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We have demonstrated that alpha-spectrins (alphaSpISigma* and alphaSpIISigma1) are major ubiquitinated proteins in terminally differentiated hippocampal neurons in culture. Western blotting experiments, using alphaSpISigma1, alphaSpIISigma1, and ubiquitin antibodies and lysates of 11-day-old cultured rat hippocampal neurons, have demonstrated that a single band comigrating with alphaSpISigma* and alphaSpIISigma1 in a 5% polyacrylamide sodium dodecyl sulfate gel is recognized by ubiquitin antibodies when (125)I-protein A is used for detection. Immunofluorescence staining of the 7- and 12 -day-old rat hippocampal neuron cultures using ubiquitin, alphaSpISigma1, and alphaSpIISigma1 antibodies demonstrated that all of these antibodies label neurons but not the astrocytes in the cultures. Immunoprecipitation of spectrin subunits in lysates of 12-day-old rat hippocampal neurons under stringent conditions (9.5 M urea) using alphaSpISigma1 and alphaSpIISigma1 antibodies followed by Western blot experiments of the immunoprecipitated spectrin subunits using alphaSpISigma1, alphaSpIISigma1 and ubiquitin antibodies confirmed that both alphaSpISigma* and alphaSpIISigma1 are ubiquitinated in rat hippocampal neurons. Furthermore, we demonstrated by immunohistochemistry that alpha-spectrins are components of the cytoplasmic ubiquitinated inclusions in hippocampal neurons in Alzheimer's and Parkinson's disease patients.

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The results of treatment after closed reduction of elbow dislocation vary. Twenty consecutive patients with closed posterior elbow dislocations were treated prospectively on a rapid motion, nonimmobilized functional regimen. This treatment protocol emphasizes immediate active range of motion under close supervision. No slings or splints were employed. Final range of motion averaged -4 degrees to 139 degrees. All patients attained final extension within 5 degrees of the contralateral side. Each patient achieved his final range of motion within an average of 19 days after reduction of the dislocation. Arm circumference returned to normal at an average of 6.5 days. There was one redislocation. After treatment, all patients met qualification for graduation from the U.S. Naval Academy and were able to pursue unrestricted athletic and career options. Our findings suggest that an aggressive immediate motion rehabilitation allows nearly full final elbow motion and an excellent functional outcome.

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The pre- and postnatal development of the catecholamine (CA) innervation to the hypoglossal nucleus (nXII) in the rat was investigated immunocytochemically with antisera to tyrosine hydroxylase (TH). Immunoreactive profiles positive for TH were first identified in nXII on gestational day (GD) 16. By GD 18, the adult-like distribution pattern was evident, characterized by the preferential targeting of the ventromedial region of nXII, but this pattern was not consistently found in all fetuses until GD 19. From GD 19 to postnatal day (PD) 180, the overall density of TH immunoreactivity, particularly in the ventromedial region, increased with further growth and maturation of nXII. These results establish the early prenatal CA innervation of nXII and support the hypothesis that CA are important in regulating motor tongue behavior in the newborn. Moreover, because the ventral compartment of nXII contains motoneurons that innervate protrusor muscles of the tongue, and tongue protrusor mechanisms play an essential role in suckling, deglutition, and respiratory (maintaining a patent upper airway) behaviors, it is further proposed that the CA innervation of nXII is critical to the survival of the newborn.

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One of the characteristic manifestations of chronic neuronal lipofuscinosis (Batten disease) is a marked predisposition for epileptic seizures. The management of these seizures is very difficult. The present study was initiated to determine what mechanisms could account for the seizure disorder. Tissue was examined from a patient with a history of Batten disease that was histologically verified. Reduced silver and Golgi impregnations were done on the parietal cortex of the patient. There was no evidence of the marked dendritic abnormalities seen in classic epileptic foci. Instead there was marked swelling and dilatation of the axon hillock and initial segment. This finding suggested that inhibition of these pyramidal neurons was markedly attenuated due to disruption of initial segment inhibitory synapses. Studies are continuing to determine if the GABA decreases seen in Batten disease may in part be due to trophic sequences brought about by loss of these critical inhibitory synapses.

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The relationship between free radicals and scavenger enzymes, and the disorders called the neuronal ceroid-lipofuscinoses, has long been an argumentative one. Recent evidence would seem to support the fact that such a relationship might exist but that it is indirect. The relationship does not seem due to an inborn error of free radical scavenger enzyme metabolism. Anticonvulsants play a role, as they influence free radical generating systems. At this juncture, no one has studied the relationship of anticonvulsant therapy, neuronal ceroid-lipofuscinosis, and the free radical-scavenging enzyme system, and their interplay. We have studied a large number of patients with epilepsy who are on either monotherapeutic or polytherapeutic regimens of most of the common anticonvulsants. We have found excessive free radical production in many of these patients, ranging from minor effects in the simpler anticonvulsants when used monotherapeutically, to more complex changes in polytherapeutic combinations. Likewise, we have found subtle and inconsistent findings in the free radical-scavenging enzyme system in a variety of examples of neuronal ceroid-lipofuscinosis. When refractory seizure disorders stimulate the vigorous use of polytherapy with a variety of free radical-facilitating anticonvulsants, free radical production becomes deleterious. Likewise, in certain types of neuronal ceroid-lipofuscinosis, polypharmacy with anticonvulsants, by enhancing the production of free radicals or suppressing scavenging enzymes, tends to be deleterious and induces a worsening in the disease process.

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The role of free oxygen radicals in blood-brain barrier (BBB) disruption and postischemic hyperemia was evaluated in the rabbit model of focal cerebral ischemia-reperfusion. Six groups of rabbits underwent clipping of the anterior cerebral, middle cerebral, and intracranial internal carotid arteries. Cerebral blood flow (CBF) was measured by using radiolabeled microspheres, before, during, and 15 minutes after 1-hour occlusion of these arteries. After 50 minutes of ischemia, Group 1 animals (control) received a placebo. Animals in Groups 2-4 received one of three drugs: catalase at 10 mg/kg, methimazole at 5 mg/kg, or indomethacin at 10 mg/kg. A fifth group received a tungsten-supplemented diet for 14 days before ischemia was induced, and a sixth group was sham operated. Microvascular integrity within the brain was determined by the presence or absence of Evan's Blue (EB)-albumin dye leakage across the BBB and was measured by microspectrofluorometry. In the control group during ischemia, CBF dropped to 14%, 7%, and 11% of preischemic levels in rostral, middle, and caudal sections of the brain, respectively, as characterized by extensive EB-albumin dye leakage through the BBB into the ischemic hemisphere. During early reperfusion, postischemic hyperemia was associated with an increase in CBF of 128%, 123%, and 129% of control in the rostral, middle, and caudal sections of the brain, respectively. In all treated groups and in the group receiving a tungsten-supplemented diet, BBB integrity was protected during reperfusion without inhibition of postischemic hyperemia. This study suggests that early disruption of the BBB to large molecules is mediated by free oxygen radicals, which inhibit rather than cause postischemic hyperemia.

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To study the involvement of free oxygen radicals of the blood-brain barrier (BBB) disruption during early reperfusion, we isolated the distal internal carotid artery, and the middle and anterior cerebral arteries via the transorbital approach in anesthetized rabbits. Using radiolabeled microspheres, regional cerebral blood flow (rCBF) was measured before, during and after 1-hour unilateral occlusion of these vessels. Fifty-five minutes after ischemia, animals received intravenous saline placebo (control), superoxide dismutase (SOD) at 8 mg/kg = 30,000 U/kg, or weakened superoxide dismutase (wSOD) at 8 mg/kg = 30,000 U/kg. Integrity of the BBB was assessed by leakage of Evan's Blue-albumin dye (EB-albumin dye), which was given at 15 minutes of reperfusion and allowed to circulate for an additional hour. In the control and wSOD-treated groups, rCBF decreased (26% and 40% of control, respectively) within the blue-tinted tissue of the occluded hemisphere during ischemia; hyperemia was observed during early reperfusion. In the control and wSOD-treated groups, EB-albumin dye leakage across the BBB increased 49% within the occluded hemisphere. However, within the SOD-treated group, the BBB showed minimal dye leakage even though rCBF of the occluded hemisphere (so-called blue-tinted tissue) decreased by 38% during ischemia. We conclude that 1-hour focal cerebral ischemia and reperfusion produce a vascular endothelial injury at the BBB. Since SOD administration showed significant protection, free-oxygen-radical production during early reperfusion is associated with breakdown of the BBB to large molecules.

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In brief Inflammation of the iliotibial brief band at the lateral femoral epicondyle-called iliotibial band syndrome-can be treated effectively with a two-phase conservative regimen. Phase 1, for treating the initial symptoms, involves anti-inflammatory drugs, icing, stretching, and using a knee immobilizer and crutches. In phase 2, which focuses on return to activity, the patient continues the stretches and runs to the point of feeling iliotibial band tightness, but not pain.

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The sources of noradrenergic (NA) innervation to the hypoglossal nucleus (nXII) in the rat were investigated with double-labeling histochemical/immunocytochemical and lesion/degeneration techniques. Following injection of wheat germ-agglutinin conjugated to horseradish peroxidase into nXII, brain stem sections were reacted with tetramethylbenzidine, stabilized, and incubated in antiserum to tyrosine hydroxylase (TH). Double-labeled neurons were observed in three pontine sites bilaterally, although mainly ipsilaterally, that included the nucleus subceruleus (nSC; 68.75%) and the A7 (21.09%) and A5 (10.15%) cell groups. Confirmation of the above results and identification of the course taken by descending NA-nXII projections was accomplished by lesioning the rostral pons, the nSC, or the medullary catecholamine bundle (MB), the suspected route by which NA afferents reach nXII. Quantitative estimates of the reduction of TH immunoreactivity on the lesioned compared to nonlesioned side of nXII were made densitometrically. In each case, TH immunostaining was significantly decreased (75%) in the ipsilateral caudoventromedial district of nXII, the predominant target area of NA input. The results from this study establish that multiple NA sources in the pons project to nXII in the rat, the majority of NA-nXII afferents are derived from the nSC, and descending NA-nXII projections course in the MB. These data are discussed relative to tongue control.

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Visual Evoked Potentials (VEPs) are gaining ground in the research for diagnosis of neurological disorders and visual defects, as a non-invasive diagnostic tool. Yet, the methods used towards these goals are not universal and far from able to provide a common ground among researchers in collecting, analyzing and comparing their results. This paper is an attempt to close the gap. We have developed a PC data-base and a set of analysis programs with graphic capabilities, frequency analysis, as well as an objective way of describing the signals obtained during VEP experiments.

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The effects of MK-801 at doses from 0.005 to 1 mg/kg IP on linguopharyngeal events (protrusions, retrusions and swallows) were determined in rats to find out whether MK-801 resembles ketamine in its capacity to increase the frequency of recurrence of such events that we have demonstrated in previous studies. All rats receiving a dose of 0.05 mg/kg or higher showed an increase in linguopharyngeal event frequency within 5 min and this enhancement (3-fold from baseline level) was maintained for longer than 1 h. At the lowest dose of 5 micrograms/kg the effect lasted only very briefly. A general increase in motor behavior was also observed within 10 min of drug administration. More complex patterns of motor behavior, consisting of stereotypical head bobbing, paw movements reminiscent of walking activity, nystagmus, and ataxia were observed with doses of 0.25 mg/kg and higher. All rats showed a marked startle response at early stages post-injection and hypersensitivity to external stimuli such as noise or movement in the room. However, there was an absolute lack of coordinated avoidance responses normally associated with such startle responses or arousing stimuli.

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A correlative light and electron microscopic investigation was undertaken to determine the morphology and distribution of catecholamine (CA)-containing axon terminals in the hypoglossal nucleus (XII) of the rat. This was accomplished immunocytochemically with antibody to tyrosine hydroxylase (TH). The major findings in this study were the following: 1) Immunoreactive profiles were found throughout XII and included unmyelinated axons, varicosities, axon terminals and dendrites; 2) Nonsynaptic immunoreactive profiles (preterminal axons, varicosities) were more frequently observed (55.2%) than synaptic profiles (43.5%); 3) CA-containing axon terminals ending on dendrites were more numerous (71.8%) than those synapsing on somata (25.4%) or non-labeled axon terminals (2.7%); 4) The morphology of labeled axon terminals was variable. Axodendritic terminals typically contained numerous small, round agranular vesicles, a few large dense-core vesicles and were associated with either a symmetric or no synaptic specialization, axosomatic terminals were often associated with a presynaptic membrane thickening or a symmetric synaptic specialization and contained small, round and a few elliptical-shaped vesicles, while axoaxonic synapses formed asymmetric postsynaptic specializations; and 5) CA-positive dendritic processes were identified in XII. These findings confirm the CA innervation of XII, and suggest a complex, multifunctional role for CA in controlling oro-lingual motor behavior.

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The morphology and distribution of serotonin-containing axon terminals in the rat hypoglossal nucleus (XII) was investigated immunocytochemically at the electron microscopic level. Serotonin-positive profiles were found throughout all regions of XII and included unmyelinated axons, varicosities and axon terminals. Most labeled profiles (68.1%) were nonsynaptic unmyelinated axons and varicosities, while synaptic profiles, ending on dendrites and somata, were seen less frequently (28.7%). The majority of labeled axon terminals (76.9%) ended on small-to-medium-sized dendrites. Most axodendritic terminals contained small, round agranular vesicles (20-55 microns), several large (60-100 microns) dense core vesicles, and were associated with a pronounced asymmetric postsynaptic specialization. By contrast, labeled axosomatic terminals were seen less often than those ending on dendrites (23.0%). Axosomatic terminals typically contained small, round, agranular and large dense core vesicles and were associated with a symmetric or no postsynaptic specialization. These results provide the structural substrates for elucidating the functional role of serotonin in tongue control.

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We tested the effects of clozapine (0.02-20 mg/kg i.p.) on ketamine-induced linguopharyngeal events in rats anesthetized with i.m. injections of ketamine hydrochloride (100 mg/kg) and mounted on a stereotaxic with the tip of the tongue tied to a force displacement transducer monitoring tongue protrusions, retrusions and swallows. Reduction began at the 0.04 mg/kg dose. At 4.8 mg/kg there was total suppression of events. At 20 mg/kg, suppression lasted for 1 h. Notably clozapine doses causing total suppression of events in our model were much lower than those usually reported to alter dopamine turnover.

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1. Cortico-lingual and linguo-cortical interconnectivity was investigated in ketamine-anaesthetized rats mounted onto a stereotaxic apparatus. The tip of the tongue was tied to a force displacement transducer to monitor tongue retrusions. The tongue cortical area was exposed in one or both hemispheres to record evoked potentials or spontaneous electroencephalographic (EEG) activity, or to stimulate electrically with single square pulses of up to 50 V and 0.25 ms pulse width. 2. The results showed that (i) tongue retrusions elicited by electrical stimulation were identical to those induced by ketamine; (ii) ketamine-induced tongue contractions correlated in time with cortical EEG potentials which were easily distinguished from the background noise; (iii) haloperidol (2.5 mg/kg, i.m.) suppressed the cortically evoked tongue contractions as well as the ketamine-induced contractions. 3. These results suggest that ketamine-induced tongue retrusions may involve the cortex in their mediation if not their generation and that this may provide a basis for the suppression of dyskinetic activity during sleep or unconsciousness.

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This study examined the consequences of alcohol (ethanol) exposure during fetal life on lesion-induced dopaminergic synapse responsiveness (plasticity) in the olfactory tubercle of the adult rat. Normally, in the olfactory tubercle, olfactory bulbectomy elicits alterations in pre- and postsynaptic dopaminergic markers, including, respectively, (1) increased tyrosine hydroxylase activity and immunoreactivity, which is associated with dopaminergic axon sprouting, and (2) increased dopaminergic receptor density and potentiated dopamine activation of adenylate cyclase. We have utilized biochemical and quantitative immunocytochemical methodology to examine these synaptic markers in olfactory bulbectomized or sham-operated adult rats. These animals were offspring of dams which were administered one of the following diets during pregnancy: (1) liquid diet containing 35% ethanol-derived calories ad libitum; (2) liquid diet containing an isocaloric amount of maltose-dextrin instead of ethanol, pair-fed; or (3) unaltered liquid diet ad libitum. The results show that prenatal alcohol exposure leads to suppression of the lesion-elicited dopaminergic synapse responsiveness in the olfactory tubercle. There were no significant differences between offspring born to control and pair-fed animals, indicating that the observed abnormalities were not due to alterations in their nutritional status. In conclusion, the present data are a biochemical and quantitative immunocytochemical demonstration of impaired lesion-induced synaptic responsiveness. This renders a new dimension in support of previous evidence indicating that prenatal alcohol exposure leads to altered neuroanatomical, neuroendocrinological and behavioral responsiveness to various challenges. Such impaired synaptic responsiveness may underlie brain functional abnormalities characteristic of fetal alcohol syndrome.

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1. The purpose of this study was to demonstrate that ketamine anesthesia (100 mg/kg) induces tongue protrusions (P) in addition to retrusions (R) and swallows (S) in adult rats. 2. These linguo-pharyngeal events occur alone or combined in various sequential patterns. 3. The SPR sequence is not the predominant pattern in all preparations suggesting profound disruption of physiological linkages by ketamine. 4. Haloperidol administration suppresses these events for 1-120 min depending on the dose (0.75-2.5 mg/kg). 5. Swallows are the least vulnerable to haloperidol. 6. This and previous findings provide further evidence that ketamine induced linguo-pharyngeal activity can serve as a model for acute or tardive dyskinesia better than stereotypies.

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The effects of metoclopramide on ketamine-induced linguopharyngeal events exemplified by tongue retrusions, protrusions, and swallowing acts were tested in ketamine-anesthetized rats mounted on a stereotaxic frame with the tip of the tongue tied to a force displacement transducer to monitor retrusion and protrusion and a pressure transducer inserted into the mouth at the level of the soft palate to monitor swallowing. Metoclopramide at doses ranging from 0.5 to 50 mg/kg im failed to decrease protrusions, retrusions, or swallowing. It rather increased all three events for up to 2.5 hours. The significance of these findings is discussed.

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Injections of wheat germ agglutinin-HRP into the medullary reticular formation (MRf) or the substantia nigra reticulata (SNr) revealed the presence of reciprocating fiber connections between the two areas. Large injections in the MRf demonstrated the existence of labeled neurons in the lateral portions of the SNr. Isolated injections into the parvocellular nuclei of the MRf resulted in the presence of terminal fields in the SNr particularly its lateral portions. Injections in the SNr resulted in the presence of labeled cells in the parvocellular nuclei. The significance of these findings is discussed in terms of oro-facial dyskinesias.

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The catecholamine innervation of the hypoglossal nucleus (XII) was investigated immunocytochemically by comparing the distribution patterns of tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in the rat. Numerous TH- and DBH-positive profiles were found throughout XII, while only occasional PNMT immunoreactivity was observed. Significantly, the distribution patterns of TH and DBH immunoreactivity were coextensive with the most intense staining found ventromedially along the caudal half of XII. We conclude, therefore, that the catecholamine innervation of XII is largely noradrenergic, and that motoneurons innervating the genioglossi muscles, the principal protrusors of the tongue, are the primary targets of this input.

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