelial cells. Tissue irradiation results in both reproductive and histologically evident cell death. The correlation between these is poor. Irrespective of dose and fraction sterilized, many cells behave as if unirradiated (cell cycle and maturation activity). The fraction of histologically observable dead cells is usually less than 0.1, with most in the intestine being positioned in the presumptive stem cell region. The data strongly suggest different epithelial sub-populations with differing radioresponses. These may be the stem and differentiated proliferative cells.


Characteristic species dependent growth patterns of mammalian neoplasms. Evidence is presented, arising from an analysis of published data on tumour growth in three species of laboratory animals and in human multiple myeloma supporting a species specific relation between two supposedly independent parameters in the Gompertz equations frequently used to quantify tumour growth curves. This evidence supports the conjecture of Norton et al. (1976), based on their observations of the growth kinetics of a murine melanoma and a rat mammary carcinoma, that such a relation may be a general feature of tumour growth. Published data on the growth of xenografts of human colorectal tumours in immune-deprived  mice suggests that the observed growth relation reflects the ability of a particular species to support a tumour of a certain maximum size. The existence of this relation greatly simplifies the task of predicting complete patterns of undisturbed neoplastic growth in these species.


Analysis of the growth kinetics of a human lymphoma cell line. The growth kinetics of an established human lymphoma cell line were analyzed by a variety of techniques utilizing various cell inocula (5 X 10(4)--5 X 10(5) cells) dispensed into 60 mm diameter dishes. Techniques included pulse-labeled mitosis (PLM), continuous labeling with 3H-TdR, time-lapse photography (TLP), cell counts by electronic particle counter, and DNA histography obtained by pulse cytophotometry (PCP). There were no significant differences among values determined for any kinetic parameters as a function of cell concentration. The average doubling time of exponentially growing cells, regardless of cell inoculum, was 44.1 hr. The generation time determined by PLM was 31.1 hr with a SD of 4.7 hrs. Transit times for each stage were: TG1 = 10.6 hr, TS = 9.9 hr, TG2 = 9.9 hr, and TM = 0.7 hr. Repeated experiments using continuous labeling with 3H-TdR demonstrated a TG2 of 6.3 hr. The longer value determined by PLM is possibly due to the technical manipulations of this procedure which may delay pulse-labeled cells from resuming cell cycle transit. Hence, values for cell cycle stages were recalculated to give TG1 = 14.1 hr, TS = 9.9 hr, TG2 = 6.3 hr, and TM = 0.7 hr. These results were used to compute the size of each cell cycle stage compartment pool and corresponded very closely to values defined directly by PCP. TLP analysis considered only cells that produced colonies of at least thirty-two cells. Generation times ranged from 8 to 89 hr and showed a positive skewness. The average value measured for 330 divisions was 34.5 hr with a SD of 13.2 hr. Thus, the variance predicted by curve fitting of the PLM data did not correlate with that defined by time-lapse photography nor did it encompass the range in generation times observed directly by TLP. There was a positive correlation between sister-sister cell generation times (+0.66) but no relation was noted for mother-daughter values.


Analysis of growth of tetraploid nuclei in roots of Vicia faba. Growth of nuclei of a marked population of cells was determined from G1 to prophase in roots of Vicia faba. The cells were marked by inducing them to become tetraploid by treatment with 0.002% colchicine for 1 hr. Variation in nuclear volume is large; it is established in early G1 and maintained through interphase and into prophase. One consequence of this variation is that there is considerable overlap between volumes of nuclei of different ages in the cell cycle; nuclear volume, we suggest, cannot be used as an accurate indicator of the age of the cell in its growth cycle. Nuclei exhibit considerable variation in their growth rate through the cell cycle. Of the marked population of cells, about 65% had completed a cell cycle 14--15 hr after they were formed. These tetraploid nuclei have a cell cycle duration similar to that of fast cycling diploid cells of the same roots. Since they do complete a cell cycle, at least 65% of the nuclei studied must come from rapidly proliferating cells, showing that variability in nuclear volumes must be present in growing cells and cannot be attributed solely to the presence, in our samples, of non-cycling cells.


Development of the filiform hairs on the cerci of Gryllus bimaculatus deg. (saltatoria, gryllidae). The filiform hairs, mechanoreceptors of Gryllus, pass through six developmental stages during the last larval stage. The cytoplasm of their sense cells suggests intensive synthesis of protein for cellular metabolism and intercytoplasmic exchange of material via glial evaginations. Ultrahistochemical tests demonstrated acid phosphatase in the lysosomes as well as in components of the Golgi apparatus. There was no significant change in the appearance of the sense cell cytoplasm, indicating a maintained functional state also during molting. The new cuticular apparatus is formed after apolysis by the three enveloping cells. Formation of the replacement hairs is initiated by a cytoplasmic outgrowth of the trichogen cell. During morphogenesis of the new hair, the microtubules serve as a cytoskeleton and probably control the flow of vesicles, which contain phenol oxidase, also demonstrated in the Golgi apparatus, and are incorporated into the new cuticle. Bundles of microfibrils are involved in the surface sculpturing of the replacement hair. The trichogen cell also forms a number of structural elements, e.g. the "cup" and "strut" marked geometric peculiarities of which indicate that they are important in the spatial orientation of the dendrite and thus also in transduction. Reduction of the apical cell membrane of the tormogen cell after apolysis permits unrestricted growth of the new hair into the exuvial space. The tormogen cell participates in the formation of the joint membrane, parts of the socket and the articulation of the hair.


Scanning electron microscopy of the renal corpuscle of the mesonephros in the lamprey, Entosphenus japonicus Martens. The renal corpuscle of the lamprey mesonephros was studied under the scanning electron microscope. Bowman's capsules with individual spaces are chockshaped sacs closely packed together along a medial artery. The lateral walls of the capsules are apposed to those of neighbouring capsules. Glomerular capillaries from the medial artery extend radially between the apposed walls of neighbouring Bowman's capsules. Bulgings of capillaries into the capsular space are associated with mesangial folds of the capsular epithelium. The transitional zone of the visceral layer with podocytes and the parietal layer of squamous epithelium is bounded by linearly arranged rod-shaped epithelial cells. Apertures of the urinary tubule are lined by cells equipped with a fascicle of cilia.


Unusual mitochondrial ultrastructure in the pig adrenal cortex. Unusually large mitochondria with few cristae were observed in the cells of the boundary layer between the zonae fasciculata and reticularis of the pig adrenal. These mitochondria occasionally contained parallel arrays of beaded filaments which appeared to be composed of repetitive electron opaque particles, measuring 10 to 11 nm in diameter. The possibility that these filaments are arranged in closely packed arrays of tubular structures with a central filament is discussed.


Osteodentine and vascular osteodentine of Anarhichas lupus (L.). TEM, SEM and X-ray diffraction analysis demonstrate the heterogeneity of the dentinal tissue on Anarhichas lupus, a vascular osteodentine. The disordered aspect of collagen fibres, incompletely mineralized (the periodical striation being still visible), explains the scattered distribution of crystallites since they are responsible for their arrangement. The low degree of mineralization revealed by the visible collagen striation is confirmed by X-ray diffraction analysis (the crystallinity of vascular osteodentine being much lower than that of the peripheral dental tissue) as well as by high resolution TEM, since no lattice planes could be observed. Osteodentine, supporting bone and proper bone have in common a mineral phase, more or less organized, different from the apatite system.


Neural regulation of compensatory enlargement of the parotid gland of the rat. The role of the innervation in mediating compensatory enlargement of the parotid gland of the rat after partial desalivation was examined. The results of denervation experiments show that full compensatory growth requires both parasympathetic and sympathetic innervation. The presence of the parasympathetic innervation alone results in an increase in the number of cells, but not the size of the cells. The sympathetic innervation alone does not mediate either response. We, therefore, conclude that the two types of innervation have a synergistic action on the parotid to produce the maximal compensatory response, which includes an increase in both number and size of acinar cells.


Endocrine cells in the gut of the ascidian Styela clava. Ultrastructural studies have shown the presence of two types of granulated endocrine cell in the gut of Styela clava. Type I, which occurs in the stomach and intestine contains small irregular granules, each with a distinct halo. Type II, found only in the oesophagus contains larger rounded granules, often with little or no halo. The characteristics of these two cell types are compared with those of endocrine cells found in the digestive tracts of other protochordates and discussed with special reference to the evolution of gastrointestinal endocrine cells in vertebrates.


The differentiation of the decidua and the distribution of metrial gland cells in the pregnant mouse uterus. A study was made with the light microscope of the cellular changes involved in the formation of the decidua in the pregnant mouse uterus up to day 11 of pregnancy. The differentiation sequence was similar to that found by previous workers but the morphology and development of the basal zone is described in more detail. In addition, the morphology of glycogen rich cells in an area termed the lateral decidual zone is described. The distribution of granulated metrial gland cells and their precursors is described. These cells are first found in the uterine stroma before the blastocyst has implanted. Later they occur in the decidua and  in the circular smooth muscle zone beneath the mesometrial triangle prior to the formation of the metrial gland. Granulated metrial gland cells are also found in the maternal blood spaces of the implantation site.


Early effects of prolactin on lactating rabbit mammary gland. Ultrastructural changes and stimulation of casein secretion. Effects of prolactin on the secretion of milk proteins have been investigated by incubating mammary tissue fragments from lactating rabbits. Within 15 min of adding the hormone to the incubation medium, cell morphology is modified: the relative volume occupied by the Golgi region is greatly increased. When prolactin is added immediately after a pulse labelling of proteins (3 min with 3H-L-leucine), the amount of labelled caseins secreted during one hour is significantly increased. This increase proceeds neither from an acceleration of intracellular transit of caseins (as shown by electron microscopic autoradiography) nor by an enhancement of amino acid uptake (as measured by incorporation of non-metabolizable amino acids) nor by an increase of overall protein synthesis, during the first hour. The action of prolactin on the morphology of such subcellular organelles as the Golgi apparatus and its influence on casein secretion are discussed.


Further investigations on the structure and function of the saccus vasculosus of the rainbow trout, Salmo gairdneri Richardson. Ultrastructural cytochemistry of membrane-bound alkaline phosphatase. Alkaline phosphatase activity in coronet cells of the saccus vasculosus of the rainbow trout was localized ultracytochemically. Deposits of reaction product were found in varying amounts on the membranes of primary vesicles in the globules. This observation is discussed in relation to other morphological data and the possible resorptive function of the coronet cells in the homeostasis of the CSF.


The ultrastructure and renewal of the intestinal epithelium of the juvenile grasscarp, Ctenopharyngodon idella (Val.). The intestinal absorptive epithelium of starved and fed fish has been studied electron microscopically. After feeding, cells of the proximal segment of the intestine show morphological characteristics of lipid absorption. Absorptive cells in the middle segment contain many pinocytotic vesicles in both fasted and fed specimens. Absorption of protein macromolecules is supposed to be one of the main functions of this part of the gut. In the most caudal part of the intestine, absorptive cells carry relatively few and short microvilli. The proximal and distal segments show structural indications of a function in osmoregulation. The renewal of the epithelium has been studied with light microscopic autoradiography, using tritiated thymidine. The intestinal mucosal fold epithelium represents a cell renewal system. The cells proliferate at the base of the fold and migrate towards the apex in 10--15 days at 20 degrees C. The functional absorptive cells proved to be generally present in the intestinal epithelium, including the proliferative area. Undifferentiated cells have not been identified. The results will be compared with data on absorption of lipid and protein macromolecules in teleostean and mammalian intestines and with descriptions of the cell renewal system in the mammalian intestine.


Uptake of horseradish peroxidase from CSF into the choroid plexus of the rat, with special reference to transepithelial transport. Protein uptake from cerebral ventricles into the epithelium of the choroid plexus, and transport across the epithelium were studied ultrastructurally in rats. Horseradish peroxidase (HRP, MW 40,000) was used as protein tracer. Steady-state ventriculo-cisternal perfusion with subatmospheric pressure (-10cm of water) in the ventricular system was applied. HRP dissolved in artificial CSF was perfused from the lateral ventricles to cisterna magna for various times, and ventriculo-cisternal perfusion, vascular perfusion or immersion fixation with a formaldehyde-glutaraldehyde solution was performed. Coated micropinocytic vesicles containing HRP were seen both connected with the apical, lateral and basal epithelial surface and within the cells. Heavily HRP-labeled vesicles were often fused with the lining membrane of slightly labeled or unlabeled intercellular spaces. Since the apical tight junctions of the epithelium never appeared open or never contained HRP in the spaces between the fusion points, and since the intercellular spaces between adjacent epithelial cells below the junctions only infrequently contained tracer after 5 min, by increasing amounts after 15-60 min of HRP perfusion, a vesicular transport of HRP from the apical epithelial surface to the intercellular spaces, bypassing the tight junctions, is suggested. In addition to the transepithelial transport, micropinocytic vesicles also transported HRP to the lysosomal apparatus of the epithelial cells. With increasing length of exposure to HRP, a sequence of HRP-labeled structures could be evaluated, from slightly labeled apical vacuoles and multivesicular bodies to very heavily labeled dense bodies.