The lack of an effect of applied d.c. electric fields on peripheral nerve regeneration in the guinea pig. This study was undertaken to provide evidence of enhanced regeneration of mammalian peripheral nerves in response to applied d.c. electric fields. Peroneal nerves of adult guinea-pigs were crushed or transected and anastomosed. Constant current d.c. stimulators (20 microA) were implanted in the flank with platinum/iridium electrodes routed to the ankles. Animals with crush lesions were tested for toe spreading ability from the 14th to the 23rd day following the lesion. Animals with transection lesions were allowed to recover for 40 days and isometric force measurements of toe abduction and foot flexion were made. Both myelinated and unmyelinated fiber densities were determined. There proved to be no difference between legs treated with an anode, a cathode, or a sham electrode as evaluated by: the time to return of the toe spreading reflex, the isometric force of either twitches or tonic contractions, the latency between stimulation and contraction, or the number or density of either myelinated or unmyelinated fibers. These negative results are at variance with other studies that have reported beneficial effects of d.c. electric fields on peripheral nerve regeneration. The stimulation and analysis techniques used in this study were well within the variety of protocols that have yielded reports of highly significant positive effects with smaller numbers of animals than used in this study. The conclusion is that either there is a subtle but highly specific and critical difference between the present protocol and others, or the other studies need to be reevaluated. In either case, it seems that the ability of applied d.c. fields to enhance peripheral nerve regeneration in vivo remains open to question.


Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Accumulation of quinolinic acid and neuroactive kynurenines derived from tryptophan are of potential significance in human neuropathologic diseases because of their neurotoxic and convulsant properties. Clinical studies have established that sustained elevations of quinolinic acid, L-kynurenine and kynurenic acid within the cerebrospinal fluid occur in patients with a broad spectrum of inflammatory diseases and correlate with markers of immune activation and interferon-gamma activity. The present study describes an animal model that replicates these clinical observations and investigates the role of interferon-gamma as a mediator between immune activation and increased kynurenine pathway metabolism. Marked elevations in quinolinic acid, L-kynurenine and 3-hydroxykynurenine as well as an increased ratio of quinolinic acid: kynurenic acid in brain occurred 24 h after systemic pokeweed mitogen administration to C57BL6 mice. In plasma, L-tryptophan and kynurenic acid levels were reduced by pokeweed mitogen, while the concentrations of L-kynurenine, 3-hydroxykynurenine and quinolinic acid were increased. Interferon-gamma, pokeweed mitogen and lipopolysaccharide induced indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway, and increased both L-kynurenine and quinolinic acid concentrations of brain and systemic tissues, particularly in the lung, gastrointestinal tract and spleen. In contrast, hepatic tryptophan-2,3-dioxygenase activity was either reduced or unaffected. Increases in kynurenine pathway metabolism were sustained in mice given daily injections of interferon-gamma for seven days and subsequent responses to interferon-gamma were further enhanced. In contrast, daily administration of lipopolysaccharide was associated with subsequent attenuated responsiveness (tolerance) to lipopolysaccharide, pokeweed mitogen and interferon-gamma. Systemic administration of a monoclonal antibody to mouse interferon-gamma either attenuated or abolished the responses of kynurenine pathway metabolism to pokeweed mitogen and interferon-gamma. We conclude that acute and chronic increases in quinolinic acid and neuroactive kynurenines follow immune stimulation in mice, and result from indoleamine-2,3-dioxygenase induction. The results demonstrate that interferon-gamma is an important mediator between immune stimulation and indoleamine-2,3-dioxygenase induction. These increases in kynurenine pathway metabolism closely parallel the responses documented in patients with a broad spectrum of inflammatory diseases. Mice treated with immune stimuli are a useful model to investigate the relationships between immune activation and kynurenine pathway metabolism.


Ethanol uncouples dentate granule neurons by increasing junctional resistance: a multineuronal system model approach. The effects of an acute intoxicating concentration of ethanol (50 mM) on the electrotonic membrane properties of hippocampal dentate granule neurons were studied using a system model incorporating electrotonic coupling between neurons. Uncoupling of cells by other alcohols has been shown in several tissues. The system model allows a quantitative estimation of the changes in coupling and other neuronal electrotonic properties. The input impedance of a neuron was measured from the voltage decay of a short hyperpolarizing current pulse. An analytic expression of the input impedance has been written incorporating somatic, dendritic, and electrical coupling parameters. Using this particular current stimulation, the modelling results showed that ethanol selectively increased the junctional resistance by more than 2.5 times, hence uncoupling the neurons. A 30% increase in the final time-constant, tau 0, was also obtained from the voltage transient. Other parameters were not significantly affected. A neuronal model without electrotonic coupling to other neurons gave rise to physiologically impossible values for the membrane resistance and capacitance. With resistive and capacitive coupling in the model, uncoupling did not occur with ethanol. It is concluded that ethanol uncouples neurons by increasing the effective gap junctional resistance in dentate granule neurons.


Regulation of transient dopamine concentration gradients in the microenvironment surrounding nerve terminals in the rat striatum. Synaptic overflow of dopamine in the striatum has been investigated during electrical stimulation of the medial forebrain bundle in anesthetized rats. Dopamine has been detected with Nafion-coated, carbon-fiber electrodes used with fast-scan voltammetry. In accordance with previous results, dopamine synaptic overflow is a function of the stimulation frequency and the anatomical position of the carbon-fiber electrode. In some positions the concentration of dopamine is found to respond instantaneously to the stimulus when the time-delay for diffusion through the Nafion film is accounted for. In these locations the measured rates of change of dopamine are sufficiently rapid such that extracellular diffusion is not apparent. The rate of dopamine overflow can be described by a model in which each stimulus pulse causes instantaneous release, and cellular uptake decreases the concentration between stimulus pulses. Uptake is found to be described by a constant set of Michaelis-Menten kinetics at each location for concentrations of dopamine from 100 nM to 15 microM. The concentration of dopamine released per stimulus pulse is found to be greatest at low frequency (< or = 10 Hz) with stimulus trains, and with single-pulse stimulations in nomifensine-treated animals. The frequency dependence of release is not an effect of dopamine receptor activation; haloperidol (2.5 mg/kg) causes a uniform increase in release at all frequencies. The absence of diffusional effects in the measurement locations means that the constants determined with the electrode are those operant inside intact striatal tissue during stimulated overflow. These values are then extrapolated to the case where a single neuron fires alone. The extrapolation shows that while the transient concentration of dopamine may be high (200 nM) at the interface of the synapse and the extrasynaptic region, it is normally very low (< 6 nM) in the bulk of extracellular fluid.


Developmental regulation of phosphoprotein gene expression in the caudate-putamen of rat: an in situ hybridization study. The regional and cellular ontogeny of the mRNA encoding the dopamine- and cAMP-regulated phosphoprotein, DARPP-32, has been studied in rat striatum by quantitative in situ hybridization histochemistry. The mRNA for DARPP-32 exhibited a characteristic developmental profile. The hybridization signal was first visible on the day of birth, at which time DARPP-32 mRNA was concentrated in patches in the caudate-putamen. By the end of the first postnatal week, the majority of neurons in the caudate-putamen expressed the DARPP-32 message. Levels of mRNA per cell increased markedly during the second postnatal week, and peaked around the beginning of the third week. The adult level of DARPP-32 mRNA was lower than that observed at the apex of mRNA expression, on a per cell basis, while the proportion of neurons expressing detectable levels of message remained relatively constant. In the nucleus accumbens and olfactory tubercle, DARPP-32 mRNA development lagged somewhat behind that observed in the caudate-putamen, but was similar in other respects. A non-quantitative study employing an oligonucleotide probe complementary to the mRNA encoding another cAMP-regulated phosphoprotein, ARPP-21, revealed a similar developmental sequence to DARPP-32. The present results suggest that for DARPP-32 mRNA, genetic and, possibly, environmental factors play a role in determining the developmental patterns observed.


Voltage-dependent fast (20-40 Hz) oscillations in long-axoned neocortical neurons. Fast (20-80 Hz) oscillations of cortical activity, occurring during an increased level of focused alertness or elicited by optimal sensory stimuli, have been described by recording field potentials and neuronal firing in various cortical areas. Despite the increasing interest in this topic, little is known about the cellular mechanisms of the fast (generally termed 40-Hz) rhythm. An in vitro study demonstrated that, in sparsely spiny interneurons of frontal cortex, the 40-Hz rhythm is generated by a voltage-dependent persistent Na+ current, with the involvement of a delayed rectifier. Here we report depolarization-dependent 40-Hz oscillations in cat's motor and association neocortical neurons with identified projections to contralateral homotopic cortical area and thalamus. Our data indicate that this fast rhythm may be synchronized through intracortical and corticothalamic linkages.


Distribution of nicotinic receptors in cynomolgus monkey brain and ganglia: localization of alpha 3 subunit mRNA, alpha-bungarotoxin and nicotine binding sites. The distribution of nicotinic receptors in the brain and ganglia of the Cynomolgus monkey was studied by in situ hybridization and receptor autoradiography. A 35S-labeled antisense riboprobe for the mRNA of the alpha 3 subunit of the human nicotinic receptor, [3H]L-nicotine and [125]alpha-bungarotoxin were used as markers. The highest levels of alpha 3-mRNA were observed in the hippocampus, the medial habenula, the lateral geniculate, the granular layer of the cerebellum, as well as in the pineal gland; moderate levels were found in other nuclei of the thalamus and in the deeper layers of the cerebral cortex. High-affinity binding sites for [3H]L-nicotine were observed mainly in the thalamus. The distribution of [125I]alpha-bungarotoxin binding sites was different from that observed for alpha 3-mRNA and [3H]L-nicotine; they were most abundant in a few specific thalamic nuclei, in the medial habenula and in lamina I of the cerebral cortex. The localization of these three markers was also investigated in the sympathetic, parasympathetic and sensory ganglia of the monkey. Intense labeling was observed for alpha 3-mRNA and for [125I]alpha-bungarotoxin in the sympathetic and parasympathetic ganglia, whereas no positive signal was seen in the ganglion of Gasser. [3H]L-nicotine binding was not detected in any of the ganglia examined. High levels of mRNA for the alpha 3 subunit of the nicotinic receptor were also detected in human sympathetic ganglia. Comparison between alpha 3-mRNA distribution and [3H]L-nicotine binding suggests that in the Cynomolgus monkey brain, the alpha 3 subunit may participate in the formation of more than one nicotinic receptor subtype: a high-affinity binding site for [3H]L-nicotine in the thalamus, and other sites with low affinity for nicotine in the medial habenula and cerebral cortex. Both the alpha 3-mRNA and the [125I]alpha-bungarotoxin are highly expressed in the sympathetic ganglia; however, since no information is presently available on the intraneuronal cellular localization, it cannot be established whether or not they are both present at synaptic sites.


Differential regulation of alpha-calcitonin gene-related peptide and preprocholecystokinin messenger RNA expression in alpha-motoneurons: effects of testosterone and inactivity induced factors. alpha-Calcitonin gene-related peptide expression in alpha-motoneurons is regulated by spinal cord transection, axotomy and testosterone, but to date there are no studies which examine the regulation of cholecystokinin expression in motoneurons. In the present study, we compared the regulation of preprocholecystokinin and alpha-calcitonin gene-related peptide messenger RNA levels in motoneurons of the spinal nucleus of the bulbocavernosus. Previously, we demonstrated that manipulations which decrease activity in target muscles of the spinal nucleus of the bulbocavernosus motoneurons increase alpha-calcitonin gene-related peptide message and peptide levels in spinal nucleus of the bulbocavernosus motoneurons. This muscle-nerve interaction is mediated by a soluble factor which is increased by castration. We now report that decreasing plasma testosterone levels decreased preprocholecystokinin messenger RNA levels. Testosterone replacement at the time of castration restored preprocholecystokinin messenger RNA levels to intact values. Injections of crude extracts prepared from denervated bulbocavernosus/levator ani into the homologous muscles of gonadally intact rats increased the levels of alpha-calcitonin gene-related peptide messenger RNA in spinal nucleus of the bulbocavernosus motoneurons. The levels of preprocholecystokinin messenger RNA did not differ in rats injected with denervated bulbocavernosus/levator ani extract or buffer, both of which were significantly higher than in intact, untreated rats. The results of the present experiments imply that levels of preprocholecystokinin and alpha-calcitonin gene-related peptide messenger ribonucleic acid are differentially regulated in spinal nucleus of the bulbocavernosus motoneurons.


Voltage-dependent 40-Hz oscillations in rat reticular thalamic neurons in vivo. Extra- and intracellular recordings of thalamic reticular and relay neurons were performed in rats under urethane anaesthesia. Under this type of anaesthesia it was found that, throughout the whole reticular thalamic nucleus, a large proportion of cells (approximately 34%) discharged like clocks within a 25-60 Hz frequency band width (i.e. 40 Hz). Simultaneous recordings of pairs of reticular cells showed that the regular discharges of nearby units were not synchronous. Thus, the asynchronous 40-Hz firing of reticular thalamic cells was not correlated with any 40-Hz extracellular activity as revealed by the spectral analysis of the electroencephalogram and by recordings performed in various thalamic nuclei. In relay cells of the ventrobasal, ventral lateral and posterior thalamic nuclei, the regular firing of reticular thalamic neurons induced a rhythmic inhibitory modulation that was detected by the time-series analysis of the inhibitory postsynaptic potentials. In many relay cells, however, the disclosure of this inhibitory modulation required cellular depolarization since the resting potential in these cells was maintained at the reversal potential of the inhibitory events. Intracellular recordings of reticular thalamic cells showed that their regular firing was not driven in an all-or-nothing manner by 40-Hz synaptic inputs but rather that it depended upon the activation of a voltage-dependent pacemaker mechanism; this pacemaker activity was manifested by the presence of subthreshold oscillations that drove spike discharges and whose frequency was voltage dependent. In the context of data already published on the genesis of 40-Hz oscillations in the brain, and given the key position of reticular thalamic neurons in thalamocortical networks, the present results indicate that the reticular thalamic nucleus might play a pacemaker function in the genesis of 40-Hz oscillations in the thalamus and cortex during states of focused arousal.


Intrinsic and synaptically generated delta (1-4 Hz) rhythms in dorsal lateral geniculate neurons and their modulation by light-induced fast (30-70 Hz) events. Thalamocortical neurons of cat dorsal lateral geniculate nucleus were recorded under urethane anesthesia. Neurons were identified by antidromic invasion from the internal capsule and by orthodromic stimulation from the optic chiasm or light stimuli. An intrinsic oscillation within the frequency of sleep delta waves (1-4 Hz) was induced by hyperpolarizing current pulses triggering a rhythmic sequence of low-threshold spikes alternating with after hyperpolarizing potentials. The increased propensity to oscillation after blockage of inputs arising in the retina indicates that afferent synaptic drives interfere with the intrinsic oscillation of lateral geniculate cells. The relatively rare occurrence of this type of oscillation in impaled neurons, as compared with extracellular recordings in the same nucleus or to intracellular recordings in other dorsal thalamic nuclei, suggests that the interplay between the two intrinsic currents generating delta oscillation is particularly critical in lateral geniculate cells. Another type of delta oscillation was characterized by excitatory postsynaptic potentials which gave rise to action potentials or to low-threshold spikes at more depolarized or hyperpolarized levels, respectively. It is suggested that this rhythm reflects synaptic coupling by intranuclear recurrent axonal collaterals. Light stimulation induced fast (30-70 Hz) excitatory events that were blocked after lidocaine injections into the eye. In all tested cells, changes in the ambient luminosity of the experimental room blocked the intrinsic as well as the synaptic oscillation within the delta frequency. In some cells, this suppressing effect was associated with depolarization and increased firing rate. These results demonstrate different types of sleep delta oscillations in visual thalamic neurons and show that they are modulated not only by brainstem regulatory systems, but also by specific drives along the visual channel.


Delta frequency (1-4 Hz) oscillations of perigeniculate thalamic neurons and their modulation by light. Neurons in the perigeniculate sector of the reticular thalamic nuclear complex were recorded extra- and intracellularly under deep urethane anesthesia. They were identified by burst responses to optic chiasm stimulation and depolarizing spindle oscillations in response to internal capsule stimulation. Perigeniculate neurons displayed oscillations within the frequency range of electroencephalogram delta waves (1-4 Hz). One-third of extracellularly recorded neurons discharged rhythmic (2.5-4 Hz), high-frequency (150-200 Hz) spike bursts. This was similar to an intrinsic oscillation that was recently observed in dorsal lateral geniculate cells studied in vitro and in vivo. Other oscillating neurons displayed trains of single spikes (20-50 Hz) crowning rhythmic (2.5-4 Hz) depolarizing envelopes that were best expressed at the "resting" membrane potential (-60 to -65 mV). It is suggested that this oscillation reflects synaptic drives from dorsal lateral geniculate neurons. Changes in ambient room luminosity disrupted both types of delta rhythms. These data demonstrate for the first time that delta oscillations are present in the visual sector of the reticular thalamic nucleus. The results suggest that the two types of delta rhythmicity result from intrinsic and network properties of visual thalamic neurons and that perigeniculate cells may synchronize, through backward connections, the activity of dorsal lateral geniculate cells during deep stages of resting sleep.


An [Na+ + K+]coupled L-glutamate transporter purified from rat brain is located in glial cell processes. Polyclonal antibodies were generated against the major polypeptide (73,000 mol. wt) present in a highly purified preparation of the [Na+ + K+]coupled L-glutamate transporter from rat brain. These antibodies were able to selectively immunoprecipitate the 73,000 mol. wt polypeptide as well as most of the L-glutamate transport activity--as assayed upon reconstitution--from crude detergent extracts of rat brain membranes. The immunoreactivity in the various fractions obtained during the purification procedure [Danbolt et al. (1990) Biochemistry 29, 6734-6740] closely correlated with the L-glutamate transport activity. Immunoblotting of a crude sodium dodecyl sulphate brain extract, separated by two-dimensional isoelectric focusing-sodium dodecyl sulphate-polyacrylamide gel electrophoresis, showed that the antibodies recognized one 73,000 mol. wt protein species only. Deglycosylation of the protein gave a 10,000 reduction in molecular mass, but no reduction in immunoreactivity. These findings establish that the 73,000 mol. wt polypeptide represents the L-glutamate transporter or a subunit thereof. The antibodies also recognize a 73,000 mol. wt polypeptide and immunoprecipitate L-glutamate transport activity in extracts of brain plasma membranes from rabbit, pig, cow, cat and man. Using the antibodies, the immunocytochemical localization of the transporter was studied at the light and electron microscopic levels in rat central nervous system. In all regions examined (including cerebral cortex, caudatoputamen, corpus callosum, hippocampus, cerebellum, spinal cord) it was found to be located in glial cells rather than in neurons. In particular, fine astrocytic processes were strongly stained. Putative glutamatergic axon terminals appeared non-immunoreactive. The uptake of glutamate by such terminals (for which there is strong previous evidence) therefore may be due to a subtype of glutamate transporter different from the glial transporter demonstrated by us.


Immunohistochemical distribution of neurons containing the G-proteins Gq alpha/G11 alpha in the adult rat brain. A new class of G-proteins, the Gq family, has been recently identified and found to be involved in phospholipase C activation. The alpha subunits of the Gq and G11 members of this family are separate polypeptides but appear to have the same function. In this study, the cellular distribution in the adult rat brain of these G-proteins, Gq alpha/G11 alpha, was determined by immunohistochemistry using an antipeptide antiserum directed against the predicted C-terminal decapeptide which is conserved between these polypeptides. The specificity of the antiserum was verified by Western blot analysis using rat brain homogenates. Immunoreactivity was detected in neurons, where it was localized in the dendrites and at the periphery of the cell bodies. The staining was abundant in the dendrites of cerebellar Purkinje cells and hippocampal CA1 pyramidal cells. Staining was also found in neurons in the olfactory bulb, minor and major islets of Calleja, anterior olfactory nuclei and piriform cortex; the different cortical areas especially in their superficial layers; caudate-putamen, accumbens and olfactory tubercle; lateral septum and amygdala; hippocampal CA2-4 sectors of Ammon's horn, dentate gyrus and hilus; hypothalamic supraoptic nucleus; cerebellar granular layer; colliculi and superficial layers of the dorsal horn of the spinal cord. In conclusion, the brain neuronal localizations of Gq alpha/G11 alpha match that of phospholipase C, 1,4,5-triphosphate receptor and, to a lesser extent 1,4,5-triphosphate-3-kinase.


Localization of the tachykinin neurokinin B precursor peptide in rat brain by immunocytochemistry and in situ hybridization. Tachykinins exert a broad range of actions in the mammalian nervous system. While much is known about the localization of peptides derived from one of the two mammalian tachykinin genes (substance P- and neurokinin A-encoding preprotachykinin), little has been reported on the localization of peptides derived from a second tachykinin gene encoding neurokinin B. Using an antiserum raised against a 30-residue peptide fragment (Peptide 2) of the protein precursor to neurokinin B, we have mapped the distribution of Peptide 2 by immunocytochemistry. Peptide 2 antiserum specificity was determined by western blot analysis (which showed antibody cross-reactivity to a neurokinin B fusion protein from a cloned neurokinin B-encoding complementary DNA) and by the elimination of immunoreactive product in brain tissue sections upon preabsorption with a 10 microM concentration of Peptide 2 peptide. In addition, we report on the distribution of neurokinin B-messenger RNA with a full-length complementary RNA probe to localize cells that express the neurokinin B precursor. Peptide 2 immunoreactivity and neurokinin B-messenger RNA-positive cells were found, in some instances, paralleling the distribution of substance P and in other cases existing separately from substance P. Peptide 2 immunoreactivity as well as neurokinin B-messenger RNA-positive cells were found in the main olfactory bulb, cortex, olfactory tubercle, nucleus accumbens, hippocampus, bed nucleus of the stria terminalis, amygdala, medial habenula, periaqueductal gray, superior and inferior colliculus, and nucleus of the spinal trigeminal tract. Whereas substance P is found throughout the rat brain, neurokinin B appears to be partitioned more to forebrain than to brainstem structures. The marked differences in the distribution of both tachykinins in the rat central nervous system suggests that neurokinin B may play an important role in olfactory, gustatory, visceral, and neuroendocrine processing of information.


The prodynorphin system in the rat hippocampus is differentially influenced by kainic acid and pentetrazole. Administration of kainic acid (15 mg/kg, i.p.) or pentetrazole (75 mg/kg, i.p.) to rats evoked recurrent limbic or tonic-clonic seizures, respectively. Radioimmunoassay showed that the level of alpha-neoendorphin (prodynorphin-derived peptide) in the hippocampus was decreased after 3 h (by c. 60%) and 72 h (by c. 40%), but was not changed after 24 h following kainic acid administration. The basal release of alpha-neoendorphin from hippocampal slices of kainic acid-treated rats was decreased after 3, 24 and 72 h following the drug injection by c. 50%. The K(+)-stimulated release was decreased after 3 and 24 h (by c. 300 and 200%, respectively) and was back to the control level after 72 h. An in situ hybridization study showed that kainic acid strongly enhanced the prodynorphin messenger RNA levels in the dentate gyrus after 3 and 24 h (by c. 200%), whereas after 72 h it tended to decrease. Twenty four hours after pentetrazole injection the hippocampal level of alpha-neoendorphin was elevated (by c. 33%) and remained unchanged after 3 and 72 h. No significant changes in the basal or K(+)-stimulated alpha-neoendorphin release from hippocampal slices of pentetrazole-treated rats were found at any time points measured. Three and 24 h after pentetrazole administration the level of prodynorphin mRNA in the dentate gyrus was slightly decreased (by c. 30%), but was back to the control values after 72 h. Hence seizure-related changes in hippocampal prodynorphin neuron activity seem to depend on the experimental model of epilepsy.(ABSTRACT TRUNCATED AT 250 WORDS)


Expression of c-fos in regions of the basal limbic forebrain following intracerebroventricular corticotropin-releasing factor in unstressed or stressed male rats. Corticotropin-releasing factor has an integrative role on the behavioral, endocrine and autonomic responses to stress. Immediate-early gene (c-fos) expression was used to determine patterns of neural activity in the limbic system following i.c.v. infusion of corticotropin-releasing factor. Either 250 or 1000 pmol corticotropin-releasing factor infused into the lateral ventricle of precannulated and handled male rats resulted in marked c-fos expression 60 or 120 min later in localized regions of the basal forebrain, including the ventrolateral septum, the dorsal and medial parvicellular divisions of the paraventricular nucleus, the central nucleus of the amygdala, and dorsal bed nucleus of the stria terminalis. Pre-infusion of alpha-helical corticotropin-releasing factor (2500 pmol), a competitive corticotropin-releasing factor antagonist of corticotropin-releasing factor, had no effect on immediate-early gene expression alone but reduced that elicited by exogenous i.c.v. corticotropin-releasing factor (250 pmol)--in some areas to control levels. Fifteen minutes of restraint stress, a situation in which corticotropin-releasing factor is released endogenously, also activated c-fos expression in a pattern that resembled corticotropin-releasing factor infusions but was not identical. There was enhanced expression in the dorsal and medial areas of the paraventricular nucleus, but not its magnocellular region, and increased expression in the ventrolateral septum; however, there was no detectable response on the central amygdala. Preinfusion of alpha-helical corticotropin-releasing factor (2500 pmol) had no significant effect on stress-induced c-fos expression in the ventrolateral septum or paraventricular nucleus. This suggests that corticotropin-releasing factor release may form only a part of the central neurochemical response to restraint stress. Rats given i.c.v. corticotropin-releasing factor (250 pmol) before restraint stress showed additive effects on c-fos in the ventrolateral septum but not in the paraventricular nucleus; the central nucleus of the amygdala reacted as if corticotropin-releasing factor alone had been infused. Corticosterone levels were raised by both stress and corticotropin-releasing factor, but pretreatment with alpha-helical corticotropin-releasing factor reduced them after either procedure, which correlates with c-fos expression in the paraventricular nucleus and ventrolateral septum. These results show that corticotropin-releasing factor induces a specific pattern of c-fos expression in localized regions of the amygdala, hypothalamus and septum, which may indicate a corresponding pattern of neural activation. Restraint, one form of stress, activates c-fos in a similar but not identical manner, suggesting that corticotropin-releasing factor may not be the only neuropeptide involved in the response to this stressor.(ABSTRACT TRUNCATED AT 400 WORDS)


In vitro and in vivo modulation of 5-hydroxytryptamine-, thyrotropin-releasing hormone- and calcitonin-gene related peptide-like immunoreactivities in adult rat sensory neurons. In a previous work we have shown that culturing adult rat dorsal root ganglia neurons modifies their neurotransmitter phenotype in such a way that cultured neurons synthesize transmitters that are not found in situ, while several other transmitters are expressed in a much higher percentage of neurons in culture than in situ [Schoenen J. et al. (1989) J. Neurosci. Res. 22, 473-487]. The aim of the present study was to investigate the origin and the nature of the relevant environmental signals that allow this plasticity to be expressed, focusing on three neurotransmitters: 5-hydroxytryptamine, thyrotropin-releasing hormone and calcitonin-gene related peptide. The main results can be summarized as follows: (1) culturing cells in fetal calf serum or on feeder layers of astrocytes, Schwann cells or fibroblasts partially inhibits the serotoninergic phenotype of dorsal root ganglia neurons; (2) in vivo disconnection of dorsal root ganglia from their spinal targets but not from their peripheral or supraspinal targets induces a significant increase of the percentage of 5-hydroxytryptamine- and thyrotropin-releasing hormone-positive neurons in disconnected ganglia; (3) growth factors such as ciliary neuronotrophic factor or basic fibroblast growth factor but not nerve growth factor repress 5-hydroxytryptamine and calcitonin gene-related peptide immunoreactivity in cultured sensory neurons. In conclusion, neurotransmitter gene expression of adult dorsal root ganglia neurons is controlled by complex influences. Our data suggest that thyrotropin-releasing hormone and 5-hydroxytryptamine gene expression are tonically repressed in vivo by factors originating from the spinal segmental level and that growth factors such as ciliary neurotrophic factor or basic fibroblast growth factor could be potential vectors of this repressing effect.


Age-induced changes in electrophysiological responses of neostriatal neurons recorded in vitro. The present studies were undertaken to determine whether the major electrophysiological characteristics of neostriatal neurons are altered during aging. The passive and active membrane properties of 130 neostriatal neurons obtained from young (three to five months, N = 65) and aged (24-26 months, N = 65) Fischer 344 rats were compared using an in vitro slice preparation. The results indicated that in a population of aged neostriatal neurons the majority of the electrophysiological changes that occurred resulted in decreases in cellular excitability. These changes included increased threshold to induce action potentials by intracellular current injection and decreased negativity of membrane potentials at which such action potentials were induced. In addition, there were increases in the amplitude of the action potential afterhyperpolarization and increases in the frequency of occurrence of accommodation when trains of action potentials were induced. These two latter effects can limit the frequency of action potential generation. The thresholds to elicit synaptically evoked depolarizing responses and action potentials were increased. The results also indicated that a number of basic electrophysiological parameters were unchanged by the aging process. These included action potential amplitude, rise time and duration, resting membrane potential, input resistance and time constant. Although thresholds for the induction of synaptic and action potentials by extracellular stimulation were increased, the latency, amplitude and duration of the evoked depolarization remained unchanged. These findings suggest that the ability of neostriatal neurons to integrate spatiotemporal inputs must be severely compromised in this population of aged cells. Furthermore, the present findings, when compared with age-induced electrophysiological alterations in neurons in other brain areas, indicate that age may differentially alter electrophysiological properties of neurons in separate nuclei. Profiles of age-related changes in neurophysiological properties of neurons provide important information that can be related to the contributions of individual neural areas to the behavioral effects of aging.


GABA-immunoreactive basal forebrain afferents innervate GABA-immunoreactive non-pyramidal cells in the cerebral cortex of the lizard Podarcis hispanica. The basal forebrain projection to the cerebral cortex was studied in the lizard Podarcis hispanica by anterograde transport of Phaseolus vulgaris leucoagglutinin. After injections of the lectin into the septal-basal forebrain area, Phaseolus vulgaris leucoagglutinin-labelled fibres were mainly detected in the outer plexiform layer of the medial cortex and in the inner plexiform layer of the dorsal and dorsomedial cortices. Ultrathin sections from these areas were obtained and processed for postembedding immunogold staining for GABA. Most of the Phaseolus vulgaris leucoagglutinin-labelled boutons in the dorsal and dorsomedial cortical areas were GABA immunoreactive and all the double-labelled boutons established symmetric synaptic contacts on cell bodies and dendrites that were also found to be GABA immunoreactive in all cases. In contrast, Phaseolus vulgaris leucoagglutinin-labelled varicosities in the outer plexiform layer of the medial cortex made asymmetric synaptic contacts on GABA-immunonegative profiles and they were themselves negative for GABA. In double-labelled sections, GABA-, calbindin D28k- and neuropeptide Y-immunoreactive neurons were found to be innervated by multiple Phaseolus vulgaris leucoagglutinin-labelled varicosities in the dorsal and dorsomedial cortical areas, whereas in the medial cortex Phaseolus vulgaris leucoagglutinin-labelled fibres were not observed in contact with any subpopulation of GABAergic cells. The results demonstrate that in lizards the septal-basal forebrain projection to the cortex has a GABAergic component, which selectively terminates on GABAergic non-pyramidal cells including the neuropeptide Y- and the calbindin D28k-containing subpopulations. This synaptic organization is remarkably similar to that in mammals, and suggests that the mechanisms of control of the cortical activity by the basal forebrain have been highly preserved during phylogeny.


The effect of cortical lesion on systemic penicillin epilepsy in rats. There is a certain recovery of function following brain damage, due to neuronal plasticity. The experiments were performed in order to investigate the effects of cortical lesion on seizural activity in rats induced by systemic application of penicillin. The sensorimotor cortex was unilaterally removed in the lesioned animals, while the control animals were only sham operated or non-operated (before implantation of the electrodes). Seizural activity was recorded by means of electroencephalograms before and after penicillin treatment (1,000,000 I.U./kg, i.p). Testing of penicillin started at least 30 days after cortical lesion. Seizural activity was characterized by spike and wave complexes accompanied by vigilance reduction and sometimes by mild myoclonic jerks in both control and lesioned animals. The early period (about 2 h after penicillin administration) with appearance of the spike-wave discharges with relative increase of the mean total electroencephalogram powers as well as the succeeding period 2.5-5.5 h after penicillin administration) with maximum number of spike-wave discharges did not differ in the electroencephalogram of the control and lesioned animals. The late period of penicillin effect (from 6-11 h after penicillin administration) with frequent spike-wave discharges and still large mean total electroencephalogram powers was observed only in lesioned animals. It is concluded that a cortical lesion destabilizes the brain function in the rat model of epilepsy induced by parenteral administration of penicillin.


Dynamics of responses of V1 neurons evoked by stimulation of different zones of receptive field. The dynamics of receptive fields of 73 neurons in area 17 of cat visual cortex were studied using the temporal slice method. Three-dimensional maps of the receptive fields were plotted using the criterion of spike number in successive fragments (step 10 or 20 ms) of responses to 100 local flashes presented at different parts of the receptive field in random order. The size and configuration of such dynamically recorded receptive fields were then estimated. This allowed us to reveal the dynamic reorganization of all receptive fields 20-400 ms after stimulation. A small zone of responses appeared in the receptive field after initial latency, then it widened, received definitive configuration, and after that decreased and disappeared. The effect was reproducible under repeated estimations. The relationships between receptive field and the previously described orientation tuning dynamics, as well as between dynamics of receptive fields and their summation zones, mechanisms and possible functional meaning of the revealed effects for signal processing in the primary visual cortex are discussed.


Sensory stimulation induces local cerebral glycogenolysis: demonstration by autoradiography. Brain glycogen stores are localized primarily to glia and undergo continuous utilization and resynthesis. To study the function of glycogen under normal conditions in brain, we developed an autoradiographic method of demonstrating local-glycogen utilization in the awake rat. The method employs labeling of brain glycogen with 14C(3,4)glucose, in situ microwave fixation of brain metabolism, and anhydrous tissue preparation. With this technique, tactile stimulation of the rat face and vibrissae was found to accelerate the utilization of labeled glycogen in brain regions known to receive sensory input from face and vibrissae: the contralateral somatosensory cortex and the ipsilateral trigeminal, sensory and motor nuclei. These findings demonstrate a link between neuronal activity and local glycogen utilization in mammalian brain and suggest that, like other tissues, brain may respond to sudden increases in energy demand in part by rapid glycolytic metabolism of glycogen. As cerebral glycogen is restricted primarily to glia, these observations also support a close coupling of glial energy metabolism with neuronal activity.


Quantification of 5-hydroxytryptamine1A receptors in the cerebellum of normal and X-irradiated rats during postnatal development. 5-Hydroxytryptamine1A receptors were studied in rats during the first postnatal month in the normal cerebellum and in the granule cell-deprived cerebellum produced by X-irradiation at postnatal day 5. Quantitative autoradiographic studies on sagittal sections of cerebellar vermis, using [1251]BH-8-MeO-N-PAT as radioligand or specific anti-receptor antibodies, revealed that 5-hydroxytryptamine1A receptors existed in the molecular/Purkinje cell layer but at variable density from one lobule to another. Thus, in both normal and X-irradiated rats, the posterior lobules were more heavily labelled than the anterior ones, and the density of 5-hydroxytryptamine1A sites decreased progressively in all the cerebellar folia down to hardly detectable levels at postnatal day 21. However, the intensity of labelling remained higher at postnatal day 8 and postnatal day 12 in X-irradiated rats than in age-paired controls. Measurements of [3H]8-OH-DPAT specific binding to membranes from whole cerebellum confirmed that the density of 5-hydroxytryptamine1A sites per mg membrane protein (Bmax) was higher in X-irradiated animals than in age-paired controls. However, on a "per cerebellum" basis, no significant difference could be detected between the total number of 5-hydroxytryptamine1A sites, which progressively increased in both control and X-irradiated animals during the first postnatal month. These results therefore show that 5-hydroxytryptamine1A receptors are not located on developing granule cells. The progressive decrease in 5-hydroxytryptamine1A receptor density during the first postnatal month did not reflect a transient expression of 5-hydroxytryptamine1A receptors in the cerebellum of newborn rats, but resulted from the progressive "dilution" of these sites in this growing structure. The higher density of 5-hydroxytryptamine1A sites in X-irradiated rats simply reflected a lower "dilution" due to the delayed growth of the cerebellum in these animals.


Startle reflex habituation in functional psychoses: a controlled study. The habituation of the startle reflex in a paradigm using electrical stimulation was studied in 17 psychotic patients and 18 healthy controls. The magnitude of the R2 component of the blink reflex differed between the groups (ANOVA, F = 5.81; P = 0.022) and during the course of trials (F = 25.72; P < 0.0001). Furthermore a statistically significant interaction of diagnosis x trials (F = 3.34; P = 0.022) emerged suggesting that an impairment in habituation of startle is present in patients but not in healthy controls despite a comparable reactivity.


Walking of cats on a grid: performance of locomotor task in spinal intact and hemisected cats. We have investigated interlimb coordination during walking by observing locomotion of cats on a grid. Control cats made no error in forelimb placement on the grid, and landed their hindlimbs on the rung where each ipsilateral forelimb left moments earlier. This suggests that locomotor command signals were modified by grid information including its size and direction and affected the pattern generators of both forelimbs and hindlimbs. Hemisected cats, made both at high cervical and lower thoracic, showed deteriorated placement of the hindlimbs suggesting that interlimb coordination is carried out mainly by descending pathways from the brainstem such as ventrolateral fasciculus and dorsolateral fasciculus. Interlimb reflex pathways may play a limited role.


In vivo binding of [11C]Ro15-4513 in human brain measured with PET. Ro15-4513, an azide derivative of benzodiazepine antagonist flumazenil (Ro15-1788), and Ro15-1788 were labelled with carbon 11. Sequential PET scans following injection of [11C]Ro15-4513 or [11C]Ro15-1788 into normal male healthy volunteers were measured, and kinetic analysis using pons as a reference region was performed. [11C]Ro15-4513 was highly accumulated in frontal cortex, temporal cortex, hippocampus and relatively lower accumulation in occipital cortex, whereas almost homogeneous distribution of Ro15-1788 throughout cortex area was seen. The kinetic analysis revealed that such differences of regional distribution in brain between two labelled ligands were mainly due to the regional difference of the dissociation rate constants in vivo (k4). [11C]Ro15-4513 may be a useful tool for the in vivo study of benzodiazepine receptors in human brain.


An intrinsic mechanism to stabilize posture--joint-angle-dependent moment arms of the feline ankle muscles. The neuromuscular system can use sensory feedback to regulate motion, but these feedback loops involve relatively long delays (50-100 ms) and may produce undesirable oscillations. However, stabilizing changes in muscle force can also be provided intrinsically (i.e. without feedback) by 2 properties of the muscle itself, its force-length and force-velocity relationships. We have discovered another intrinsically stabilizing mechanism in the musculoskeletal architecture of the cat ankle joint. Many of its muscles have their predominant moment arms about the adduction/abduction axis, with smaller moment arms for inversion/eversion and about the principal axis of motion, dorsiflexion/extension. The magnitudes of the moment arms in ab/adduction and in/eversion depend strongly on joint angle, increasing for positions away from neutral that lengthen the muscles. Thus, co-activation of agonist-antagonist pairs, known to occur in these muscles, would provide immediate stabilizing changes in torque when the ankle is perturbed away from neutral position.


The effect of experimentally induced diabetes mellitus on the lipid order and composition of rat cerebral microvessels. To determine whether diabetes mellitus alters the lipid order and composition of cerebral microvessels, streptozotocin-induced diabetic rats were studied after 5 weeks of chronic hyperglycemia. Diabetes did not affect membrane order or the thermotropic transition temperature of cerebral microvessels as determined from the fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH). The cholesterol, phospholipid and fatty acid composition of isolated cerebral microvessels was also not significantly affected in diabetic rats. On the other hand, the cerebral microvessels of diabetic rats had significantly increased concentration of lipid peroxidation byproducts, namely conjugated dienes (the calculated O.D./mg phospholipids was 6.98 +/- 0.52 in controls and 11.82 +/- 0.40 in diabetic rats (P < 0.01). The accumulation of conjugated dienes in cerebral microvessels of diabetic rats in the absence of an alteration in the availability of substrates for peroxidation is consistent with the hypothesis that diabetes mellitus is a disease state which is associated with increased free radical activity. Increased oxidative damage may contribute to the changes in the blood-brain barrier observed in animal models of diabetes.


Comparison of the level of mRNA encoding m1 and m2 muscarinic receptors in brains of young and aged rats. We compared the concentration of mRNA encoding the m1 and m2 muscarinic receptors in several brain regions obtained from young (5-8 months) and aged (24-28 months) male Fischer 344 rats. DNA-excess solution hybridization was employed as a quantitative measure of mRNA concentration. The results indicate the absence of changes in the m1 receptor message with aging in the cerebral cortex, hippocampus and striatum. While there was no statistically significant aging-associated alteration in the concentration of the message encoding the m2 receptor in the thalamus, midbrain, cerebellum and brainstem, there was a decrease in the message level in the hypothalamus.


The microsomal calcium-ATPase inhibitor thapsigargin is a neurotoxin in perinatal rodent brain. Thapsigargin is a potent inhibitor of the microsomal calcium-ATPase. We hypothesized that thapsigargin-induced liberation of calcium from sequestered intracellular sites could result in irreversible brain injury. To assess neurotoxicity, intracerebral injections of 0.1-100 nmol thapsigargin were performed in 7-day-old rats, and the severity of injury was assessed 5 days later by microscopy and measurements of lesioned areas. We found that thapsigargin elicited dose-dependent tissue injury in perinatal rodent brain.


Acute starvation decreases acetylcholinesterase activity in different regions of rat brain. The activity of acetylcholinesterase (AChE) was assayed spectrophotometrically in four brain regions of rats that had been deprived of food for 96 h. A significant decrease in the total AChE activity (by 4-45%) as well as in its specific activity (by 14-28%) was observed in the supernatant and total particulate fractions from cerebral hemispheres, cerebellum, brainstem and diencephalon + basal ganglia. Similarly, blood glucose, body weight and protein content of subcellular fractions from most brain regions showed decreases after starvation.


Tau pathology in a case of familial Alzheimer's disease with a valine to glycine mutation at position 717 in the amyloid precursor protein. The brain tissue from a case of familial Alzheimer's disease (FAD) caused by a missense (valine to glycine) mutation at codon 717 of the amyloid precursor protein (APP) gene has been examined for the presence of abnormally phosphorylated paired helical filament tau (PHF-tau). There was abundant PHF-tau present, which on Western blots, was indistinguishable from the PHF-tau typical of cases of sporadic Alzheimer's disease and that of another FAD mutation (valine to isoleucine), previously (Neurosci. Lett., 137 (1992) 221-224). This result implies that the cytoskeletal pathology in Alzheimer's disease is biochemically linked to abnormal APP processing and amyloid deposition.


Centrally administered aminoglycoside antibiotics antagonize naloxone-precipitated withdrawal in mice acutely dependent on morphine. The effects of i.c.v. administration of several aminoglycoside antibiotics on naloxone-precipitated morphine withdrawal symptoms were evaluated in mice acutely dependent on morphine. Neomycin (10-40 micrograms/mouse), gentamicin (40-160 micrograms/mouse) and kanamycin (80-320 micrograms/mouse) produced a dose-dependent reduction of the number of precipitated jumps, forepaw tremors and head shakes. The order of potency of the aminoglycoside antibiotics on all withdrawal symptoms was neomycin > gentamicin > kanamycin, which is the same order that these drugs show as N-type calcium channel blockers. The capacity of several drugs that decrease neuronal calcium availability (such as lanthanum and L-type calcium channel blockers) to antagonize opiate withdrawal is well known. In the light of these findings, our results suggest that the mechanism of aminoglycoside-induced inhibition of morphine abstinence may be related to the capacity of these antibiotics to block N-type calcium channels, and to decrease neuronal calcium availability.


Tectal projection to an unusual nucleus in the diencephalon of a teleost fish, Pantodon buchholzi. Nucleus rostrolateralis, a newly identified nucleus, has been found to date in only three species of ray-finned fishes, two of which are osteoglossomorphs. It is relatively large and well developed in only one of the osteoglossomorphs, Pantodon buchholzi, in which it receives a relatively sparse, primarily contralateral, input from the retina. The present report describes a relatively intense, bilateral projection from the optic tectum to nucleus rostrolateralis.


Nicotinic acetylcholine receptors in human neuroblastoma (SH-SY5Y) cells. Whole-cell patch-clamp recordings were used to investigate nicotinic acetylcholine receptors (nAChRs) in the human neuroblastoma cell line, SH-SY5Y. Acetylcholine, nicotine and the neuronal nAChR agonist dimethylphenylpiperazinium iodide (DMPP), but not muscarine, all evoked inward currents in the cells (voltage-clamped at -60 mV). DMPP's actions were concentration- and voltage-dependent, and were antagonised by the neuronal nAChR antagonist mecamylamine (1-3 microM). Atropine was ineffective at 0.1 microM, but at 1 microM caused significant reductions in current amplitudes. Pre-incubation of cells with 2 microM alpha-cobratoxin had no effect on the actions of DMPP, and inward currents could also be induced when extracellular NaCl was replaced with CaCl2. DMPP also reversibly depolarized SH-SY5Y cells. These findings clearly identify nAChRs in SH-SY5Y cells, and provide two possible mechanisms by which receptor activation may lead to noradrenaline release, namely by triggering Ca2+ influx through the nAChR itself or by opening voltage-gated Ca2+ channels.


Effect of caerulein on expression of the immediate-early genes c-fos and zif/268 in the rat brain. The effect of caerulein, an analog of cholecystokinin-8, on expression of the immediate-early genes c-fos and zif/268 was studied in the rat brain using Northern blot analysis and an in situ hybridization technique. Intraperitoneal injection of caerulein did not change the basal c-fos and zif/268 expression. Administration of the convulsant, pentylenetetrazole (PTZ), caused a dramatic increase of c-fos and zif/268 mRNAs in the hippocampus and dentate gyrus. Pretreatment with caerulein suppressed the PTZ-induced c-fos and zif/268 expression. It is considered that systemically administrated caerulein modifies neuronal activities by exerting a suppressed effect on induction of the immediate-early genes.


Distribution of D5 dopamine receptor mRNA in rat brain. The distribution of the messenger RNA encoding the dopamine D5 receptor was determined in the rat brain by in situ hybridization. Using [35S]-labelled riboprobes to either the rat or human D5 receptor, this mRNA was localized to the hippocampus and the parafascicular nucleus of the thalamus. This mRNA could not be visualized in the more traditional brain regions associated with dopaminergic cell bodies or projection fields. This unusual distribution suggests a novel function in the brain for this subtype of the dopamine receptor.


Melatonin infusions restore sleep suppressed by continuous bright light in pigeons. Constant bright light (LL) suppresses 24-h melatonin and many other behavioral and physiological rhythms in pigeons. LL also strongly suppresses sleep. Daily melatonin infusions in LL restore sleep to normal nocturnal levels of a light-dark cycle and continuous infusions sustain it for at least 10 days. Restoration of sleep in LL by melatonin indicates its key role in avian sleep mechanisms.


Spinal commissural neurons mediating vestibular input to neck motoneurons in the cat upper cervical spinal cord. Spinal commissural neurons (CNs) activated di- or trisynaptically by stimulation of ipsilateral vestibular afferents were stained with intraaxonal injection of horseradish peroxidase in the cat upper cervical spinal cord. Stem axons of CNs in lamina VIII or VII, after crossing the midline, had ascending and/or descending main branches that gave off multiple axon collaterals to laminae IX and VIII over a few cervical segments. Terminal boutons appeared to make contact with proximal dendrites and somata of retrogradely-labelled neck motoneurons. Therefore, these CNs were regarded as mediating vestibular afferent input to contralateral neck motoneurons trisynaptically at the shortest.


Intermediate cells of Lugaro are present in the immature rat cerebellar cortex at an earlier stage than previously thought. The maturation of the intermediate cell of Lugaro, impregnated by classical silver methods, was studied on parasagittal sections of cerebellar vermis of newborn rat pups. Using morphological criteria characteristic of the adult cell type, immature Lugaro neurons can be recognized from the second part of the first postnatal week on. This implies that these cells differentiate at a much earlier age than previously inferred from studies using tritiated thymidine.


Quinolinic acid in culture media used for in vitro neurotoxicology studies. Serum from several species is frequently added to the incubation media of cells in vitro. The excitotoxin and N-methyl-D-aspartate receptor agonist quinolinic acid was found to be present in serum in concentrations ranging from 59 to 4895 nM. Some neuronal systems are reported to be particularly sensitive to the neurotoxic effects of quinolinic acid. Therefore, quinolinic acid in serum should be considered as a potentially confounding variable in neurotoxicology studies in vitro.


Recognition and management of alcohol-related nutritional deficiencies. Alcoholic beverages comprise an appreciable percentage of the total caloric intake of individuals in Western societies. Alcohol contains no usable nutrients and, in the chronic drinker, often replaces food. Chronic alcoholics frequently have evidence of nutritional deficiencies due to decreased intake, reduced uptake and impaired utilization of nutrients. Syndromes of nutritional deficiency seen in the alcoholic include anemias, neurological disorders, and vitamin and mineral deficiencies. Alcoholics represent the largest group of patients with treatable nutritional disorders in Western countries. Recognition and management of alcohol-related nutritional deficiencies may assist in the identification of high-risk individuals and may result in improved health status with reduced morbidity and mortality.


The diagnosis and treatment of cholera.

The diagnosis and treatment of cholera. Cholera is a diarrheal disease that results from colonization of the small intestine by the Vibrio cholerae organism. The disease is spread primarily by means of fecal contamination of drinking water and may begin with the sudden onset of profuse, watery diarrhea. Vomiting, rapid dehydration, acidosis, muscular cramps and circulatory collapse are other prominent features of severe cholera. Diagnosis is confirmed by identification of the organism in a stool specimen. Treatment requires immediate replacement of the massive fluid loss before diagnostic studies are ordered. Clinicians should suspect cholera in any case of massive, shock-producing diarrhea, especially if the patient has traveled to a cholera-affected country. This article presents epidemiology and public-health measures, pathophysiology, diagnosis, clinical signs and symptoms, and treatment modalities for adults and children infected with the V. cholerae organism.


Didanosine use in the adult HIV patient. There have been reports in the medical community of hesitation regarding the administration of didanosine to adult HIV patients because of the fear of the documented toxicities associated with didanosine. The most worrisome toxicities include pancreatitis and peripheral neuropathy. With close observation and follow-up, these toxicities can almost always be avoided or easily reversed. This article attempts to allay these fears so that the practitioner can administer this effective antiretroviral confidently and safely. The development of nucleoside and the pharmacology of didanosine are discussed. Drug administration information is provided, including a description of the different forms of didanosine currently available. Guidelines for assessing toxicities associated with didanosine, as well as suggestions for patient education, are also provided. Data gathered at the National Cancer Institute in the phase I didanosine trial indicate that early detection and discontinuation of didanosine, in nearly all cases, can limit or lessen the extent of morbidity.


Neuroanatomical localization for clinical SPECT perfusion brain imaging: a practical proportional grid method. For the purpose of facilitating anatomical localization in interpretation of 99Tcm-hexamethylpropyleneamine oxime (HMPAO) brain single photon emission tomographic (SPECT) scans, a stereotaxic proportional grid system was applied in the form of an interactive computer program. This method takes advantage of a rotating gamma camera system which permits planar scout imaging for the determination of anatomical reference lines, and standardization of tomographic slices for brain size. Using measurements made on a lateral planar HMPAO image, proportional grids were constructed onto standardized transaxial images. This method was implemented for 33 clinical HMPAO SPECT studies. It required less than 15 min of an operator's time. This simple and practical neuroanatomical localization technique can be instrumental as an aid to the interpretation of routine clinical HMPAO SPECT images.


99Tcm and 111In leucocyte scintigraphy in inflammatory bowel disease. A comparative study of 99Tcm-hexamethylpropyleneamine oxime (HMPAO) and 111In leucocyte scintigraphy was performed in inflammatory bowel disease. Two hundred and thirty-four patients were studied, 146 had 99Tcm-HMPAO, 82 had 111In and six had both. The sensitivity, specificity and accuracy of the 99Tcm leucocyte scan were 96, 97 and 97%, respectively, and 96, 97 and 97%, respectively, for the 111In leucocyte scan. 99Tcm-HMPAO leucocytes demonstrated similar diagnostic accuracy to 111In-labelled leucocytes with improved image quality and reduced radiation dose.


99Tcm-MIBI single photon emission tomography (SPET) for detecting myocardial ischaemia and necrosis in patients with significant coronary artery disease. The ability of 99Tcm-methoxyisobutylisonitrile (MIBI) single photon emission tomography (SPET) to detect myocardial ischaemia and necrosis was assessed in 56 patients (45 male, 11 female, aged 55 +/- 5 years), with clinically recognized ischaemic heart disease (IHD). All underwent coronary angiography (CA) and left ventriculography (LV). SPET images were obtained at rest and at peak exercise (Modified Bruce) 90 min after injection of 99Tcm-MIBI (650-850 MBq). Data were acquired in 30 min over 180 degrees (from 45 degrees RAO to 45 degrees LPO) with no correction for attenuation, using a 64 x 64 matrix. The presence of persistent (P) or reversible (R) perfusion defects (PD) was then correlated to the resting and exercise ECG and to the results of CA and LV. Of the 56 patients, 34 had reversible underperfusion (RPD), 46 persistent underperfusion (PPD) and 31 had both. The occurrence of RPD correlated well with the occurrence of exercise-induced ST segment depression and/or angina (27 patients of 34 patients, 79%) and with the presence of significant coronary artery disease (CAD) (33 of 44, 73%). In 45 of 46 patients (98%) PPD corresponded to akinetic or severely hypokinetic segments (LV) usually explored by ECG leads exhibiting diagnostic Q waves (42 of 46 patients, 91%). The scan was normal both at rest and after stress in four of 11 patients with no CAD, and in two of 45 patients with CAD. Finally, an abnormal resting scan was seen in seven of 11 patients with normal coronary arteries, of whom six had regional wall motion abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)


What does rCBF-SPECT offer in schizophrenia? Schizophrenia is a major psychiatric problem common in the younger population. Structural imaging and findings on autopsy have not yet revealed a specific deficit in these patients. Uncertainty in clinical diagnosis based on a set of signs and symptoms is another drawback in the management of this patient population. Regional cerebral blood flow studies (rCBF) using single photon emission computed tomography (SPECT) offers the opportunity to study the underlying phenomenon and to detect the specific functional deficits in schizophrenia.


Tumour detection and localization using 99Tcm-labelled OV-TL 3 Fab' in patients suspected of ovarian cancer. Fab' fragments of the monoclonal antibody OV-TL 3, that recognizes an ovarian carcinoma-associated antigen (OA3), were labelled with 99Tcm using D-glucarate as a ligand. Twenty patients suspected of having primary or recurrent ovarian cancer received intravenously 1 mg of the Fab' labelled with 740 MBq 99Tcm. Both planar and single photon emission computed tomographic (SPECT) scintigraphy were performed up to 30 h after intravenous infusion. In 19 out of 20 patients surgical and histopathological evaluation was performed between 2 and 6 days postinfusion. Imaging results were compared with X-ray computed tomography (CT), ultrasonography (US) and CA 125 serum level. Blood clearance was fast with median t1/2 beta of 9.5 h. Thirty-seven per cent of the injected dose (% ID) was excreted in the urine within the first 24 h, whereas 7% ID was excreted in the 24 h faeces. In one patient with an OA3 negative ovarian carcinoma, radioimmunoscintigraphy (RIS) did not visualize the tumour. In two other patients a benign ovarian cyst was found, also showing no elevated uptake. In 13 out of 17 patients ovarian cancer lesions were detected with RIS, whereas CT and US detected lesions in, respectively, 15 and 12 patients. Of 36 surgically defined tumour deposits larger than 1 cm in diameter, 53% were detected and localized with RIS, whereas CT and US detected 61 and 40%, respectively. Radioimmunoscintigraphy with 99Tcm-OV-TL 3 Fab' is less distressing for the patients but the overall imaging performance is not improved when compared with 111In-OV-TL 3 F(ab')2.


Is gall bladder ejection fraction a reliable predictor of acalculous gall bladder disease? The use of quantitative 99Tcm-EHIDA imaging with cholecystokinin and the measurement of gall bladder ejection fraction in a prospective study of 89 patients with right upper quadrant pain is described. Correlation with surgical and histological findings and clinical follow-up suggests that gall bladder ejection fraction < or = 35% is a reliable and accurate indicator of acalculous gall bladder disease.


Breast cancer survival in relation to sex and age. Crude and relative survival rates were analyzed using data from 4,199 incident breast cancers in females and 39 breast cancers in males registered between 1974 and 1988 in the Cancer Registry of the Swiss Canton of Vaud. The relative survival rates were 0.94 for females and 0.95 for males at 1 year, 0.87 and 0.95 at 2 years, 0.71 and 0.75 at 5 years, and 0.57 and 0.65 at 10 years. In relation to age at diagnosis, among females the relative survival increased from 0.62 for cases diagnosed under the age of 35 years to 0.78 at the age of 45-49 years, decreased to 0.66-0.68 in the age group 50-59 years, and rose again to reach 0.76 at the age of 65-69 years, declining thereafter to 0.69 at the age range 80-84 years. This pattern was already evident during the first 2 years of follow-up and persisted up to 10 years after diagnosis, although somewhat less defined. For males, no significant difference was evident in relative survival between breast cancers diagnosed before or at the age of 65 years and over, and only the 10-year survival rate was apparently (though not significantly) lower at older ages. Thus, these population-based data show remarkable similarities in survival for female and male breast cancer, despite possible heterogeneities in diagnosis and ascertainment of the disease as well as differences in steroid hormone levels in the two sexes and possible differences in biological characteristics of the disease. Further, they confirm that breast cancer survival varies across subsequent age groups. This possibly reflects selection and modifying effects on incidence and survival of hormone dependency of a proportion of breast cancers, the growth of which could be accelerated during the premenopause and the survival favourably influenced by the decline in steroid hormone levels after the menopause.


Mitomycin C + high-dose medroxyprogesterone versus cyclophosphamide+doxorubicin plus fluorouracil as first-line treatment for metastatic breast cancer. A pilot study was undertaken to compare mitomycin C plus oral high-dose medroxyprogesterone acetate (MMPA) to cyclophosphamide+doxorubicin+ fluorouracil (CAF). Thirty-four women were randomized at first relapse to receive MMPA or CAF. Patients were balanced with respect to age, performance status, hormone receptor status, prior adjuvant treatment, site of metastases, and number of metastatic sites. On MMPA 9/18 objective responses occurred and on CAF 12/18. Median time to treatment failure was 5.7 months on MMPA and 7.6 months on CAF; median survival on MMPA was 22.5 months and on CAF 16.7 months. Although there were more objective responses on CAF, this was not statistically significantly different, and CAF was associated with significantly more hemopoietic toxicity. It is concluded that mitomycin C should be further studied in front-line regimens for patients with metastatic breast cancer.


Variations in estrogen and progesterone receptor levels after short-term tamoxifen treatment in breast carcinoma. The modification of estrogen and progesterone receptor status was prospectively studied in mammary carcinoma after short-term (7 days) administration of tamoxifen citrate (30 mg/day). Seventeen patients fulfilled the stringent criteria required for final evaluation. Tamoxifen was administered to them immediately prior to surgery and receptor status was studied on the surgical specimen. Estrogen receptor levels were significantly (p < 0.05) decreased after treatment, whereas progesterone receptors remained statistically unaltered, although they showed a tendency towards significant increase (p = 0.12). Following these results, short-term tamoxifen treatment seems inadequate for the induction of significant levels of progesterone receptors in mammary carcinoma.


Latent coagulation disorders evaluated by the assay of plasma thrombin-antithrombin III complexes in a large series of 'solid tumours'. Coagulation disorders are frequently detected in patients affected by different tumours even though clinical symptoms occur in a very small percentage of such subjects. Coagulation processes are probably involved in the mechanism of metastatic spread. We assayed the plasma levels of thrombin-antithrombin III (TAT) complexes in a group of 276 patients with several tumours in different stages in order to achieve a better understanding of the complex interactions between coagulation disorders and either tumour growth or metastatic spread. High levels of TAT complexes were found in 51% of localized, 66.3% of metastatic and 58.3% of patients with no evidence of disease; a statistically significant difference was observed comparing metastatic cancer either with localized (p < 0.00015) or with free-of-disease (p < 0.004) groups. Gastrointestinal tract neoplasms showed higher levels of TAT complexes in the metastatic than in the localized group. No difference was seen between small-cell and non-small-cell lung-localized cancer. Our results confirm the frequent coexistence of cancer and subclinical blood coagulation disorders. The evidence of higher levels of TAT complexes in metastatic cancer than in the other groups could be related to the mechanisms involved in tumour spread.


Altered pattern of lipid metabolism in patients with lung cancer. Cholesterol distribution in tumoral tissues and lipid composition in the plasma compartment were determined in patients affected by different histologic types of lung cancer. The results showed that tumoral lung tissues contained 2-fold more total cholesterol and 3.5-fold more esterified cholesterol than normal lung tissues. In the patients the alterations in intracellular cholesterol were also associated with peculiar changes in cholesterol distribution in the plasma compartment. Serum high-density lipoprotein (HDL) cholesterol levels were markedly lower in than in controls. No significant changes in other lipid parameters were observed in these patients. We suggest that the reduced levels of serum HDL cholesterol observed in patients with lung tumors may be a consequence of the disease, probably mediated by the greater utilization of cholesterol for new membrane biogenesis and by the accumulation of esterified cholesterol in tumoral tissues.


Intraperitoneal cisplatin in the treatment of refractory or recurrent advanced ovarian carcinoma. Twenty-three patients with advanced ovarian cancer were entered into a phase II trial of intraperitoneal cisplatin (60 mg/m2 with escalation to 90 mg/m2 per course). All patients had either minimal residual disease after systemic chemotherapy or a recurrence after attainment of a clinically or surgically complete response. After a median follow-up of 3 years, 12 patients had died and of the 11 remaining alive 4 were without recurrence. Survival ranged between 4 and 48+ months with a median of 30 months. A definite survival advantage with this treatment modality does not appear evident and needs to be demonstrated by randomized studies.


The interaction of 5-fluorouracil, hydroxyurea, and radiation in two human head and neck cancer cell lines. We have investigated the effects of 5-fluorouracil (5-FU) and hydroxyurea (HU) with radiation on two human head and neck squamous carcinoma cell lines. SQ-20B has a D0 of 239 cGy and an S phase fraction of 37%, while SQ-38 has a D0 of 146 cGy and an S phase fraction of 31%. For SQ-20B the surviving fraction at 100 cGy was significantly reduced (p < 0.05) when cells were exposed to HU or to 5-FU or both chemotherapy agents together with radiation. No significant effect was seen for SQ-38 with either chemotherapy agent alone or in combination with radiation as compared with radiation alone. Therefore, additive cytotoxicity between 5-FU and HU and radiotherapy was observed only in a head and neck cancer cell line with a higher D0 and a higher S phase fraction.


Changes in the Ki-67 labeling rates of head and neck squamous cell carcinomas during preoperative radiation therapy. Immunostaining with Ki-67 monoclonal antibody was performed on frozen sections of biopsy specimens obtained before and during preoperative radiation therapy from 21 patients with head and neck squamous cell carcinoma. The Ki-67 labeling rates before radiation therapy and at radiation doses of 10 and 20 Gy ranged from 21 to 71% (mean: 35.0%), from 7 to 49% (mean: 25.8%) and from 1 to 44% (mean: 14.8%), respectively. One of the 2 patients whose tumors showing Ki-67 labeling rates of greater than 48% (mean +1 SD) before radiation therapy suffered local relapse shortly after the treatment. Moreover, tumors with rapidly decreased Ki-67 labeling rates (lower than 3%) at radiation doses of 20 Gy were related to poor clinical outcome: 4 out of 6 patients whose tumors showed Ki-67 labeling rates below 3% (mean -1 SD) at 20 Gy of irradiation had local relapses or showed distant metastases. These findings indicate that immunostaining with Ki-67 monoclonal antibody of biopsy specimens of head and neck squamous cell carcinoma, before and during radiation therapy, is very useful in assessing the clinical outcome of the patients.


Benign thyroid diseases and the risk of death from breast cancer. A survey of the causes of death among women with benign thyroid disease was conducted to assess the risk of breast cancer mortality in thyroid patients. The study population was all women diagnosed with one of several types of thyroid disease at the Massachusetts General Hospital Thyroid Clinic from 1925 to 1974. A population-based comparison group was matched to the Clinic patients for age and socioeconomic status, resulting in a total of 9,520 matched pairs. A search of the Massachusetts mortality records located death certificates for 10.9% (1,039) of the Thyroid Clinic patients and 10.5% (995) of the comparison women. Cancer was the cause of death in 21% (218) of the Thyroid Clinic patients and 24% (239) of the comparison women. Fewer patients than comparison women died from cancers of the digestive organs (30.2 vs. 45.5%), but more patients died from thyroid cancer (3.7 vs. 0%), lymphatic and hematopoietic cancers (11.5 vs. 4.2%), and cancers of other sites (8.3 vs. 3.8%). Breast cancer deaths accounted for 21.6% of cancer deaths in the patients and 22.2% of cancer deaths in the comparison women. When specific thyroid diagnoses were considered, the percent of all deaths due to breast cancer ranged from 1.9 to 5.6%, compared to 5.3% in the comparison women. Of the diagnostic groups studied, patients with Hashimoto's thyroiditis had the lowest percent of deaths due to breast cancer, while those with nontoxic nodular goiter had the highest.


Experience with intraperitoneal alpha-2a interferon. Eighteen patients affected with epithelial ovarian cancer have been treated by intraperitoneal alpha 2a-Interferon. The usual single dosage was 54 x 10(6) U at weekly intervals for four times (eight times in responders): 10 histologically confirmed complete remissions and 3 partial remissions have been obtained; the toxicity was represented by fever in the majority of the cases, by abdominal discomfort in some cases, and by a mild transitory neurological complication in 1 case. Seventeen of 18 patients were pretreated, and 11 of 18 had only cytologic and/or microscopic disease. alpha 2a-Interferon has proven to be very effective and moderately toxic in microscopic peritoneal disease of ovarian epithelial cancer previously treated with extensive surgery and intravenous cytotoxic chemotherapy.


Evaluation of an implantable venous access system in a general oncology population. Venous access has been a problem for the practicing oncologist. Previous approaches, such as arteriovenous fistulas, grafts, or percutaneous catheters, have not gained widespread acceptability. We report our experiences with 230 Port-a-Cath devices, a totally implantable venous access system. The catheters were placed in 218 general oncology patients for the administration of chemotherapy. One patient had three catheters placed and 10 patients had two catheters each. Most patients received standard bolus chemotherapy, while 25 patients were treated with continuous ambulatory infusions. The catheters were in place for an average of 271 days (range 2-1,427 days) for a total of 62,330 catheter days, representing the largest published experience with devices of this type in cancer patients. A total of 24 complications occurred in 22 patients. Catheter insertion was associated with four pneumothoraces, two of which required chest tube drainage. Five catheters were removed because of infection. There were 6 cases of venous thrombosis, but none resulted in pulmonary embolism. Other complications were manageable and included catheter occlusion, migration, and extravasation of chemotherapy agents. The Port-a-Cath is safe and is associated with a low rate of complications. Implantable venous access systems represent a significant advantage in the management of oncology patients with poor venous access.


Antiemetic efficacy of high-dose metoclopramide and dexamethasone in patients receiving cisplatin chemotherapy: a randomized trial. In a prospective randomized trial we compared the antiemetic efficacy of metoclopramide (MCP) and dexamethasone (DXM). A total of 172 patients receiving chemotherapy based on cisplatin 100 mg/m2/day were randomly allocated to four groups. CP was administered in 5 doses of 1.5 mg/kg (group A), 2 mg/kg (group C), or combined with 4 doses of DXM 4 mg/6 h (MCP: 1.5 mg/kg in group B; 2 mg/kg in group D). Vomiting was decreased in the DXM groups compared to groups A and C (p < 0.002), and the duration of nausea was greater in group A than in group D (P < 0.004). A greater disturbance in appetite was observed in group A compared to groups B (p < 0.028), D(p < 0.001) and C (p < 0.045). Activity problems were greater in group A than in C (p < 0.003) and D(p < 0.005). We noticed that a small increase in MCP (0.5 mg/kg) did not influence the antiemetic effect. The addition of DXM did not significantly alter the antiemetic results at the lower MCP dose, but improved them when MCP was slightly increased. We conclude that DXM slightly improves the antiemetic effect of MCP and the effects are related to the MCP dose.


Primary extranodal non-Hodgkin's lymphoma of the head and neck. Among 387 cases of non-Hodgkin's lymphoma (NHL) treated in our units between January 1977 and December 1990, 52 (13.4%) had primary extranodal (PE) NHL of the head and neck. The median age was 55 years with a M:F ratio of 1.9:1. The most frequent primary site was the tonsil (28 cases), followed by oral cavity, parotid gland, orbit and other sites. The aggressive histological subtypes predominate. 55.2% of the patients were in stage I and 44.8% in stage II of disease. The CR rate was high (94.2%). The 5 years' overall survival rate was 65% and it was influenced mainly by stage (stage I 82.5% vs. 48.7% in stage II). Sex, age and histology did not significantly affect survival rate. Patients with primary Waldeyer's ring involvement (WR group) did not differ significantly from the other primary sites analyzed as a group (non-WR group) in respect to median age, sex distribution, histology and CR rates. They differed, however, in: (1) stage distribution with stage II disease more frequent in the WR group; (2) overall survival and disease-free survival both of which were significantly better in the non-WR group; and (3) the high incidence of GI tract involvement as initial manifestation of relapse in the WR group. It is concluded that the behaviour of the Waldeyer's ring PE-NHL is rather distinctive and should be considered separately from the other PE-NHL of the head and neck.


Intracavitary oxytetracycline in malignant pericardial tamponade. We started a treatment trial for malignant pericardial tamponade with intracavitary oxytetracycline, 500-1,000 mg/day, administered via an indwelling pericardial cannula after extraction of as much pericardial fluid as possible. This procedure was repeated every 24 h for 6 consecutive days or until no more fluid could be drained. Eleven consecutive patients were entered in the study. The responses were obtained by clinical examination, chest roentgenogram and echocardiogram, prior to and after treatment. The primary cancer was located in the breast in 7 patients, in the stomach in 2 patients, and in the lung in 2 patients. In all cases, systemic chemotherapy or hormonal therapy was started after the pericardial tamponade was cured. The mean tetracycline dose per patient was 3,000 mg (range 1,500-6,000). All patients responded to the treatment with rapidly improving symptoms. Response persisted during a median of 9 months coinciding roughly with the median survival because all patients died because of progression of the neoplasm at sites other than the pericardium with no evidence of pericardial relapse. The main concomitant effects were mild local pain during tetracycline instillation in 4 patients, and transient fever (less than 39 degrees C) in 3. These data suggest that intracavitary oxytetracycline is perhaps less toxic and similar by successful as tetracycline hydrochloride in malignant pericardial tamponade.


Palm carotene inhibits tumor-promoting activity of bile acids and intestinal carcinogenesis. The effects of palm carotene on chemical carcinogenesis was studied. Palm carotene suppressed mouse epidermal ornithine decarboxylase activity induced by glycocholic acid. In a two-stage mouse epidermal carcinogenesis experiment using 7,12-dimethylbenz(a)anthracene as the initiator, glycocholic acid as the 1st stage promoter, and mezerein as the 2nd stage promoter, palm carotene inhibited the promoting activity of glycocholic acid. Furthermore, in N-ethyl-N'-nitro-N-nitrosoguanidine-induced mouse duodenal carcinogenesis, 0.05% of palm carotene given in drinking water decreased the percentage of tumor-bearing mice significantly.


A method for screening the quality of hospital care using administrative data: preliminary validation results. Applying a computerized algorithm to administrative data to help assess the quality of hospital care is intriguing. As Iezzoni and colleagues point out, there are major differences of opinion as to the worth of such efforts. This article significantly advances the state of the art in using administrative data to screen for potential quality-of-care problems. In addition, this work on identifying complications of care goes well beyond the emphasis of many government organizations on hospital mortality rates. One question, however, not raised in the paper is: What is a practical upper limit to the sensitivity and specificity in comparing computerized screen results with the consensus judgments of a group of independent physicians? Advanced statistical techniques (such as bootstrapping) might be used to estimate the stability of consensus judgments by physician groups. When the judgments of two groups of physicians are compared with each other, the resulting sensitivity and specificity will not be .99! In addition, more training of members of the physician panels would probably have increased interrater reliability. While acknowledging this problem, the researchers' detailed analysis of the panel results is intriguing and represents a model for such studies. It is hoped that the authors will follow up on the avenues opened here. Furthermore, what degree of accuracy is necessary to identify facilities with higher-than-expected rates of complications? The authors discuss problems involved in using administrative data to target hospitals and departments for more costly in-depth reviews of quality. It is hoped that the promising findings that are reported here will be validated in other studies. Certainly their algorithms should find a ready audience in insurers and hospitals willing to try them out. Finally, should we expect additional research to lead to improvement in the authors' algorithms? I believe the algorithms will prove difficult to improve upon; but perhaps we should not worry about this. At some point, however, the cost of trying to identify and correct quality problems in "minimally outlier" hospitals will exceed the benefits, particularly given alternative uses for the funds. Might we now be close the the "flat of the curve" in the development of such systems for identification of quality problems? This issue should be discussed much further in future studies.


Is QA antiquated, or was it at the right place at the wrong time? Much has been written about the strengths and weaknesses of quality assurance (QA) and continuous quality improvement (CQI) as approaches to achieving optimal quality and value in health care. In the past, the motivation behind QA was largely regulatory. Today, the driving force for CQI is corporate America, whose clout has key provider constituencies ready to cooperate as never before. This article argues that many of the functions of traditional QA will remain an integral component of quality management strategies for health care organizations and that the success of these efforts will depend on a coordinated effort by professionals from QA, quality management, and health services research. Furthermore, quality engineering concepts from other industries provide a useful framework to enable coordination among these three fields.


Managing transitions: assuring the adoption and impact of TQM. Assuring the full adoption and impact of total quality management (TQM) requires the understanding that TQM involves transitional challenges to managers, individuals, work groups, and the organization as a whole. This article presents some of these challenges and describes how they might be met over time to determine the ultimate success of TQM adoption in an organization.


Investigations on the mechanism of the salt-induced peptide formation. The applicability of the salt-induced peptide formation in aqueous solution--the simplest model so far for peptide synthesis under primitive earth conditions--is demonstrated for valine as another amino acid, and the formation of mixed peptides in systems containing glycine, alanine and valine is investigated. The dominant dipeptides formed are Gly-Gly, Gly-Ala and Gly-Val, at longer reaction times sequence inversion produces Ala-Gly and, considerably slower, Val-Gly. Ala-Ala is also produced and the relative amounts of the diastereomers prove the high conservation of optical purity of the original amino acids over a considerable time. The results lead to some further conclusions about the reaction mechanism and the possible dominance of peptide sequences in primordial dipeptides.


External fixation of unstable Malgaigne fractures: the comparative mechanical performance of a new configuration. An external fixator has been designed that is rigid enough to eliminate the need for skeletal traction in patients with unstable pelvic-ring fractures. This Wichita frame is similar to the Pittsburgh frame but is stiffened by the use of locked crossbars connecting the side triangles. The frame was tested in cadaveric specimens by techniques previously reported. In addition, finite-element modeling of the various frame designs was performed to ensure that the frame configuration was optimal and to supplement in vitro test results. Multiple variables that can influence frame failure loads were examined.


Internal versus external fixation of bicondylar tibial plateau fractures. Comminuted bicondylar tibial plateau fractures remain a difficult problem for the orthopaedic surgeon. Treatment has ranged from traction to cast immobilization to open reduction and internal fixation; none of these has emerged as ideal. Recently, one of the senior authors (DJC) used a technique of indirect reduction followed by application of a hybrid circular external fixator, noting a stability similar to that of an open reduction and internal fixation but with fewer complications. This paper reviews both the authors' experience and citations from the literature with regard to this problematic fracture.


Understanding the os odontoideum.

Understanding the os odontoideum. Five cases of os odontoideum and associated instability of C1-2 involving patients who underwent a posterior spinal fusion are reviewed, along with the literature. Four of the patients had Down's syndrome, and two of them were symptomatic at the time of presentation. In the two asymptomatic patients, the os odontoideum was an incidental finding on routine roentgenographic survey. The fifth patient presented with trauma and neck pain. The operation was successful in all of the patients with Down's syndrome but one, who had preoperative signs of myelopathy. Patients known to have an os odontoideum must be followed closely; if there is instability, posterior spinal fusion is recommended to avoid the risk of neurologic compromise. An understanding of the pathoanatomy of this condition is essential to recognize and properly treat these patients.


Repair of a glenoid fracture using a powered stapler. Scapular fractures account for only 1% of all fractures, and displaced intra-articular glenoid fractures are very rare. This report describes the operative treatment of a displaced intra-articular fracture of the glenoid in a 33-year-old man. The fracture was repaired by open reduction and internal fixation, using a pneumatically powered stapler for initial stabilization of the fracture fragment and anatomic reduction of the articular surface.


Tips of the trade. Computerized tomography--guided excision of osteoid osteoma. Excision of osteoid osteoma nidus utilizing a Kirschner wire for preoperative marking of the lesion and a CORB biopsy set for excision is described. The procedure is performed in a computed tomographic scan unit under local anesthesia and results in minimal postoperative discomfort.


A model to assess the risk of recurrences of superficial bladder carcinoma. A preliminary report based on 27 patients with a two-year follow-up. Being able to identify patients with superficial bladder carcinoma at high risk of tumour relapse would be helpful in reducing the high recurrence rate observed in these cases, because a more aggressive prophylactic treatment could be applied. We obtained a series of cystoscopic and histological findings from 27 patients with pTa and pT1 bladder carcinomas, of whom 19 recurred within 2 years following transurethral resection. Histological grade, shape and number of tumours were chosen as discriminating features between patients who relapsed and those who did not. These three variables were used to derive a discriminant function which classified correctly 23 out of the 27 patients on the basis of their actual situation of tumour relapse at 2 years. This method might therefore prove to be useful in predicting accurately the outcome of each patient, thus allowing us to follow an individualized protocol of surveillance and treatment based on a quantified risk for tumour recurrence.


[Validity of the AgNOR count in cervical pathology]. Nucleolar organizer regions (NORs) were counted on ten cases each of normal ectocervix, CIN 1, 2 and 3 to verify the possibility of a differentiation between the various grades of CIN and between them and condylomata. Counts were performed on the full thickness of the tissue, layer by layer (stratified counts). A significant difference (p < 0.05) was found between the means of normal tissue toward condylomata and CIN 2 and 3 and between CIN 1 and CIN 2 and 3. There was no significance (p < 0.05) between normal tissue and CIN 1, between CIN 2 and 3 and between condylomata and CIN 2 and 3. The range of variations on the counts was associated with overlapping between the various cases. Our data showed also a progressive rise in mean NOR values from normal tissue to CIN 3. The stratified counts showed in all the groups a rise from basal to parabasal cells. Counts on parabasal and intermediate layers distinguished two groups of cases. In one there was either the same number of dots or a further rise from one layer to the next, while in the other a definite decrease was seen. The former pattern may be related to a potential for malignant evolution of the lesion. NORs should be counted in all cases of CIN and condylomata to treat more aggressively those lesions which present the pattern of a progressive rise of NORs from basal to intermediate cells.


Autopsy and the internal medicine department. The accuracy of major clinical diagnoses and causes of death was estimated from the analysis of clinical diagnoses and autopsy findings of patients deceased at the internal medicine department of a large university hospital in two different periods (1965-1967 and 1985-1987). The autopsy cases from the second period were subdivided in two groups i.e. less and more than seven days of hospital stay prior death. From 100 randomly selected autopsy cases in each period there was no statistically significant variability in clinico-pathological concordance. In three groups studied (1965-1967, 1985-1987 < seven days and 1985-1987 < seven days hospital stay) the major clinical diagnosis was confirmed in 85, 94 and 86% respectively. A decrease of nearly 27% in the number of autopsies performed is shown between analysed periods. Clinico-pathological conferences are regularly held weekly, this being one of the reasons for a stable and extremely high clinico-pathological concordance.


[Measurement of breast cancer dimensions: correlation between mammographic and macroscopic data]. In this study the maximum diameters of 48 mammary carcinomas of various istotype detected preoperatively on mammography are compared with the diameters of neoplasms diagnosed by the anatomo pathologist on macroscopic examination of the excised part. Statistical analysis has shown that for every mammographic value it is possible to infer the corresponding real macroscopic value by adding or subtracting 0.45 cm.


[DNA index of colorectal carcinoma and follow-up]. In relation to DNA index we have studied 18 cases of differently evoluted carcinoma of the colon, some incoherently (8) other in agreement (10) with staging. Static and flow cytometric techniques have been employed, the first by means of densitometric study on paraffin sections with the Feulgen method, the second based on application of Hedley method on paraffin included material. DNA content, pressed by the DNA index, is inversely proportional to survival with similar results in both techniques, from which the possible prognostic significance is argued.


The application of AgNOR technique on glycol-methacrylate embedded human normal and pathological tissues. The Authors have applied the AgNOR technique to a series of normal and pathological human tissues fixed in neutral buffered formalin and methacarnoy and embedded in glycol-methacrylate. The results show the compatibility of the AgNOR technique with this embedding medium as well as the possibility to obtain an adequate visualization of the specific silver precipitates (AgNORs) on a unique focal plane without appreciable nuclear overlap, making thus the valuation of the AgNORs less subjective.


The experimental systemic perfused lung: histological observations in the dog. An experimental model of pulmonary hypertension was obtained in the dog implanting the left main pulmonary artery in the descending thoracic aorta. The main histological lesions consisted in an increased muscularity of the pulmonary artery itself and of its lobar branches.


Acute pulmonary edema after over-infusion of crystalloids versus plasma: histological observations in the rat. An experimental model of acute pulmonary edema was obtained in the rat, with over-infusion of normal saline and of plasma: histology demonstrated essential differences between edema from crystalloids, developed in the interstitial space, and that from colloids, affecting the alveoli.