Synaptic associations between oxytocin-containing magnocellular neurons and neurons containing corticotropin-releasing factor in the rat magnocellular paraventricular nucleus. In the paraventricular nucleus (PVN) of the rat hypothalamus, we determined synaptic associations between oxytocin (OXT)-containing magnocellular neurons and parvocellular neurons containing corticotropin-releasing factor (CRF) by using a double immunolabeling technique in 7 animals. In single vibratome sections of the hypothalamus, immunoreactive CRF and OXT were labeled with silver-gold particles and diaminobenzidine (DAB) chromogen, respectively. By light microscopy CRF-containing fibers appeared to be black dots, some of which encircled magnocellular perikarya labeled with brown DAB chromogen in the PVN. By electron microscopy we discriminated OXT neurons having fine DAB-chromogen particles distributed throughout the cytoplasm and on large secretory granules from CRF neurons having dense coarse particles of silver-gold. Occasional CRF axons terminated on perikarya or dendritic processes of OXT neurons, making synaptic contacts. The terminals which were characterized by having clusters of small clear vesicles and a few dense core vesicles showed equal thickenings of pre- and postsynaptic membranes at the synaptic junctions.


Temperature sensitivity of thin unmyelinated fibers in rat hippocampal cortex. The effect of changes in temperature on the activity of thin intracortical unmyelinated fibers was investigated in rat hippocampal slices. The amplitude of the presynaptic volley was increased by 40% when the temperature was raised from 23 degrees C to 30 degrees C, whereas the area of the presynaptic volley was reduced. Increasing the temperature above 30 degrees C was without further effect on the amplitude. The conduction velocity was 0.3 m.s-1 at 35 degrees C and 0.1 m.s-1 at 12 degrees C. The Q10 of velocity (25 degrees C-35 degrees C) was 1.6.


Terminal distribution of mossy fibers traversing the superior cerebellar peduncle in the mouse. The carbocyanine membrane probe DiI was applied to cut fibers of the superior cerebellar peduncle in the fixed brains of adult mice. Labeled mossy fibers in the cerebellar cortex formed rosettes only in the most superficial aspect of the granular layer, just beneath the Purkinje cell layer. These results provide evidence for a functional division of the cerebellar granular layer into horizontal laminae, in addition to the commonly recognized lobular and sagittal divisions of the cerebellar cortex.


Decrement of muscarinic receptor-stimulated low-KM GTPase in striatum and hippocampus from the aged rat. Previous studies have shown that there is an age-related loss of responsiveness in several different receptor systems (e.g. beta-adrenergic, dopaminergic and muscarinic). Our research, using perifused striatal slices and examining muscarinic agonist enhancement of K(+)-evoked dopamine release, has determined that at least part of the loss of sensitivity in muscarinic receptors (mAChR) may occur early in the post-receptor signal transduction process. The present study was carried out to further characterize and localize this deficit by examining carbachol- and oxotremorine-stimulated low-KM guanosine triphosphatase (GTPase) activity in striatal as well as hippocampal tissue obtained from adult (6 months) and old (24 months) Wistar rats. Receptor stimulated low-KM GTPase catalyzes the conversion of GTP to GDP to end the signal transduction cycle and is an indicator of receptor-G-protein coupling/uncoupling. The results showed that stimulated GTPase activity was significantly reduced in hippocampal and striatal tissue from the old animals. These findings suggest that there may be an age-related coupling/uncoupling deficit between muscarinic receptor and G-proteins, and that this deficit may contribute to the reduced mAChR responsiveness in senescence.


Neuropeptide Y-like immunoreactive neurons in the suprachiasmatic-subparaventricular region in the hedgehog-tenrec. The distribution of the neuropeptide Y (NPY) was studied in geniculate and peri-chiasmatic regions in the lesser hedgehog-tenrec, Echinops telfairi (Insectivora). Only few neurons demonstrated NPY-like immunoreactivity in the ventral lateral geniculate nucleus. In contrast, NPY-immunoreactive perikarya were clearly present in the suprachiasmatic nucleus (SCh) and dorsal and caudal to it. The latter region might correspond to the subparaventricular zone (SPV), recently identified in the rat as an additional area involved in processing circadian rhythms. While the distribution of a distinct cell population across nuclear boundries in both SCh and SPV might conform to the present idea of processing circadian rhythms, the presence of NPY-like immunoreactive neurons in these areas is rather unusual. In mammals, such neurons have only been demonstrated so far in the mentioned insectivore as well as in man.


Muscle lactate dehydrogenase activity is decreased in murine motor neuron disease. Lactic dehydrogenase (LDH) activity was examined in affected skeletal muscles of the wobbler mouse, a murine model in which denervation follows degeneration of spinal cord motoneurons. Average biceps brachii LDH activity was reduced at 7 and 15 but not at 3 postnatal weeks. These results demonstrate a progressive alteration in muscle energy metabolism in a natural model of motor neuron disease.


Effects of a non-peptide angiotensin receptor antagonist on drinking and blood pressure responses to centrally administered angiotensins in the rat. Both angiotensin II (ANG II) and angiotensin III (ANG III) administered centrally produce drinking and increases in blood pressure. The recent characterization of two subtypes for the ANG II receptor, the AT1 and AT2, raises the questions of whether drinking and pressor responses to ANG II can be separated pharmacologically and whether ANG III acts via the same receptor subtype. Therefore, the current study examined drinking and blood pressure responses to ANG II and ANG III administered centrally in adult male Sprague-Dawley rats in the presence or absence of a selective AT1 receptor antagonist. Blockade of the AT1 receptor abolished both drinking and pressor responses to ANG II and ANG III. However, drinking to the cholinergic agonist, carbachol, was unaffected. These results demonstrate that centrally administered ANG II and ANG III increase both water intake and blood pressure via the AT1 receptor subtype.


Networks formed by dorsal root ganglion neurites within spinal cord explants: a computer-aided analysis of HRP intracellularly labeled neurons. Dorsal root ganglion (DRG) neurons from rat embryos were explanted either alone or with the attached spinal cord (SC). Neuritic processes were mapped out histologically using an intracellular iontophoretic HRP method. Computer reconstructions and morphometric parameters allowed a comparative quantitative analysis of the DRG neurons and of their neuritic processes in both models. The first model, strongly dependent on nerve growth factor (NGF) for its survival, developed large multidirectional processes. The second model showed a bipolar distribution of its neuritic processes, the central one entering predominantly the dorsolateral part of the cord explant and ramifying both homo- and heterolaterally. The quantitative data revealed a significant decrease in the overall size of the neuritic networks of the second model (with attached SC). A discriminant analysis permitted the recognition of these two populations of DRG neurons. The role of the spinal cord explant, and more precisely the target cells of the dorsal horn, was considered to be a prominent factor in the development of the DRG neuritic networks.


Evidence for a common network of brain structures involved in parkinsonian tremor and voluntary repetitive movement. Repeated measurements of regional cerebral blood flow (rCBF) were obtained in 7 patients who underwent a stereotactic thalamic electrode implantation in the nucleus ventralis intermedius (nVIM) of the thalamus for severe hemi-parkinsonian tremor. Using positron emission tomography and oxygen-15 labelled water, rCBF was studied in each patient in two conditions: in absence of tremor, e.g. under nVIM electrical stimulation, and in presence of tremor. X-ray tomograms permitted individual definition of anatomical regions of interest. In presence of tremor, normalized rCBF increases were observed in the following regions: postcentral (13.6 +/- 8.4%, P = 0.0003), precentral (7.7 +/- 8.8%, P = 0.016), paracentral (7.7 +/- 8.4%), supplementary motor (8.2 +/- 10.4%, P = 0.025), caudate nucleus (5.7 +/- 7.6%, P = 0.03), vermis (9.7 +/- 7.3%, P = 0.007), cerebellar grey nuclei (9 +/- 6%, P = 0.016) on the electrode side and on the contralateral vermis (17.8 +/- 7.5%, P = 0.0003) and cerebellar grey nuclei (22 +/- 6.3%, P = 0.0004). These results clearly indicate an activation of the sensory-motor cortex, as well as an involvement of the supplementary motor area and the cortico-cerebellar pathways in Parkinsonian resting tremor (PRT). They demonstrate that PRT shares common network of brain structures with repetitive voluntary movement.


Uptake of 3-hydroxykynurenine measured in rat brain slices and in a neuronal cell line. The uptake of 3-hydroxykynurenine (3HK), a tryptophan metabolite with reported convulsant and cytotoxic properties, has been investigated in a neuronally derived hybrid cell line and in tissue slices prepared from rat brain. In both systems, the observed uptake was temperature-dependent and inhibited in the presence of large neutral amino acids. The apparent Km and Vmax determined for 3HK uptake into N18-RE-105 cells were 1.65 mM and 25.5 nmol/(min x mg protein), respectively. The uptake of 3HK into rat brain slices could be resolved into two components on the basis of their requirements for sodium. Kinetic analyses performed using hippocampal slices revealed a Km of 1.1 mM and Vmax of 18.8 nmol/(h x mg protein) for the sodium-independent process and a Km of 4.8 mM and Vmax of 54.5 nmol/(h x mg protein) for the sodium-dependent process. While sodium-dependent uptake was abolished following treatment with metabolic inhibitors, sodium-independent uptake was only slightly impaired. Sodium-independent uptake was inhibited in the presence of the non-metabolizable amino acids, aminoisobutyric acid (AIB) and aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH), but not by N-methylated amino acid substrates. Sodium-dependent uptake was insensitive to AIB and was completely abolished by BCH. These results indicate that an uptake process for 3HK is present in the mammalian brain, and suggest that the sodium-dependent component of 3HK transport may be mediated by a system which has not previously been described in CNS tissue.


Hippocampal laminar glucose utilization and theta rhythm following unilateral fimbria-fornix lesions in rats. Laminar profiles of glucose utilization were related to the presence or absence of movement-related hippocampal theta rhythm in CA1 and dentate gyrus of rats after aspirative unilateral combined lesions of the fimbria-fornix and cingulum. Three groups were studied: (1) sham-operated rats, (2a) lesioned rats with an ipsilateral loss of theta activity at 4 weeks post-lesion that persisted at 12 weeks post-lesion, and (2b) lesioned rats with a loss of theta activity at 4 weeks post-lesion, but a recovery of theta rhythm at 12 weeks post-lesion. Fimbria-fornix/cingulum lesions served both to abolish ipsilateral theta rhythm and to decrease ipsilateral glucose metabolism in all cell layers of CA1 and the dentate gyrus, when normalized to the contralateral hemisphere. Although glucose metabolism in lesioned animals with a recovery of theta rhythm was not as high as control levels, in several laminae it was significantly higher than that of lesioned animals with persistent loss of theta rhythm. These laminae included the dentate hilus and strata oriens, pyramidale and lacunosum-moleculare of CA1. The increased glucose metabolism associated with the return of theta rhythm suggests a functional reinnervation of these layers of the hippocampus in such animals.


Involvement of pertussis toxin sensitive G-proteins in conditioned fear-potentiated startle: possible involvement of the amygdala. The present study evaluated the effects of intraventricular or intracerebral administration of pertussis toxin on fear-potentiated startle (a measure of conditioned fear) and shock sensitization (a measure of unconditioned fear). In Experiment 1 all animals were unilaterally implanted with cannulae into the lateral ventricle 1 week prior to 2 days of fear conditioning (ten light-shock pairings on each of 2 days). Five days later, animals were infused with either 1 microgram pertussis toxin or saline and tested for fear-potentiated startle 24 h after infusion and tested for shock sensitization 26 or 50 h after infusion. Pertussis toxin blocked the ability of a light conditioned stimulus to facilitate startle but did not alter the ability of acute footshock to increase startle amplitude in the same animals. In Experiment 2 bilateral infusion of 1 microgram pertussis toxin into the basolateral nuclei of the amygdala, but not the interpositus nuclei of the cerebellum, also blocked fear-potentiated startle when animals were tested 6 h after infusion. These findings suggest a role for pertussis toxin sensitive G-proteins, perhaps within the amygdala, in the expression of conditioned but not unconditioned fear.


Immunohistochemical evidence that Met-enkephalin and GABA coexist in some neurones in rat dorsal horn. A pre-embedding immunohistochemical method to detect Met-enkephalin was combined with postembedding immunohistochemistry with GABA and glycine antisera, in order to determine whether or not Met-enkephalin coexisted with either of these inhibitory transmitters in neuronal cell bodies within the superficial dorsal horn of the rat. The distribution of immunostaining with the three antisera was similar to that which has been described previously. Of 74 enkephalin-immunoreactive neurones in laminae II and III, 51 were immunoreactive with the GABA antiserum and 23 were not. All of the neurones which were not GABA-immunoreactive were located in lamina II. None of the enkephalin-immunoreactive cells showed glycine-like immunoreactivity. These results suggest that enkephalin is present both in GABAergic neurones and in neurones which do not contain GABA within the rat superficial dorsal horn. It is likely that the population of neurones immunoreactive with both enkephalin and GABA antisera includes lamina II islet cells and that the population which were enkephalin-immunoreactive but not GABA-immunoreactive includes stalked cells. In addition, this latter group may correspond to those cells which possess both enkephalin- and substance P-like immunoreactivity and which have been described previously in this area.


Bombesin, neuromedin C and neuromedin B given intrathecally facilitate the tail flick reflex in the rat. Evidence from an earlier study suggested that bombesin, neuromedin C and neuromedin B may play a role in spinal nociceptive transmission; iontophoretic administration of these peptides onto dorsal horn neurones in the cat was found to preferentially depress those neurones activated by noxious stimulation. Therefore, to further examine the possible function of these peptides in the spinal cord, the present study compares the effects of intrathecal administration of bombesin, neuromedin C and neuromedin B on reaction time in the tail flick test in the rat. Intrathecal injection of bombesin and neuromedin C to the lower lumbar vertebral level produced a dose-dependent decrease in reaction time which lasted up to 46 min. Similar administration of neuromedin B had a biphasic effect; there was a dose-dependent decrease in reaction time lasting about 6 min followed by a delayed increase in reaction time to above control values at 31-46 min. In addition, administration of these peptides induced behavioral responses such as spontaneous vocalization and vocalization in response to innocuous touch. These results provide physiological evidence for a role of neuromedin C and neuromedin B in sensory transmission at the spinal level. In this model, bombesin was a potent agonist which may selectively activate the neuromedin C receptor.


Dorsal root potentials and afferent input to the spinal cord in rats with an experimental peripheral neuropathy. Compound action potentials (CAPs), dorsal root potentials (DRPs) and cord dorsum potentials evoked by stimulating the sciatic nerves have been measured in 4 control rats and in 19 rats with a constriction injury of one sciatic nerve produced by loose ligation of the nerve at mid-thigh level 5 days (n = 8) or 10 days (n = 11) before the acute experiments. The contralateral nerve was exposed but not ligated in a sham procedure. In all cases, the nerve was stimulated proximal to the lesion. At 5 days post-operative (PO) the maximal A-fibre CAPs on the nerve-injured side were not significantly different from those on the sham-operated side. At 10 days PO all animals showed a decrease in the CAP on the nerve-injured side. The mean CAP area on the nerve-injured side was 74.0% +/- 4.2 of the sham-operated side, which was significantly different (P less than 0.005). The sciatic nerves and L5 dorsal roots from 4 of the 10 day PO animals were examined histologically and showed no signs of demyelination or degeneration. The amplitude and area of the maximal DRPs were significantly smaller on the nerve-injured side than on the sham-operated side in all of the nerve-injured animals (P less than 0.01 at 5 days PO; P less than 0.05 at 10 days PO). The mean area of DRPs from the nerve-injured side was 61.7% +/- 10.1 and 46.8% +/- 7.5 of the DRPs from the sham-operated side in the 5 and 10 day PO animals, respectively. The DRPs evoked by sub-maximal afferent volleys were also measured. In all of the nerve-injured animals the CAP-DRP curve on the nerve-injured side was shifted to the right compared to that of the sham-operated side, such that a given size of CAP evoked a smaller DRP on the nerve-injured side than on the sham-operated side. We conclude that the constriction injury produces a decrease in the DRP generated by a volley in the injured nerve and that this change is independent of the decrease in the CAP seen in the injured nerve. We propose that the constriction injury affects the central mechanism responsible for generating primary afferent depolarization (PAD), and thus the pre-synaptic inhibitory control of the afferent input from the injured nerve is impaired.


Differential radioligand binding properties of [3H]5-hydroxytryptamine and [3H]mesulergine in a clonal 5-hydroxytryptamine1C cell line. [3H]5-Hydroxytryptamine ([3H]5-HT) and [3H]mesulergine were used to label 5-HT1C receptors expressed in NIH 3T3 mouse fibroblast cells. Using a rapid filtration assay, saturation analysis of the [3H]5-HT radioligand data indicate that the binding is biphasic. Based on computerized analysis of the data, a 2-site model of radioligand binding is significantly more consistent with the data than a one-site model (P less than 0.01). The KD values of [3H]5-HT for the 2 populations are 0.5 +/- 0.1 nM and 31 +/- 15 nM, while the Bmax values are 400 +/- 90 pmol/g protein and 3,000 +/- 600 pmol/g protein, respectively. A biphasic binding pattern is also observed with [3H]5-HT using a centrifugation assay (KD1 = 0.6 +/- 0.06 nM, KD2 = 60 +/- 10 nM; Bmax1 = 740 +/- 90 pmol/g, Bmax2 = 4,000 +/- 700 pmol/g). By contrast, saturation analysis of [3H]mesulergine binding is monophasic (KD = 4.7 +/- 0.7 nM) with a Bmax value (6,800 +/- 1,000 pmol/g protein) that is significantly greater than that obtained using [3H]5-HT (P less than 0.01). Drug competition studies confirm that both [3H]5-HT and [3H]mesulergine label at least 2 subpopulations of expressed 5-HT1C receptors in NIH 3T3 cells. 10(-4) M GTP eliminates the high affinity [3H]5-HT-labeled binding sites with minimal effect on the low affinity [3H]5-HT-labeled sites and no effect on [3H]mesulergine-labeled sites. These data demonstrate that at least 2 distinct subpopulations of 5-HT1C receptors in NIH 3T3 cells can be differentiated using radioligand binding techniques.


Synaptic inputs to medullary respiratory neurons from superior laryngeal afferents in the cat. Synaptic inputs from afferents in the superior laryngeal nerve (SLN) to medullary respiratory neurons (n = 154) in the dorsal respiratory group (DRG), ventral respiratory group (VRG) and the region of the Bötzinger complex (BOT) were studied in anesthetized cats. Single pulse stimulation of the SLN-evoked monosynaptic EPSPs in most inspiratory bulbospinal (I-BS) neurons in the DRG, and disynaptic or oligosynaptic chloride-dependent IPSPs in other I-BS neurons in the DRG and VRG. Stimulation of laryngeal afferents also inhibited oligosynaptically expiratory bulbospinal neurons in the VRG, and all types of respiratory neurons recorded in the BOT region. Oligosynaptic potentials (usually EPSPs) were recorded in inspiratory and expiratory laryngeal motoneurons. These results provide evidence of a processing of SLN-evoked synaptic responses by all tested groups of medullary respiratory neurons. The pathways mediating these synaptic responses are discussed.


Differential distribution of cellular forms of beta-amyloid precursor protein in murine glial cell cultures. The production and localization of cell-associated forms of beta-amyloid precursor protein (APP) of Alzheimer's disease was investigated in primary cultures of mouse glial cells. In both oligodendrocytes and astrocytes, immunofluorescence staining with an antibody against the carboxy terminus of APP revealed an intense cytoplasmic immunoreactivity. Immunoblotting of the cell extracts detected differences in the composition of APP between oligodendrocytes and astrocytes, notably the abundance of 107 kDa subtype in oligodendrocytes. Differences in immunoblot patterns were also noted between two buffer-insoluble, membrane-rich subcellular fractions of the glial cells, nuclear-mitochondrial and microsomal; the 119 kDa APP was enriched in the former, whereas the 73 and 115 kDa APPs in the latter. The results suggest that each APP subspecies may play a distinct functional role in different cell types and subcellular fractions.


Entrainment of the rat circadian clock controlling the pineal N-acetyltransferase rhythm depends on photoperiod. Entrainment of the circadian clock as a function of time when a light stimulus is presented has been studied in detail while little attention has been paid to a role photoperiod may play in the resetting. To find out whether and how photoperiod affects the entrainment, resetting of the rat circadian pacemaker by delays in the evening light offset and by advances in the morning light onset, respectively, was studied in rats maintained either under a short photoperiod, with 8 h of light and 16 h of darkness per day (LD 8:16) or under a long, LD 18:6 photoperiod. To assess phase shifts of the clock, the suprachiasmatic nucleus controlled rhythm in the pineal N-acetyltransferase (NAT), namely the time of the evening NAT rise and the time of the morning decline, were followed. One day after a delay in lights off, on LD 8:16 the NAT rhythm with a normal amplitude was retained following longer delays of the light offset and the maximum phase delay of the NAT rise was 3 times larger than on LD 18:6. One day after an advance in lights on, the NAT decline was phase advanced under both photoperiods; on LD 8:16 the maximum shift was 3 times as large as on LD 18:6. On LD 8:16, the NAT rise was not shifted after shorter advances in lights on and became phase delayed only when the light onset was brought forward to before midnight while on LD 18:6 the NAT rise was phase delayed after any, even a mere 1 h, advance in lights on. The data show that magnitude and direction of phase shifts of the NAT rhythm depend not only on the time of light presentation but on photoperiod as well. Difference in resetting of the rhythm under various photoperiods may reflect photoperiod-dependent changes of an underlying pacemaker.


Ethanol dependence and withdrawal selectively alter localized cerebral glucose utilization. The 2-deoxyglucose technique was used to determine local cerebral glucose utilization (LCGU) in over 50 brain regions of rats physically dependent upon ethanol and compared to those of acutely intoxicated and those undergoing an overt ethanol-withdrawal syndrome. Dependent-intoxicated rats (average blood ethanol concentration 64 mM) had decreased LCGU in 13/54 regions, including those associated with the limbic system, cerebellum, and motor system. The ethanol withdrawal syndrome was associated with 17/50 gray regions showing an increase, including regions involved with motor function, auditory system, and mammillary bodies-anterior thalamus-cingulate cortex pathway. The most pronounced differences between these groups occurred in regions associated with motor function, cerebellar function, anterior thalamus, and median raphe. Comparisons between dependent-intoxicated and acutely intoxicated rats (average blood ethanol concentration 66 mM) revealed that acute intoxication was associated with a relatively greater reduction in LCGU in regions involved with sensory-related functions, mammillary bodies, and median raphe. With the development of dependence, adaptation occurred in these regions except for inferior colliculus and median raphe. Dependence was also associated with a relative decrease in LCGU in white matter, limbic system, and extrapyramidal motor system.


An in vitro circadian rhythm of protein synthesis in the rat suprachiasmatic nucleus under tissue culture conditions. Because inhibitors of protein synthesis produce changes in the circadian rhythm of wheel-running activity in rodents, we examined the circadian changes of in vitro protein synthesis by the rat suprachiasmatic nucleus (SCN). We demonstrated a robust circadian rhythm of [14C]leucine incorporation as well as [3H]2-deoxyglucose (2DG) uptake by the SCN. The peak time of 2DG uptake was around circadian time 6-9 h (CT6-CT9). In contrast to 2DG uptake, the maximum rate of leucine incorporation occurred around CT22-CT0. Thus, the leucine incorporation rate preceded 2DG uptake by 6-9 h. Leucine incorporation was inhibited by protein synthesis inhibitors, but not by tetrodotoxin. Since a robust circadian rhythm of leucine incorporation by the SCN was detected in vitro by using our method, this procedure may be useful to study the circadian clock function of the SCN.


Microinjection of opioid antagonists into the substantia nigra reduces stress-induced eating in rats. Stress produced by pinching the tail has been shown to cause satiated animals to eat and to display oral stereotypies. Endogenous opioids and central dopamine systems have been implicated in the mediation of these effects. In order to test the possibility that the substantia nigra (SN) might be involved, the amount of food intake and gnawing produced by mild tail pinch were assessed following bilateral microinjections of opioid antagonists into the SN. Evaluations of nociceptive thresholds were also conducted using tail flick and hot plate tests. Eating induced by tail pinch was reduced by microinjections of the non-selective opioid antagonist naloxone (3, 10, 20 and 30 nmol) and by the mu-selective antagonist Cys2, Tyr3, Orn5, Pen7 Amide (CTOP) (1, 3 and 10 nmol). These effects on eating occurred in the absence of effects on gnawing. kappa- and delta-antagonists (10 nmol) had no effect on eating or gnawing. Naloxone did not alter either tail flick or hot-plate response latencies. The highest dose of CTOP increased response latency on the hot-plate test only. The results are interpreted as suggesting that the SN may be an important central site of action for opioid antagonists in reducing stress-induced eating. The possibility that the SN may be a central site mediating the effects of dopamine on this phenomenon is also discussed.


Microheterogeneity of dopamine transporters in rat striatum and nucleus accumbens. Previously we have shown that the [125I]DEEP-labeled dopamine transporter from the rat nucleus accumbens has a higher apparent molecular weight than that from striatum. The present study confirms and extends these observations. Experiments with nucleus accumbens showed [125I]-DEEP to specifically bind to a protein with an apparent molecular weight of 76 kDa and with the pharmacological properties of the dopamine transporter. In exoglycosidase studies, treatment with neuraminidase, but not alpha-mannosidase, reduced the apparent molecular weight of the dopamine transporter from both the striatum and nucleus accumbens; however, a difference in the apparent molecular weight was still observed. N-Glycanase treatment, on the other hand, did reduce the apparent molecular weight of the dopamine transporters from the two regions to a similar value, approximately 56 kDa. In radioligand binding studies examining the effect of partial deglycosylation on striatal dopamine transporters, neuraminidase did not affect specific [3H]WIN 35,428 binding at 4 and 40 nM concentrations. In conclusion, the present study demonstrates that the difference in the apparent molecular weight of the dopamine transporter from these two regions is due to a difference in glycosylation and that the dopamine transporter from both regions contains similar amounts of sialic acid in their carbohydrate structure. Furthermore, the present data also indicate that the polypeptide portion of the dopamine transporter from both regions could be the same gene product.


Serotonergic projections from the midbrain periaqueductal gray and nucleus raphe dorsalis to the nucleus parafascicularis of the thalamus. By a double-labeling method combining the retrograde tracing of horseradish peroxidase and the immunocytochemical technique, serotonin-like immunoreactive neurons in the midbrain periaqueductal gray (PAG) and nucleus raphe dorsalis (DR) of the rat were observed to send projection fibers to the nucleus parafascicularis of the thalamus bilaterally with an ipsilateral dominance. These serotonin-containing projecting neurons were observed mainly at the middle-caudal levels of the ventrolateral subdivision of the PAG and less at the middle-rostral levels of the DR.


Repeated corticosterone administration sensitizes the locomotor response to amphetamine. Repeated exposures to stressful situations has been shown to increase individual reactivity to psychostimulants, although the biological factors involved in such stress-induced changes are still poorly understood. In this study, we investigated the role of corticosterone in the effects of stress on the response to psychostimulants. We found that repeated corticosterone administration (both 1.5 mg/kg, intraperitoneally and 50 micrograms/ml in drinking water, once per day for 15 days) increased the locomotor response to amphetamine (1.15 mg/kg, i.p.). At the doses used in these experiments, corticosterone administration induced similar increases in plasma levels of the hormone to those induced by stress. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress increases the behavioral responses to amphetamine. Since an enhanced reactivity to psychostimulants has been found to be an index of a propensity for drug self-administration and a model of certain psychopathological conditions, these findings point to a role for glucocorticoids in such abnormal states.


Na(+)-activated K+ channels are widely distributed in rat CNS and in Xenopus oocytes. We recorded the activity of K+ channels activated by sodium (KNa channels) in two widely used preparations, primary cell cultures prepared from neocortex, cerebellum, midbrain, brainstem and spinal cord, and Xenopus oocytes. KNa channels from all regions shared an absolute dependence on [Na+], had conductances of 140-170 pS in symmetrical 150 mM K+ and exhibited characteristic substates. The role of this channel must now be considered in terms of its widespread distribution.


Citalopram's ability to increase the extracellular concentrations of serotonin in the dorsal raphe prevents the drug's effect in the frontal cortex. Administered intraperitoneally to rats at 1 mg/kg, citalopram, a potent and selective inhibitor of serotonin uptake, significantly increased dialysate serotonin in the dorsal raphe, but not in the frontal cortex. At 10 mg/kg citalopram had a greater effect on raphe serotonin and a moderate and short-lasting increase in the dialysate serotonin in the frontal cortex. Citalopram 1 mg/kg i.p. significantly increased the extracellular concentration of serotonin in the frontal cortex of rats which had received a continuous infusion of 1 microM methiothepine in the dorsal raphe, a condition which by itself did not change cortical serotonin concentrations. The results suggest that the ability of serotonin uptake inhibitors to enhance the extracellular concentrations of serotonin in the dorsal raphe attenuates the drug's effect in the frontal cortex.


Spinal and trigeminal lamina I input to the locus coeruleus anterogradely labeled with Phaseolus vulgaris leucoagglutinin (PHA-L) in the cat and the monkey. Terminal fibers anterogradely labeled with Phaseolus vulgaris leucoagglutinin (PHA-L) were observed in the locus coeruleus in the brainstem of the cat and the cynomolgus monkey following injections in lamina I of the spinal or medullary dorsal horn. Thus, thermoreceptive- or nociceptive-specific lamina I cells that project to the locus coeruleus could directly influence arousal, vigilance, and the descending control of spinal integration.


Excitatory amino acid antagonist administered via microdialysis attenuates lactate accumulation during cerebral ischemia and subsequent hippocampal damage. Our previous studies have shown that kynurenic acid (KYN), a broad-spectrum antagonist of excitatory amino acids (EAAs), administered in situ through a dialysis probe can delay the massive ionic fluxes in the rat hippocampus during cerebral ischemia. The present experiments demonstrated that the same procedure attenuates the increase in extracellular concentration of lactate ([lactate]e) during ischemia as measured by microdialysis. This finding suggests that the lactate accumulation is partially caused by a sudden increase in energy demand due to the rapid ionic fluxes through EAA-coupled ion channels. This inference is consistent with the hypothesis that the earlier ionic event during ischemia is a cause of energy depletion, rather than the result merely of energy failure. The present experiments also revealed that KYN administered by the same procedure attenuates death of hippocampal CA1 pyramidal cells after 5-min transient ischemia in gerbils. Since lactate accumulation is likely to be an important factor affecting cell viability, the protective effect of KYN may be attributable, in part, to inhibition of lactate accumulation.


Effect of amygdala kindling on the in vivo release of GABA and 5-HT in the dorsal raphe nucleus in freely moving rats. Our laboratory has previously reported a significant subsensitivity to iontophoretically applied GABA (gamma-aminobutyric acid) in dorsal raphe neurons of amygdala-kindled rats. This subsensitivity was selective for GABA and persisted at least 3 months after the last kindled seizure. In the present series of experiments, we explored mechanisms by which kindling could result in persistent GABA sensitivity changes, using in vivo microdialysis to quantitate neurotransmitter [including GABA and 5-hydroxytryptamine (5-HT)] release in the dorsal raphe nucleus of awake, unrestrained amygdala-kindled rats. Depolarization-induced release of GABA is markedly increased in the dorsal raphe nucleus in amygdala-kindled animals. This change in depolarization-induced GABA release appeared to be graded, dependent upon the stage to which the animal is kindled. Thus GABA release is increased in animals kindled to Stage 2 and even greater in animals kindled to Stage 5 seizures. The change in GABA release is also selective, since no consistent change in the release of other putative amino acid neurotransmitters or 5-HT was observed in these same animals. We hypothesize that this increase in depolarization-induced release of GABA in the amygdala-kindled animal underlies the development of subsensitivity to GABA in dorsal raphe neurons.


Effect of delayed treatment with nerve growth factor on choline acetyltransferase activity in the cortex of rats with lesions of the nucleus basalis magnocellularis: dose requirements. Rats received bilateral ibotenic acid-lesions of the nucleus basalis magnocellularis. Starting two weeks after the lesion, cytochrome c (0.3 micrograms/rat/day) or 0.01, 0.1, 1 or 10 micrograms/rat/day human recombinant nerve growth factor (NGF) was infused into the lateral ventricle. The highest dose of NGF reduced the weight gain of the animals. Six weeks, but not two weeks of treatment with 10 micrograms/rat/day NGF increased choline acetyltransferase (ChAT) activity in the frontal cortex, parietal cortex and hippocampus, predominantly on the side of the ventricular cannula. The 1 microgram/rat/day dose only increased ChAT activity in the frontal cortex on the infused side. Six weeks of treatment with 10 micrograms/rat/day NGF increased the size, but not the number of NGF-receptor-immunoreactive neurons in the nucleus basalis. This treatment did not affect the levels of dopamine, norepinephrine and serotonin in any of the brain regions studied. These data suggest that prolonged treatment with relatively high doses of NGF is necessary to increase ChAT activity in cortical regions of nucleus basalis-lesioned rats. This treatment will also increase ChAT activity in the intact septohippocampal system, but does not affect the levels of several non-cholinergic neurotransmitters.


Analgesic effects of intraventricular and intrathecal injection of morphine and ketocyclazocine in the infant rat. Little is known of the neural bases of analgesia in immature animals. This experiment examined the effects of intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration of morphine or ketocyclazocine in tests of antinociception in rats aged 3 to 14 days of age. Analgesia tests were conducted using both thermal and mechanical (pressure) noxious stimuli applied to the forepaw, hindpaw or tail. In the 3-day-old morphine-injected i.c.v. produced analgesia in the forepaws when either the mechanical or thermal noxious stimulus was used. There was no effect when the hindpaw or tail was tested. At 10 days of age, when the mechanical stimulus was used, morphine was analgesic in tests on all three appendages but was only effective in the forepaw when the thermal stimulus was used. Morphine was fully effective in all tests with both stimuli at 14 days of age. Ketocyclazocine had no consistent effect when given i.c.v. When injected i.t., morphine produced analgesia in the forepaws in the thermal test at 4 days of age and in all appendages by 10 days. When the mechanical test was used, morphine was effective in all appendages at all ages tested. Ketocyclazocine was analgesic at all appendages for the mechanical stimulus at all ages but was only transiently effective in the thermal test. The results demonstrate differential development of analgesia mediated at different levels of the neural axis and are consistent with the development of descending inhibitory that may mediate analgesia induced by i.c.v. injections of morphine. Neural mechanisms that are involved in the analgesic effects of these drugs against the two types of stimuli are also developmentally distinct.


[High frequency jet ventilation in heated gas saturated in water vapor without a reserve of medical gas under pressure. An original method]. A prototype of high frequency jet ventilator is compared with a classic device: Gambro Soxijet ventilator. The advantages of the prototype are: no need of pressured medical gas; warming and saturated moisture of the gas. A powerful compressor (2 M3.H-1 flow--3 bar pressure) draws up the moistened and warmed gases and injects them into a double pneumatic capacity. The first capacity is pressure limited by a relief valve (3 bar). Exhausted gases flow back to the pump. A miniature pressure regulator, placed between the two capacities, rules the driving pressure. Gas mixture is injected through a solenoid valve controlled by an electronic twin-timer. Results of both devices are similar. However, our prototype seems to be very convenient for developing countries where medical gases under high pressure are not often available.


[Premedication with midazolam in infants. A comparison of different modes of administration]. Midazolam presents the properties of a good premedication because of its sedative and anxiolytic activity. The aim of this study, concerning 84 children, was to compare the efficacy of midazolam according to the three ways of administration: intrarectal, oral and intranasal, in reference to a group without premedication. Results have shown the superiority of intrarectal midazolam at the dose of 0.35 mg.kg-1 30 minutes before surgery. The tolerance of this way of administration is excellent and it allows a greater sedative activity compared to the control group and to the intranasal group.


[Nicardipine vs trinitrin for controlled hypotension in maxillo-facial surgery]. In this study we examined perioperative blood losses during maxillo-facial surgery comparing 2 techniques for controlled hypotension using nitroglycerin (NTG) and nicardipine (NICAR). 37 ASA I and II patients electively scheduled for rhinoseptoplasties under general anaesthesia were randomly divided into 2 groups. General anaesthesia was induced with intravenous thiopental and vecuronium following a neuroleptanalgesia consisting of fentanyl (0.053 +/- 0.004 microgram.kg-1.min-1) IV and droperidol (1.98 +/- 0.35 microgram.kg-1.min-1) IV given in bolus doses. The patients were intubated and ventilated (N2O in O2) to maintain normocarbia. Controlled hypotension to maintain a mean arterial pressure (MAP) between 50 and 55 mmHg was induced using an IV infusion of NTG 6 micrograms.kg-1.min-1 in group I and NICAR 10 micrograms.kg-1.min-1 over 10 minutes followed by an infusion at 4 mg.kg-1.min-1 for group II. Measurements of heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP using an automated blood-pressure cuff and end tidal carbon dioxide (ETCO2) were recorded prior to induction (PREIND), intraoperatively (PEROP) at 15, 30, 40 and 120 minutes post-induction, and at 15, 30 and 60 minutes postoperatively (POSTOP). Blood loss, graded as minimal or frank, was assessed by the surgeon during the operative period, post-extubation and 3 days postoperatively at dressing removal. The surgeon was unaware of the randomization schedule. Student's test was applied for statistical analysis of measured variables and Fisher's test for qualitative parameters. No statistically significant differences were noted between both groups with respect to demographic data, duration of surgery and total doses of anaesthetic agents (Table I).(ABSTRACT TRUNCATED AT 250 WORDS)


[Ten years' locoregional anesthesia in children in a private hospital]. Retrospective study during a ten years period of 5,512 regional anaesthesias on children in a private hospital. This work identifies the peculiarities due to recruiting and to RA techniques, shows the practical conditions (preoperative samples, equipment, drugs) and studies the complications, before pointing out good practice rules.


[Truncal blocks of the lower limb].

[Truncal blocks of the lower limb]. Plexus nerve blocks of the lower limb have been described for many years but were seldom used until recently. Postoperative analgesia is one of the main indications of these blocks. The blockade of both lumbar and sciatic plexuses is required for most of the surgical procedures performed on the proximal part of the lower limb. Nerve stimulators account for less difficulties to perform such blocks and results are more reliable. Several pharmacokinetic studies have documented that toxic thresholds of plasma concentrations of local anaesthetics are not reached with the doses commonly injected. Many different techniques and landmarks have been described providing several alternatives to perform these blocks according to the type and the localisation of the surgical procedure. Extensive indications are reported for day case surgery or patients at risk.


[Delirium tremens. Recent neurophysiologic concepts and therapeutic outlook]. Delirium tremens is linked with a chronic depression of the central nervous system by alcohol and a compensatory hyperactivity of neurotransmitters. A sudden stoppage of alcohol intake induces excessive production of these transmitters. Firstly appearing is a noradrenergic hyperactivity which may be responsible not only for reducing the magnesium blood level but also for activating the other transmitter systems. A magnesium blood level lower than 1 mmol.l-1 involves a risk of seizures and requires IV magnesium sulfate. Noradrenergic hyperactivity can be prevented by IV alcohol associated with sedation best achieved by IV clomethiazole in alcoholic solution. Should these preventive measures fail, noradrenaline action in the central nervous system can be blocked by clonidine. Should hallucinations become manifest, linked to dopaminergic hyperactivity, haloperidol is indicated. Benzodiazepines may be useful, particularly carbamazepine, for their depressing effect on gaba-ergic hyperactivity.


[A postoperative syndrome of confusion and stupor or a central anticholinergic syndrome?]. A case is reported of a 23 year old man who sustained a central anticholinergic syndrome after undergoing upper limb surgery under regional anaesthesia and sedation with 2 mg midazolam and 75 micrograms fentanyl. The disturbances consisted of excitation and inhibition. On the 4th postoperative day, he developed progressive coma, quickly and totally reversed with 2 mg physostigmine. Chronic benzodiazepine therapy seems to be a facilitating factor of central anticholinergic syndrome. The low rate of this postoperative complication seems to proceed from failure to recognize it. Differential diagnosis and place of physostigmine therapy are discussed.


Vertebrobasilar insufficiency related to cervical spondylosis. A case report and review of the literature. A 64-year-old man suffered from symptoms of vertebrobasilar insufficiency (VBI) while turning his head to the left. Roentgenograms of the cervical spines showed severe spondylosis. Cerebral angiography demonstrated compression of the left vertebral artery by osteophytes of the cervical spine when the patient turned his head to the left. He was treated surgically by fixation of the vertebral bodies with good relief of symptoms during one year of follow-up. VBI induced by spondylotic compression of the vertebral artery is uncommon. We therefore reviewed the literature and suggested a more simple method of operation.


Idiopathic palatal myoclonus: report of two cases. We report two patients with idiopathic palatal myoclonus presenting as a synchronous up-and-down beating of the soft palate, to-and-fro thrusting of the tongue, and contraction of pharyngeal and laryngeal muscles. The obvious pulsatile movements were visible on the submental surface and a loud clicking noise was audible from a distance. The involuntary jerkings predominantly appeared when the mouth was kept shut, but could be interrupted by some oro-lingual maneuvers such as phonation, swallowing, and sticking the tongue out. Although the palatal myoclonus did not affect the function of the mouth, the patients were socially embarrassed by the loud clicking sound and pulsatile movements. On clinical examination and laboratory investigations, no evidence of lesion in the brainstem or cerebellum was obtained. A therapeutic trial with trihexyphenidyl did not bring any benefit. To conclude, because the idiopathic palatal myoclonus is a rare movement disorder which has never been documented in Taiwan, we describe its clinical characters in two Chinese patients and discuss the differential diagnosis with other involuntary lingual movements.


Gastric adenocarcinoma simulating benign gastric ulcer. The pathologic features and prognosis of patient in whom gastric cancer simulates at endoscopy as a benign gastric ulcer has been poorly characterized. We performed a retrospective study with particular reference to the long term prognosis on 191 patients treated for gastric adenocarcinoma over the period 1980-1986. In 176 of these 191 patients (92.2%), the endoscopic findings suggested cancers, while in the remaining 15 patients (7.8%), the endoscopic appearance suggested benign ulcer. Comparing gastric cancers masquerading as benign gastric ulcers with those appeared malignant endoscopically, the former had higher resectability rate (100% vs 77.3%), higher incidence of early gastric cancer (73.3% vs 6.25%), less poorly differentiated carcinoma (33.3% vs 65.4%), less lymph node metastasis (13% vs 69.5%) and a higher five-year survival rate (86.6% vs 24.8%) (p less than 0.05 in all). Our study indicated that gastric adenocarcinomas simulated benign gastric ulcers at endoscopy are mostly early gastric cancers that carry a much better prognosis.


Effect of heart rate on pressure half-time in patients with mitral stenosis. The effect of heart rate on pressure-half time has been controversial. This study attempted to clarify this issue in patients with mitral stenosis. Twenty cases were enrolled, 10 with atrial fibrillation and 10 with sinus rhythm. Twenty beats were analyzed for each patient. The results showed that in patients with atrial fibrillation the pressure half-time was hardly measurable in the cardiac cycles with a ventricular rate more than 100/min; by excluding these fast beats, the pressure half-time showed no relationship with the heart rate. Similarly, there was no significant correlation between heart rate and pressure half-time in patients with sinus rhythm when the heart rate was less than 70/min. However, if the sinus rate was more than 70/min, the correlation became statistically significant. We conclude that when using pressure half-time to derive mitral valve area we should avoid to use the beats with ventricular rate greater than 100/min in patients with atrial fibrillation. In patients with sinus rhythm, we should try to use those beats with heart rate greater than 70/min if possible. Otherwise, significant error may occur.


A prospective randomized controlled trial of sandostatin and vasopressin in the management of acute bleeding esophageal varices. To study the hemostatic effect of Sandostatin, a long-acting analogue of somatostatin, in acute variceal bleeding, a prospective randomized controlled trial comparing it with Vasopressin was conducted in 41 cirrhotic patients with esophageal variceal bleeding. Initial hemostasis was achieved within 6 hours in 75% of patients treated with Sandostatin and in 61.9% treated with Vasopressin. Recurrent bleed developed in 20% of patients in Sandostatin group and 46.2% in Vasopressin group following initial hemostasis. Complete control of bleeding for 24 hours was attained in 60% of the Sandostatin group and in 33.3% of the Vasopressin group. There was no statistically significant difference in both the rate of initial hemostasis and complete bleeding control. Hospital mortality was also similar in both groups. However, transfusion requirements were less (P less than 0.05) and side effects tended to be milder in patients treated with Sandostatin. In conclusion, Sandostatin is at least as effective as Vasopressin in the treatment of acute variceal bleeding, and carries less severe complications than Vasopressin does.


[Valve replacement for aortic stenosis]. We retrospectively reviewed 122 consecutive patients with aortic stenosis from January 1977 to December 1990. There were 68 male and 54 female patients. Their age ranged from 5 to 73 years old (47 +/- 16, mean +/- SD). Sixty eight patients also had associated mitral valve lesion, 13 patients had tricuspid valve lesion, and 3 patients had coronary artery disease. Aortic valve replacement was performed on all patients. Mechanical valves were implanted in 86 cases and tissue valves in 36 cases. Associated procedures were performed in 54 cases: mitral valve replacement in 34 cases, mitral valve repair in 18 cases and coronary artery bypass grafting in 2 cases. A bicuspid aortic valve was found in 20 cases (16.4%). Hospital mortality was 4.9% (6 cases). Follow-up was completed in 95% of the surviving cases (110 cases). The survival rate was 82 +/- 3% at 13 years and redo-free rate was 73 +/- 8% at 13 years. Seven cases required redo operation, due to tissue valve degeneration in 5 and thrombosis of the mechanical valve in 2. All 7 patients survived. Late death occurred in 6 cases: 3 from malignancy, 2 from stroke and 1 from ventricular arrhythmia. We concluded that valve replacement for aortic stenosis is a safe and satisfactory procedure with good long-term results.


[Measurements of dose distribution in small fields of 10 MV X-rays]. Dose distribution measurement in small fields include: 1. Field size factor, 2. Percentage depth dose, 3. Isodose curves charts, 4. Tissue-phantom ratio, and 5. Penumbra width. Field size factor was measured by using different detectors and it was found that the dimension of detector must be less than half of the field size to avoid under-estimation. If a 0.6 cc cylindrical ion chamber was used for small fields measurement, it would under-estimate the field size factor by 19.7% for a 2x2 cm2 field. The percentage depth dose and the tissue-phantom ratio increased with increasing the field size. The penumbra width increased with increasing the field size which was larger for a square field than the corresponding circular field by less than 1 mm.


Abdominal embryonal rhabdomyosarcoma. A case report. Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood, but it is rare in young adults. It usually occurs in the pelvis or genito-urinary tract. We report a case of abdominal embryonal rhabdomyosarcoma who received a combined treatment modality with radical pelvic surgery and combination chemotherapy of vincristine, actinomycin-D and cyclophosphamide (VAC). She is well with no evidence of tumour recurrence for 3 years after primary surgery.


Role of areca nut consumption in the cause of oral cancers. A cytogenetic assessment. Cytogenetic studies, framed to assess the possible genomic damage caused by areca nut consumption (without tobacco and not as a component of betel quid), were performed among areca nut chewers, which included normal people who chew areca nuts, patients with oral submucous fibrosis, and patients with oral cancer, and healthy nonchewing controls. The analysis showed statistically significant increases in the frequencies of sister chromatid exchanges and chromosome aberrations in peripheral blood lymphocytes and the percentage of micronucleated cells in exfoliated cells of buccal mucosa among all three groups of chewers when compared with those of the controls. The current data, the first of this type among only areca nut chewers, highlight that this popular masticatory is erroneously considered "safe" and that it increases the genomic damage even when chewed without tobacco. The data also signify that, henceforth, in cytogenetic biomonitoring, areca nut consumption also should be considered as one of the confounding factors.


Familial nasopharyngeal carcinoma in patients who are not Chinese. Nasopharyngeal carcinoma (NPC) is a malignancy that is prominent in Cantonese Chinese people. It is presumed to result from an interaction of genetic and environmental factors, including the Epstein-Barr virus (EBV). In an attempt to further clarify the pathogenesis of this disease, an evaluation of NPC occurring in racial/ethnic groups not considered susceptible to this disease could be informative. A white family with NPC occurring in three siblings was investigated and information was gleaned from literature on other reports of familial NPC in non-Chinese families. In the family being investigated, another genetically determined disease, hemophilia, was identified. Radiation early in life was noted to be a possible risk factor for NPC in the proband. A review of familial NPC in the white population revealed that in contrast to sporadic NPC, which is usually of the well-differentiated type, familial NPC usually is poorly differentiated. Familial NPC offers an important opportunity to investigate the etiology of this disease. With newer laboratory techniques to investigate pathogenetic mechanisms, detailed evaluations of non-Chinese NPC families may become increasingly important.


Pathology and prognosis of gastric carcinoma. Findings in 10,000 patients who underwent primary gastrectomy. Despite recent advances in diagnosis and treatment, gastric carcinoma remains a major cause of death in the world. The clinicopathologic profile of 10,000 consecutive patients who underwent primary gastrectomy during 1962-1989 were reviewed and prognostic factors influencing survival in those with gastric carcinoma were analyzed in 7031 patients. Incidence of gastrectomy for carcinoma has increased steadily and the rate of early carcinoma exceeded that of advanced carcinoma in the recent period of 1985-1989. Five-year and 10-year survival rates were 46.1% and 35.2% in 3868 patients with advanced carcinoma, and 88.8% and 77.3% in 3163 patients with early carcinoma, respectively. In patients with advanced carcinoma, significantly poorer survival rates were noticed for patients older than 70 years of age, those who underwent total gastrectomy, tumors involving the entire stomach or greater than 10 cm in diameter, a macroscopic diffusely infiltrative pattern, adenosquamous histologic type, positive surgical resection margins, or lymph node metastasis. None of the above poor prognostic features were identified in patients with early gastric carcinoma group except for those older than 70 years of age. Although lymph node metastases were present in 10% of early gastric carcinomas, this feature did not impart a poor prognosis. Patients with advanced carcinoma grossly resembling an early carcinoma had an intermediate prognosis, suggesting the existence of a developmentally midstage lesion between early and advanced carcinoma. The study illustrates that the most important role for clinicians treating with gastric carcinoma should be early detection and aggressive surgery for resectable tumors, followed by detailed pathologic examination.


Serum cholesterol level, body mass index, and the risk of colon cancer. The Framingham Study. Some studies have linked low serum cholesterol levels to increased risk of colon cancer, particularly in men. Results have been inconsistent, with preclinical disease frequently offered to explain any apparent association. The Framingham Study cohort of 5209 persons, initially 30-62 years of age and observed more than 30 years, was evaluated. Baseline data included lipoprotein fractions, total cholesterol levels, body mass index, alcohol intake, and cardiovascular risk variables such as cigarette smoking, hypertension, and glucose intolerance. In this population, colon cancer in men is related inversely to serum cholesterol levels, even when the first 10 years of follow-up are eliminated to reduce the effect of preclinical disease. This effect is concentrated in the Svedberg 0-20 fraction, corresponding to low-density lipoprotein levels. Another finding only in men is the direct relation of body mass index to colon cancer incidence. Combined initial low serum cholesterol levels and obesity appear to indicate a four times greater risk for colon cancer in men as compared with people with average values of both variables. The reasons for these observations are unknown.


A new enzyme-linked lectin/mucin antibody sandwich assay (CAM 17.1/WGA) assessed in combination with CA 19-9 and peanut lectin binding assay for the diagnosis of pancreatic cancer. Mucus glycoproteins are often present in the sera of patients with pancreatic cancer, and their detection and quantification can be used in serologic diagnosis. A novel enzyme-linked "sandwich" assay (CAM 17.1/WGA) has been developed in which a lectin, wheat germ agglutinin (WGA), is bound to the solid phase to capture serum glycoproteins, and after addition of test sera, a monoclonal antimucin antibody (CAM 17.1) and peroxidase-tagged second antibody are used as a detection system. The test has been applied to sera from 79 patients with pancreatic cancer and 120 controls. The CAM 17.1/WGA assay alone had a sensitivity of 78% and specificity of 76% in the diagnosis of pancreatic cancer. Combination of the CAM 17.1/WGA test with a previously described peanut lectin binding assay (PNA/ELLA) provided a sensitivity of 92% and specificity of 70%, whereas combination of the CAM 17.1/WGA assay with the CA 19-9 radioimmunoassay had a sensitivity of 85% and specificity of 76%. Combination of all three tests had a sensitivity of 94% and specificity of 66%. In nonjaundiced patients, the combination of CAM 17.1/WGA and PNA/ELLA had a sensitivity of 93% and specificity of 79% in the diagnosis of pancreatic cancer. This new test adds significantly to the armamentarium of serologic tests for pancreatic cancer. These tests are particularly effective when used in combination to detect different mucin-borne carbohydrate antigens. They deserve more widespread use, particularly in examining nonjaundiced patients with unexplained abdominal pain or weight loss.


Malignant lymphomas of the upper gastrointestinal tract. Results of a prospective study in 103 patients. There is a discrepancy between the incidence of gastrointestinal involvement by malignant lymphomas, as established in postmortem studies, and the rareness of the corresponding clinical diagnosis. Therefore, the authors performed routine upper gastrointestinal endoscopic examination, within the framework of the usual staging examinations, in 103 consecutive patients with newly diagnosed Hodgkin disease (n = 21) and non-Hodgkin lymphoma (n = 82). One patient with Hodgkin disease (4.8%), 11 of 40 patients (27.5%) with non-Hodgkin lymphoma of low-grade malignancy, and 11 of 42 (26.2%) of those with highly malignant non-Hodgkin lymphoma showed involvement of the gastric and/or duodenal mucosa, as diagnosed with esophagogastroduodenoscopy. Of the 22 patients with non-Hodgkin lymphoma, 9 had involvement of other mucosa-associated lymphoid or epithelial tissue. In two patients with Stage III, two with Stage II, and two patients with presumptive Stage I disease, the disease was reclassified as Stage IV. Because of gastrointestinal involvement, treatment for two patients was changed from radiation therapy to chemotherapy and another two patients had gastric resections so that possible treatment-related complications could be avoided. In light of these results and the fact that a major basis for the therapeutic strategy for malignant lymphomas is tumor stage, routine esophagogastroduodenoscopic examination within the framework of the usual staging examinations is recommended. In individual cases, this procedure may be of decisive importance in the therapeutic approach to and prevention of complications.


Sinonasal fibrosarcomas, malignant schwannomas, and "Triton" tumors. A clinicopathologic study of 67 cases. Sinonasal fibrosarcomatous neoplasms are uncommon tumors and there are no previous studies of a large number of such cases. The clinical and histologic features of 67 fibrosarcomatous neoplasms of the nasal cavity and paranasal sinuses are reported. Multiple clinical and histologic parameters (including immunostain results) were analyzed to characterize the features important for histologic recognition of the tumors and for correlation with patient outcomes. Some tumors could be classified as malignant schwannomas or malignant "Triton" tumors, but their behavior was similar to that of the fibrosarcomas. Histologically, most tumors were very low-grade malignant neoplasms; however, 22% of patients died of their tumors. Factors that correlated with death were mitotic rate (greater than 4 mitoses per 50 high-power fields), increased tumor cellularity, and male sex. Many tumors originally were diagnosed as benign (by others), probably causing initial undertreatment of some patients. Proper recognition and histologic evaluation of the tumor are important to ensure the best therapy and optimal patient survival.


New aspects in the staging of lung cancer. Prospective validation of the International Union Against Cancer TNM classification. To validate the new TNM definitions for lung cancer (International Union Against Cancer [UICC] TNM classification, 4th edition, 1987), the data of 3823 patients were analyzed prospectively in terms of concordance between clinical (TNM) and pathologically confirmed classification (pTNM), the value of the various diagnostic techniques in estimating the pathologically confirmed classification, and the prognostic relevance of the new TNM definitions. With regard to the primary tumor (T), clinical and pathologic classifications were identical in 63%; with regard to lymph node involvement (N), the agreement was 47%; for distant metastasis agreement occurred in 91% of cases and for the stages it occurred in 56%. As to the primary tumor (T), the accuracy of radiography (59%) was nearly identical to that of computed tomography (CT) (58%). Both techniques were less precise in determining the extent of lymph node involvement (CT, correct assessments in 50%; radiography, correct assessments in 43%). The statistically significant differences in the prognosis for the T, N, and M categories and for the stages and the categories of the new R classification could be confirmed. Allowance should be made for the different prognosis between T1N0M0 and T2N0M0 by the new Substages IA and Ib of Stage I. By the new TNM definitions for bronchus carcinoma, international conformity became feasible and practical, and the improvement of its prognostic relevance provided a more reliable basis for establishing guidelines for individual oncologic concepts.


Sensitive and specific detection of the 4B5 antigen in bronchial lavage specimens from patients with primary bronchogenic carcinoma. The monoclonal antibody 4B5 binds to a mucin-like antigen elaborated by respiratory epithelium of patients with non-small cell bronchogenic carcinoma. Several immunoassay formats were used to determine the presence of the antigen in lavage specimens. A qualitative immunodrop binding assay showed immunoreactivity in 37 (64%) of 58 specimens from patients with non-small cell lung cancer. In contrast, only 11 (12%) of 93 specimens from patients with either metastatic carcinoma or benign pulmonary diseases exhibited 4B5 immunoreactivity. A quantitative radioimmunoassay using standardized amounts of mucin exhibited similar sensitivity and specificity. Positive immunoreactivity was associated significantly with tobacco use and the cytopathologic diagnoses of squamous metaplasia, atypia, or dysplasia. Conversely, no significant association was found between 4B5 immunoreactivity and age, gender, race, benign cytologic findings, frankly malignant cytologic findings, or stage of disease. The expression of 4B5 antigen in bronchial secretions from patients with bronchogenic carcinoma deserves additional evaluation as a potential marker of pulmonary carcinogenesis.


Giant cell tumor of the skull.

Giant cell tumor of the skull. Most giant cell tumors (GCT) occur at the ends of long bones. There is little information about GCT of the skull bones. The authors reviewed the Mayo Clinic files, which contained 546 cases of GCT, and their own consultation files, which contained approximately 1500 cases. Eleven tumors occurred in the sphenoid bone with extension to the surrounding bones and structures in 8 patients. One tumor (in Paget's disease) occurred in the frontal bone, one tumor was in the occipital bone, and one tumor was in the temporal bone. There were 4 men and 11 women whose ages ranged from 8 to 78 years, with a mean of 36.5 years. Radiographic findings were not suggestive of a specific diagnosis, although the features were those of an aggressive lesion. Histologically, the tumors had features typical of GCT. However, a prominent spindle cell component was seen in five tumors. The initial treatment in all patients but one was intralesional excision that was as complete as possible. The last patient had a wide excision and had soft tissue recurrence at 1 year. This was excised and she was free of disease at 2.7 years. Three patients died, one in the immediate postoperative period and the other two at 1.6 and 4 years with progression of tumor. One patient had postoperative radiation therapy and was without evidence of disease for 2 years when he was lost to follow-up. The remaining 10 patients all had postoperative radiation therapy; 6 patients were alive without disease from 4 to 34 years. However, one of these six patients had a recurrence that was treated surgically with additional radiation. Four patients were alive with tumor from 2.1 to 26 years at the time of this report. GCT of the skull bones is rare but should be distinguished from giant cell reparative granuloma because of the tendency for progression. Surgical ablation (as complete as possible) and postoperative radiation therapy seem to be the treatment of choice for GCT of the skull bones.


Angiosarcoma arising from malignant schwannoma in a patient with neurofibromatosis. A 20-year-old man with von Recklinghausen disease had a right neck mass. Pathologic examination at excision showed angiosarcoma arising in a malignant schwannoma of the cervical brachial plexus. Comparison with previous reports revealed that angiosarcoma is a rare, highly aggressive sarcomatous element in malignant schwannoma arising in patients with neurofibromatosis (NF).


Risk factors for failure of immediate breast reconstruction with prosthesis after total mastectomy for breast cancer. Immediate breast reconstruction (IBR) after mastectomy represents a clear improvement in the quality of life of patients with breast cancer, but prosthesis removal is relatively frequent. Therefore, it is important to identify risk factors related to this removal. A series of 142 patients treated with mastectomy and IBR at the Institut Gustave-Roussy between January 1976 and December 1988 were studied. Forty-seven had an in situ carcinoma, 93 an infiltrating carcinoma, and 2 a fibrosarcoma. IBR failures were defined as removal of the prosthesis, and early failures as removal during the first 7 weeks after IBR. The early failure rate was significantly higher in patients with invasive carcinomas or fibrosarcomas than patients with in situ carcinomas (12% versus 0%, P = 0.04). The risk of late IBR failure was significantly higher in patients who had received postoperative radiation therapy than patients who did not (P = 0.0002). However, this increased risk applied only to women in whom the chest wall was exposed to radiation because of a high risk of recurrence. It might be preferable to postpone breast reconstruction for patients with infiltrating breast carcinoma because early complications are not infrequent and could delay adjuvant chemotherapy. Late complications associated with chest wall irradiation could be avoided with the use of alternative techniques such as the transverse rectus abdominis myocutaneous (TRAM) flap procedure.


Reverse targeting in a media-promoted breast cancer screening project. The American Cancer Society has sponsored community-based, low-cost, Breast Cancer Detection Awareness Projects throughout the United States. The authors hypothesized that these projects tend to exclude minorities and women of lower socioeconomic status--groups with a higher incidence of late-stage disease. A cross-sectional survey was performed of participants in the 1990 Breast Screening Project in Tampa, Florida. The demographic profile of participants was compared with that predicted by 1990 census data. There were 13,920 women who called phone banks for additional information. Of these, 13,215 were deemed eligible and 6640 completed mammographic screening. Forty percent of participants were having mammography for the first time. Comparisons with census data indicated that elderly people, members of minority groups, and women of lower educational levels were underrepresented. The results of this study support the concept that "reverse targeting" occurs with these breast cancer screening projects, and recommendations for recruiting underrepresented groups are given.


Prognostic significance of DNA quantitation in stage D1 prostate carcinoma with the use of image analysis. A characteristic feature of prostatic adenocarcinoma is its great variation in biologic behavior. This variation and the observation that most carcinomas are of intermediate grade make standard histologic grading of limited value in determining the prognosis of a patient. DNA quantitation with the use of computer-assisted image analysis on Feulgen-stained nuclei was performed on the metastatic lymph nodes from patients with Stage D1 prostate carcinoma to determine whether ploidy was a useful predictor of survival or progression. The Gleason histologic score of the primary tumor, the number and extent of lymph node metastases, and the progression and survival intervals were documented. Treatment modalities included pelvic lymph node dissection, radical prostatectomy, external beam radiation therapy, and iodine 125 implantation. DNA ploidy quantitation showed that 65% (33 of 51) of cases were aneuploid, 2% (1 of 51) were tetraploid, and 33% (17 of 51) were in the diploid range. Progression to Stage D2 disease occurred in 76% of the patients with aneuploid cases and 53% of those with cases in the diploid range. There was a significant difference in progression between the two ploidy groups (Cox regression analysis, P less than 0.05).


Hodgkin disease mortality in the United States: 1979-1988. Mortality trends for Hodgkin disease in the United States were examined from 1979 to 1988 with the use of mortality data for multiple causes of death, which were obtained from the National Center for Health Statistics. A progressive decrease in the death rate from Hodgkin disease was observed over this period. The decrease in death rate was greatest among white patients. Patients who were 55 years or older had the highest death rate. Analysis by geographic region showed decreases in each of the regions, with no significant difference among groups of states with high and low incidences of acquired immune deficiency syndrome. However, the decrease in the South was approximately 35% greater than that in the North-east. In 1988 the most significant difference in death rates between male and female patients was in the 35-54-year age group, whereas a significant difference in death rates between white and black patients was seen only in patients who were 55 years of age or older. In summary, although there has been a significant reduction in deaths resulting from Hodgkin disease between 1979 and 1988, the decreases observed have varied between sexes and among age groups, racial groups, and geographic regions.


Cancer incidence in the Puerto Rican-born population of Connecticut. There are few published reports on cancer incidence in the Puerto Rican-born populations of the northeastern United States. In Connecticut, in the Puerto Rican-born population, which was of low socioeconomic status (i.e., 42% below the poverty level in the 1980 Census), the standardized incidence ratio (SIR) for all invasive cancers diagnosed in 1980-1986 was significantly reduced for female patients (SIR = 0.77) but not for male patients (SIR = 1.16), on the basis of expected numbers derived from incidence rates for the entire state of Connecticut. For female patients, only the SIR for cancers of the stomach, esophagus, and cervix were elevated significantly, whereas those for colorectal, lung, breast, and ovarian cancer were significantly reduced. For male patients, SIR were elevated significantly for cancer of the oral cavity, esophagus, and stomach and for leukemia, whereas none of the sites (including lung) had significantly reduced SIR. When incidence rates for Puerto Rico were used, the SIR for all sites combined was 1.99 (95% confidence interval = 1.78-2.22) for male patients but only 1.39 (95% confidence interval = 1.24-1.56) for female patients. These findings suggest sex differences in acculturation and lifestyle changes relevant to cancer risks in immigrants from Puerto Rico residing in Connecticut. Comparisons were made with cancer incidence and mortality data from other Puerto Rican immigrant populations.


Hyperthermia enhances the inhibition of tumor growth by 1-(2-tetrahydrofuryl)-5-fluorouracil/uracil (1:4) in tumors in mice and humans. The cytotoxicity of several antitumor drugs is enhanced by hyperthermia (HT). Using mouse Sarcoma-180 (S-180) tumors, the authors examined the effects of 5-fluorouracil (5-FU) and a combined oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) and uracil in a molar ratio of 1:4 (UFT), in combination with HT. The antitumor effect of 5-FU was not enhanced significantly by HT. Growth inhibition by UFT plus HT was significantly greater than that by UFT alone, whereas inhibition by UFT alone was significantly greater than that by 5-FU. The intracellular metabolism of 5-FU and FT in whole homogenates of S-180 cells, human tumor cell lines (SC-2 and Lu-99), and five fresh human tumor tissues also was investigated. Conversion of FT to 5-FU, phosphorylation, and degradation of 5-FU were assayed with [3H]FT or [3H]5-FU, and the products were separated by thin-layer chromatography. The conversion of FT to 5-FU and the phosphorylation of 5-FU were more rapid at 43 degrees C than at 37 degrees C, whereas the degradation of 5-FU to 2-fluoro-beta-alanine remained unchanged. This acceleration of the active metabolism of FT and 5-FU may be one explanation for the enhanced effect of UFT by HT.


Familial mesothelioma. Details of 17 cases with histopathologic findings and mineral analysis. Nine new cases of mesothelioma clustering in four families are described, and additional information is provided on four previously reported families. All of the members of these families had some exposure to asbestos. Diagnoses were confirmed histologically, and the relevance of the histologic pattern is discussed after the literature review. The lung mineral fiber burden was quantified in patients by transmission electron microscopic examination and energy-dispersive x-ray analysis, and this confirmed significant exposure to amphibole asbestos in all patients. Evidence supporting an increased incidence of mesothelioma in family members is discussed.


Surgical treatment of thoracic esophageal carcinoma directly invading the lung. The authors examined 63 patients with thoracic esophageal carcinoma directly invading the adjacent lung. Four of them had esophago-pulmonary fistulas. One patient received exploratory thoracotomy and exposure to radiation, and 62 underwent esophagectomy with mediastinal and abdominal lymph node dissection. A resection of the seized lung and the esophagus was performed in 39 patients (Group A), and 23 received esophagectomy with part of the tumor remaining intact (Group B). The results of treatment were compared between the two groups. Operative blood loss, mortality, and complications in both groups showed no difference. The average number of dissected lymph nodes in Group A was significantly larger than that in Group B (P less than 0.01). Histologic examination revealed that 22 (56.4%) lesions in Group A invaded the pulmonary parenchyma, a finding that indicates the difficulty of gross diagnosis of tumor infiltration. Five-year survival rates for patients in Groups A and B were 21.1% and 8.7%, respectively. The survival curve for patients in Group A was significantly better than for those in Group B (P less than 0.05). Pulmonary resection and aggressive lymph node dissection are recommended for patients with esophageal carcinoma that invades the adjacent lung.


Poorly differentiated medullary carcinoma of the stomach. The biologic behavior of poorly differentiated medullary carcinoma of the stomach is unclear. A clinicopathologic study on 74 poorly differentiated medullary carcinomas (PMC) and 73 nonmedullary carcinomas (NMC) of the stomach was done. PMC were defined as gastric carcinomas in which more than 50% of the tumor area contained poorly differentiated adenocarcinoma with no fibrous stroma. They were characterized by a location in the upper 33% of the stomach (49%), grossly expansive growth (69%), frequent vascular permeation (57%), and simultaneous liver metastasis (15%). Although the 5-year survival rate was similar for PMC and NMC, death of PMC was related more frequently to liver metastasis (47%) and less frequently to peritoneal dissemination (12%). The outcome of patients with PMC was influenced by frequent vascular permeation, extended lymph node metastasis, and simultaneous liver metastasis. These results indicate that PMC are characterized by expansive growth of the tumor and simultaneous or recurrent metastasis to the liver. Therefore, the biologic behavior of poorly differentiated medullary carcinoma is similar to that of well-differentiated carcinoma of the stomach.


Mucin oligosaccharide biosynthesis in human colonic cancerous tissues and cell lines. The Tn, sialosyl-Tn, and T antigens are carbohydrate-associated antigens that represent initial steps in mucin O-linked glycosylation. Previous immunohistochemical studies have shown that these three antigens are rarely, if ever, expressed in normal colonic mucosa; however, most colonic cancerous tissues express these structures. Little is known about the factors that control the expression of these antigens in colonic tissues or cell lines. One hypothesis is that cancers have increased levels of the glycosyltransferase activities responsible for synthesizing these antigens. The current study analyzed antigen expression by immunohistochemistry and glycosyltransferase enzyme activities for Tn, sialosyl-Tn, and T antigens in colonic tissues and cell lines to (1) compare values between normal and cancerous tissues and (2) correlate these results with tumor stage, histologic findings, and location. All nine colonic cancer cell lines expressed Tn antigen; sialosyl-Tn and T antigens were expressed by the more mucin-producing cell lines. Sialosyl-Tn transferase activity was higher in the more mucinous cell lines; T transferase activity was higher in those with less mucin. In paired specimens of normal and cancerous tissues, levels of each of the three glycosyltransferases were similar. In cancerous tissues, enzyme activity did not correlate with tumor location, stage, or histologic type. There also was no correlation between glycosyltransferase activity and expression of the relevant antigen. Thus, because normal and malignant colonic tissues have comparable levels of Tn, sialosyl-Tn, and T glycosyltransferases, the absence of these antigens in normal mucosa apparently is related to other factors such as antigen masking.


Antipyrine metabolism in patients with liver metastases from colorectal cancer. The influence of cancer on antipyrine metabolism is under debate. To assess the functional activity of a liver with solid metastases from primary colorectal cancer, antipyrine metabolism was studied after the drug was administered orally (18 mg/kg body weight) to 55 healthy volunteers, 62 patients with well-compensated cirrhosis, and 42 patients with small (Class A) or massive (Class B) metastatic liver involvement. In patients with cancer, antipyrine clearance (0.472 +/- 0.177 ml/min/kg) was similar to that in healthy volunteers (0.456 +/- 0.198 ml/min/kg) and significantly higher than in those with cirrhosis (0.259 +/- 0.17 ml/min/kg, P less than 0.001). There was no difference in antipyrine pharmacokinetics between Class A and B involvement. In the entire population, antipyrine clearance was correlated with serum albumin levels (r = 0.294, P = 0.0002) and prothrombin activity (r = 0.416, P = 0.001). This positive correlation was not present when only the neoplastic group was considered. No correlation was found between antipyrine clearance and alkaline phosphatase levels. In patients with cancer, no relationship was found between antipyrine clearance and carcinoembryonic antigen and lactic dehydrogenase levels. These results show that patients with livers largely replaced by solid metastases are able to metabolize antipyrine to the same extent as healthy subjects.


Carcinoma of the gallbladder. Histologic types, stage of disease, grade, and survival rates. Data on patients with gallbladder cancer listed in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were reviewed. Between 1977 and 1986, 3038 patients were recorded in the Program. Histologic grade, histologic type, stage of disease, and vascular invasion were correlated with outcome. Compared with all other histologic types of cancer, papillary carcinomas had the most favorable prognosis. The 2-year survival rate for patients with papillary carcinoma was 47%. A correlation with survival existed between grade, stage of disease, and vascular invasion. The study confirmed that cancers of the gallbladder occur more often in older age groups and are more common in women. Almost 40% of cases are found at an advanced stage. For patients whose enolase tumor was limited to the gallbladder at the time of surgery, the 2-year survival rate was 45% and the 5-year rate was 32%.


Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates. Data on patients with extrahepatic bile duct carcinomas recorded in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were reviewed. We analyzed the records of 1766 patients reported during a 10-year period (1977-1986). These tumors occurred primarily in older age groups and were slightly more common in males. Histologic grade, histologic types, and stage of disease are useful prognostic indicators. The 5-year survival rate for patients with Stage I disease was 11%. Although carcinomas of the extrahepatic bile ducts are better differentiated than carcinomas arising in the gallbladder, they have a less favorable prognosis.


The mucus-hypersecreting tumor of the pancreas. Development and extension visualized by three-dimensional computerized mapping. Mucus-hypersecreting tumor of the pancreas appears as dilated ducts and cystic spaces filled with mucus. To determine where such tumors arise and how they extend, computer-aided three-dimensional reconstruction was done of the ductal system. This also was used to visualize the spatial relationships among epithelial hyperplasia, dysplasia, and carcinoma in situ (CIS). Surgically removed pancreases were studied from 12 patients with mucus-hypersecreting tumors. The specimens were fixed in buffered formaldehyde solution 10%, embedded in paraffin and semiserially sectioned at 3 microns at an interval of 60 microns. The ductal contours were differentiated among ducts lined by ordinary epithelia, hyperplastic epithelia, dysplastic cells, or CIS and were inputted into a computer system that integrated a three-dimensional image of ducts in the display. (1) The tumors arose in the main pancreatic duct or its subbranches, and the cysts corresponded to segments expanded by the superficial growth of tumor cells; (2) areas of CIS arose in zones of preceding dysplasia, suggesting a dysplasia-carcinoma sequence; and (3) dysplastic or cancerous cells often extended intraductally over the dilated segments of ducts.


The establishment of an interleukin-6-dependent myeloma cell line (FLAM-76) carrying t(11;14)(q13;q32) chromosome abnormality from an aggressive nonsecretory plasma cell leukemia. A new myeloma cell line designated FLAM-76 was established from a patient with an aggressive nonsecretory plasma cell leukemia. The cell line exhibited morphologic features of flaming cells and contained an abundant eosinophilic cytoplasm with many dilated cisternae of rough endoplasmic reticulum. FLAM-76 cells were positive for cytoplasmic kappa (kapp)-type immunoglobulin but did not secrete it into the culture medium. The cells proliferated in the presence of exogenous interleukin-6 (IL-6) and more than 800 pg/ml of IL-6 was necessary for their continuous growth. The cells did not grow without IL-6, and they did not produce IL-6. Thus, the growth of FLAM-76 appeared to be regulated by the paracrine mechanism of IL-6. Alpha-interferon (alpha-IFN) inhibited the IL-6-dependent growth of FLAM-76 in doses greater than 1000 U/ml. FLAM-76 cells expressed CD38 (OKT10) and cell adhesion-associated antigens such as CD44 and CD54 (ICAM-1). Chromosome analysis revealed FLAM-76 to have a hypodiploid chromosome constitution with t(11;14)(q13;q32) abnormality, which frequently is seen in neoplasms of B-cell origin. Immunoglobulin (JH and Ck) gene rearrangement (but no BCL-1 gene rearrangement) was found in this cell line.


Acute leukemia arising from a myelodysplastic syndrome after long-term administration of iproplatin. Iproplatin (cis-dichloro-transdihydroxybis-isopropylamine platinum IV; CHIP) is a second generation cisplatin derivative that was developed to retain the antineoplastic effect of cisplatin with fewer toxic effects. Early clinical studies showed moderate activity in some neoplasms, with disappointing results in tumors of the lower gastrointestinal tract. Myelosuppression was the dose-limiting toxic effect in the acute setting. The authors report a patient with metastatic adenocarcinoma of the colon who received long-term therapy with CHIP. The patient achieved complete remission of disease after prolonged treatment with CHIP. The patient subsequently had a myelodysplastic syndrome that rapidly transformed to acute myelogenous leukemia. Acute leukemia may represent a late complication of CHIP therapy.


Testicular relapse in adult acute myelogenous leukemia. Testicular relapse (TR) in adult acute myelogenous leukemia (AML) is uncommon, occurring in only 1-2% of patients with bone marrow relapse. TR in the absence of systemic relapse has been reported previously in 2 adults and 12 children, of which 67% were monocytic variants of AML. This article presents the case of a 29-year-old man with AML that relapsed in his testicle without evidence of bone marrow relapse. This patient and the two previously mentioned adults experienced bone marrow relapse within 2 months and died within 7 months of their TR. TR in adult myelogenous leukemia should be considered a harbinger of systemic relapse and suggests a need for aggressive local and systemic therapy.


Erythrocyte sedimentation rate as a tumor marker in human prostatic cancer. An analysis of prognostic factors in 300 population-based consecutive cases. The natural history of prostatic cancer is variable. Our knowledge of prognostic factors is limited; therefore, research is needed. The cases of 300 population-based consecutive patients with a diagnosis of cancer of the prostate were analyzed regarding different prognostic factors (but with special reference to the erythrocyte sedimentation rate [ESR]). After a mean observation time of 100 months, M category, ESR, grade, performance status, hemoglobin level, and T category were found to correlate with disease-specific death using multivariate analysis. The variables correlating with progression in the multivariate model were M category, ESR, T category, grade, treatment, and age. Patients treated with estrogen had a significantly lower risk (relative hazard, 0.3) of relapse. ESR was highly statistically significant (P less than 0.0001) as a prognostic factor. With the variable in linear form, a 20-mm/h higher level suggested a 29% increased risk, on average, for dying of prostatic cancer (using a best-fit multivariate model). However, the relationship was not linear. After correcting for the effect of other factors, the risk for dying of prostatic cancer was lowest when the ESR was 40-50 mm/h and highest when its values were highest. ESR is an indicator of increased risk of progression and death in prostatic cancer. Other prognostic factors such as M and T categories, grade, performance status, hemoglobin level, and age currently are more important when planning treatment. It is possible that the ESR reflects aspects of tumor-host relationship and that both a low and high ESR are markers for patients with receding host defence mechanism.


Outcome of renal transplantation or dialysis in patients with a history of renal cancer. Therapeutic options for patients with bilateral renal cancer or cancer in a solitary kidney are limited to partial nephrectomy or bilateral radical nephrectomy with subsequent renal transplantation or dialysis. The outcome after partial nephrectomy is well documented, but few reports discuss the long-term survival of patients receiving chronic dialysis or after renal transplantation. Information regarding the long-term prognosis for these patients is important when deciding on the appropriate treatment. The authors retrospectively evaluated the long-term prognosis of 23 patients who lost renal function because of surgery for renal cell carcinoma or Wilms' tumor between 1970 and 1990. Twelve patients had renal transplantation (Tx group), and 11 had chronic dialysis (DS group). In the Tx group, four patients had Wilms' tumor and eight had renal cell carcinoma (Stage I, 5 patients; Stage II, 2 patients; Stage III, 1 patient). In the DS group, three patients had Wilms' tumor, and eight had renal cell carcinoma (Stage I, 5 patients; Stage III, 2 patients; Stage IV, 1 patient). Unexpectedly, 9 of 11 (82%) patients from the DS group died of cancer, compared with 1 of 12 (8%) patients who had transplantation (P = 0.0133) despite comparable stages of renal cell carcinoma and Wilms' tumor in the two groups. For patients who have had bilateral nephrectomy or removal of a solitary kidney, the authors recommend waiting at least 12 months, during which time the patient receives dialysis, before proceeding with transplantation if there is no evidence of recurrent tumor.


Long-term survival of 1986 patients with intracranial meningioma diagnosed from 1953 to 1984 in Finland. Comparison of the observed and expected survival rates in a population-based series. Intracranial meningioma was diagnosed and histologically verified in 1986 patients, 597 men and 1389 women, between 1953 and 1984 in Finland. The closing date of this survival study was December 31, 1987, and the follow-up was complete. Meningiomas, usually slowly growing and surgically curable benign tumors, caused considerable short-term mortality, with a relative survival rate (RSR) of 83% at 1 year, and slight but continual long-term mortality, with RSR of 71% at 15 years. From 1979 to 1984, when computed tomography (CT) was available, the mortality at 3 months for the patients who had surgical procedures was 2% in those younger than 45 years and 10% in those older than 64 years; patients who did not have operations had 1-year mortality of 61%. The short-term and long-term excess mortalities are associated significantly with old age, no surgical procedure, and the period of diagnosis; the long-term excess mortality also is associated with male gender.


Multiple thyroid involvement (intraglandular metastasis) in papillary thyroid carcinoma. A clinicopathologic study of 105 consecutive patients. Multiple thyroid involvement (MTI) in papillary thyroid carcinoma was clinicopathologically studied in 105 non-selected, consecutive patients. Whole thyroids resected by total thyroidectomy were sectioned at intervals of 2-3 mm (mean number of slices per gland, 19.2) and histologically reviewed. The intraglandular cancer foci, other than the tumor regarded as the primary focus, were demonstrated in 82 (78.1%) of 105 patients. The foci were usually small (less than 4 mm) and were not accompanied by sclerotic fibrous stroma or by a fibrous capsule. These small foci were distributed around the primary lesion and also were found frequently (61.0%) in the opposite lobe as bilateral disease. In the opposite lobe, a similar incidence (approximately 30%) of disease was obtained in each of the three parts (upper, middle, and lower). The mean number of foci in patients with MTI was statistically correlated to age, the presence of lymph node metastases, and the presence of solid areas or psammoma bodies in the primary tumor. It was concluded that MTI could be regarded as one of the most striking and important biologic characteristics of papillary thyroid carcinoma.