Effect of prostaglandin E1 analogue TFC 612 on diabetic neuropathy in streptozocin-induced diabetic rats. Comparison with aldose reductase inhibitor ONO 2235.

The effect of a newly developed oral agent, prostaglandin E1 (PGE1) analogue TFC 612, on diabetic neuropathy was studied by giving it for 6 wk to streptozocin-induced diabetic rats that had been diabetic for 3 mo and was compared with the effects of aldose reductase inhibitor ONO 2235. Although both compounds improved decreased motor nerve conduction velocity, the effect of TFC 612 continued during the 6 wk of treatment, whereas that of ONO 2235 became weaker from wk 4. The abnormality in sciatic nerve sorbitol and myo-inositol levels was reversed with ONO 2235, whereas it was unchanged with TFC 612. With the laser Doppler flowmetry technique, a decrease in the sciatic nerve blood flow in diabetic rats was shown to improve with both compounds, but TFC 612 had a greater effect than ONO 2235, and the increased lactate level of the diabetic nerve was corrected with both compounds, suggesting that both may be associated with the amelioration of ischemia in the diabetic endoneurium. Both TFC 612 and ONO 2235 partially but significantly normalized decreased fiber size in diabetic rats. On the other hand, TFC 612 completely normalized the dilated lumen area in diabetic rats, whereas ONO 2235 did not. These results suggest that the PGE1 analogue TFC 612 has a significant effect on diabetic neuropathy, possibly via vasotropic action, and may be a potent compound for the treatment of diabetic neuropathy.

Neurophysiological evaluation of central-peripheral sensory and motor pudendal fibres.

Extensive neurophysiological investigations were carried out in 18 healthy volunteer subjects, and 6 patients with neurological disease. The tests consisted of spinal and scalp somatosensory evoked potentials (SEPs) to stimulation of the dorsal nerve of penis/clitoris, motor evoked potentials (MEPs) from the bulbocavernosus muscle (BC) and anal sphincter (AS) in response to scalp and sacral root stimulation, and measurement of sacral reflex latency (SRL) from BC and AS. In the control subjects, the mean sensory total conduction time (sensory TCT), as measured at the peak of the scalp P40 wave was 40.9 msec (range: 37.8-44.2). The mean sensory central conduction time (sensory CCT = spine-to-scalp conduction time) was 27.0 msec (range: 23.5-30.4). Transcranial brain stimulation was performed by using a magnetic stimulator both at rest and during voluntary contraction of the examined muscle. Sacral root stimulation was performed at rest. Motor total conduction times (motor TCT) to BC and AS muscles were respectively 28.8 and 30.0 msec at rest, and 22.5 and 22.8 msec during contraction. Motor central conduction times (motor CCT) to sacral cord segments controlling BC and AS muscles were respectively 22.4 and 21.2 msec at rest, and 15.1 and 12.4 msec during contraction. The mean latencies of SRL were respectively 31.4 msec in the bulbocavernosus muscle and 35.9 msec in the anal sphincter. Combined or isolated abnormalities of SEPs, MEPs and SRL were found in a small group of patients with neurological disorders primarily or secondarily affecting the genito-urinary tract.

Evolution of motor, IA and cutaneous nerve-fibre conduction velocities in premature and fullterm newborns.

The conduction velocities of motor, IA and non-nociceptive cutaneous sensory fibres have been studied in the ulnar and median nerves of 145 healthy fullterm neonates and in 77 preterm neonates (postconceptional age-range 28 to 42 weeks). The posterior tibial-nerve motor and IA fibres were studied: the sural nerve cutaneous-fibre conduction velocities were measured in fullterm neonates only. At each age the IA fibre conduction velocities were the highest. There was no difference between the conduction velocity increase per week of postconceptional age in motor and cutaneous fibres. Except for the cutaneous-nerve fibres, conduction velocities were higher in the upper than in the lower limbs.

Electrophysiological assessment of maturation of regenerating motor nerve fibres in infants with brachial plexus palsy.

Age-related changes ('maturation') of the distal latency (L) and conduction velocity (CV) along the axilla-to-wrist segment have been analysed in the regenerating median and ulnar nerves of 24 children with brachial plexus palsy and have been compared with developmental changes in healthy nerves. Results show that maturation of L and CV is more rapid after regeneration than during normal development. Up to three years of age, when L and CV in regenerating nerves reached their maximum maturity, CV values were within normal limits for both nerves in about half of the cases, indicating good regeneration ability in newborns. No specific differences were found between L and CV in the time taken to reach full maturation in the same and in different regenerating nerves, which is contrary to normally developing nerves. The results also demonstrate that the maturation process of regenerating nerves does not lead to the attainment of different specific L values characteristic of normally developing median and ulnar nerves, but to uniform non-specific values close to the mean between them. This was explained by the lack of specific afferent inflow to developing motor neurons (the result of a sensory fibre lesion), which causes the non-specific development of motor units.

An ipsilateral cochlear efferent loop protects the cochlea during intense sound exposure.

One suggested physiological function of the efferent nerve fibers innervating the cochlea is that they protect the cochlea against the effects of intense sound exposure. In order to test this hypothesis, we studied the effects of intense sound in the presence and in the absence of strychnine which blocks the efferent nerve fibers. The results show that in presence of strychnine an ipsilateral intense sound has a greater effect on the cochlea than in the absence of strychnine. We conclude that the ipsilateral cochlear efferents may act as protectors against intense sound exposure.

Short-latency autogenic inhibition (IB inhibition) in human spasticity.

The inhibitory effect of IB interneurons on motoneurons was tested in both legs of six hemiplegic adults. On the normal side, an inhibition of 10 ms, (14.6%) was observed in all cases and was similar to that described previously. On the spastic side, the same technique results in a facilitation of same duration reaching a maximum of 15%. Hence the IB inhibitory effect is, at least functionally, absent in spasticity. Disappearance of IB inhibition is an additional mechanism to be considered in interpreting spasticity.

Inflammation of rat molar pulp and periodontium causes increased calcitonin gene-related peptide and axonal sprouting.

We have studied the response of nerve fibers containing calcitonin gene-related peptide immunoreactivity (CGRP-IR) to inflammation using a rate dental experimental system. Inflammation was induced by drilling tooth cusps to create pulpal exposures; the induced pulpitis and subsequent periapical lesions were studied 1-35 days later using standard CGRP immunohistochemistry and the avidin-biotin peroxidase method. The injury and resulting inflammation caused a disruption of CGRP-IR nerve fiber location and arborization that varied depending on whether the initial injury was limited to the pulp tip or extended throughout the pulp horn. At shorter survival periods (24 hr, 3 days) nerve fibers were either decreased or bundled into the center of the pulp with sprouting along the wound border. At 6 days necrosis and acute inflammation had advanced to varying degrees, and CGRP-IR fibers were extensively sprouted in the surviving pulp; the pulp also stained specifically for CGRP within 1-2 mm of the inflamed tissue at 6 days. At 35 days, we found total pulp necrosis in most teeth and the development of periapical bone loss, granulomatous tissue, and periapical abscesses. There was also an extensive increase in CGRP-IR nerve fibers in the tissues surrounding sites of severe periodontal inflammation and necrosis. In some cases, macrophage-like cells staining specifically for CGRP were near the abscesses. The results show important interactions between peptidergic nerve fibers and inflammatory cells, and are discussed in terms of the role of nerve fibers containing CGRP in neurogenic inflammation, mechanisms for intensification of CGRP immunoreactivity in affected fibers or neighboring cells, and implications for chronic inflammatory conditions, dental pain, and anesthesia.

Neuromuscular effects distant from the site of botulinum neurotoxin injection.

We assessed the severity and temporal profile of distant neuromuscular effects from a single dose (280 units) of botulinum neurotoxin injected into neck muscles for torticollis. We performed single-fiber EMG studies on the biceps brachii of six patients to measure jitter (20 pairs) and fiber density on the initial treatment day and then again, at least once more, after 2 to 12 weeks. No patient developed weakness beyond the neck muscles or decrement of the biceps response to repetitive 3-Hz nerve stimulation. Between the baseline and the last follow-up study, the average of mean MCD increased from 29 microseconds to 38 microseconds (31%). Mean fiber density increased concurrently or earlier from 1.35 to 1.79 (33%). There were no electrophysiologic signs of presynaptic blockade, even at 2 and 4 weeks. The effects we observed are compatible with stimulation of terminal sprouting by the neurotoxin, without significant presynaptic inhibition of acetylcholine release. We therefore believe that higher dosages of the neurotoxin may be used if clinically indicated.

Carbamazepine inhibits spontaneous activity in experimental neuromas.

In eight adult Sprague-Dawley rats the effect of parenteral carbamazepine on spontaneous discharges from saphenous neuromas (7-42 days following nerve section) was tested. Intravenous carbamazepine produced immediate inhibition of spontaneous activity originating in both A-alpha/beta and A-delta fibers at doses of 2.51-11.2 (7.9 +/- 3.3) mg/kg. In four additional animals, serum levels of carbamazepine were determined following iv administration of the drug. These results indicated that ectopic spontaneous impulse generation from experimental neuromas was inhibited by carbamazepine in the range of serum concentration in which the agent is used to treat trigeminal neuralgia and other painful neuropathies in humans. This implies that the effectiveness of this agent in the treatment of these disorders may result from suppression of peripherally originating ectopic spontaneous activity.

New catheter technique for recording left free-wall accessory atrioventricular pathway activation. Identification of pathway fiber orientation.

The ability to record accessory atrioventricular (AV) pathway activation consistently may be uniquely beneficial in improving pathway localization, identifying anatomic relations, and providing insight into unusual conduction properties. For the purpose of recording left AV accessory pathway activation, an electrode catheter was specially designed for use in the coronary sinus. The orthogonal catheter has three sets of four electrodes spaced evenly around the circumference. Electrograms were recorded at low gain (less than 1 cm/mV) between adjacent electrodes on the same set (interelectrode distance, 1.5 mm, center to center). This provides a recording dipole perpendicular to the atrioventricular groove to enhance recording of accessory pathway activation while minimizing overlapping atrial or ventricular potentials. The orthogonal electrode catheter was used in the electrophysiological study of 48 consecutive patients with 59 left AV accessory pathways. The catheter could be advanced along the coronary sinus beyond the site of earliest retrograde atrial activation in 49 of the 59 accessory pathways. Activation potentials were recorded from 45 of the 49 (92%) accessory pathways accessible to the catheter (5 of 5 anterior, 8 of 8 anterolateral, 15 of 16 lateral, 5 of 5 posterolateral, 5 of 5 posterior, and 7 of 10 posteroseptal). Accessory pathway potentials were validated by dissociating them from both atrial and ventricular activation by programmed-stimulation techniques. During surgery, accessory pathway potentials were identified from orthogonal catheter electrodes in the coronary sinus in 14 of 16 accessory pathways (12 patients). Epicardial mapping confirmed the location of the accessory pathway, and direct pressure over the orthogonal catheter electrode that recorded the accessory pathway potential resulted in transient conduction block in nine of the 14 accessory pathways. Orthogonal electrode maps of the coronary sinus identified an oblique course in 39 of 45 recorded accessory pathways. Thirty-two of 38 left free-wall accessory pathways were oriented with atrial insertion 4-30 mm (median, 14 mm) proximal (posterior) to the ventricular insertion. In the remaining six free-wall accessory pathways, the lateral excursion could not be determined because either only the atrial end of the accessory pathway was recorded or activation of multiple pathway fibers prevented tracking of individual strands. The seven recorded posteroseptal pathways exhibited accessory pathway potentials throughout an 8-18-mm (median, 10 mm) length of the proximal coronary sinus, but fiber orientation was difficult to determine.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute and chronic reactions of dental sensory nerve fibers to cavities and desiccation in rat molars.

We have studied the effects of air drying of exposed, acid etched dentin on the sensory innervation of rat molars. In the acute series of experiments, trigeminal nerve fibers were labeled by axonal transport of radioactive protein prior to the dentin exposure and desiccation, the anesthetized rats were fixed by aldehyde perfusion 10 min later, and the teeth were prepared for autoradiography. The results confirmed the hydrodynamic theory by showing outward movement of labeled nerve material in response to dentinal drilling and desiccation. It also showed that some odontoblasts could be separated from the dentinal nerve fibers. In the chronic series, teeth were injured 25 h, 5-7 days, or 21 days prior to fixation and nerves were labeled during the last 24 hours; the surviving vital nerve fibers were evident because of their axonal transport of the radioactive label. In that series, sensory nerve fibers were found to have been lost from areas with newly-formed reparative dentin, or from dentinal tubules that had lost their odontoblasts. In the teeth injured 25 h, 5-7 days, or 21 days earlier, an abnormal nonneuronal labeling occurred 0.2-0.3 mm into injured dentin. Our results are discussed in relation to the hydrodynamic theory, nerve-odontoblast interactions, differences between shallow and deep cavity injuries, altered nerve location in response to pulpal or dentinal injury, and characteristics of the pulp-dentin border.

Expression of neurofilament proteins in the hypertrophic granule cells of Lhermitte-Duclos disease: an explanation for the mass effect and the myelination of parallel fibers in the disease state.

The expression of neurofilament (NF) proteins was examined in the surgical specimen from a 42-year-old woman with Lhermitte-Duclos disease. Hypertrophic granule cell neurons of the dysplastic tissues were reactive with monoclonal antibodies, including antibodies to each of the three human NF subunits. Furthermore, antibodies to dephosphorylation-dependent epitopes on NF proteins stained the cell bodies of hypertrophic granule cells, whereas antibodies to phosphorylation-dependent epitopes stained the enlarged and myelinated axons of the hypertrophic granule cells. Enzymatic dephosphorylation of this tissue abolished axonal staining with phosphorylation-dependent antibodies and uncovered determinants recognized by antibodies to the dephosphorylated state of NF proteins. The NF protein immunoreactivity of hypertrophic granule cells was indistinguishable from that of large, NF-rich neurons in control human cerebellum, suggesting that a normal pattern of expression and phosphorylation of NF proteins occurs in hypertrophic granule cells in Lhermitte-Duclos disease. An increased expression of NF proteins by cerebellar granule cells may account for many of the observed alterations of Lhermitte-Duclos disease, including the hypertrophy of the granule cells and enlargement of their axons, leading to the myelination of parallel fibers within the molecular layer of the cerebellum. Attention should now be directed at the underlying mechanisms which lead to the coordinated up-regulation of the three NF genes and whether or not additional gene products or cell types are altered in Lhermitte-Duclos disease.

A special role of the parvocellular red nucleus in lesion-induced spontaneous tremor in monkeys.

The neural mechanisms underlying spontaneous tremor were investigated in monkeys. Tremor-producing ventromedial tegmental (VMT) lesions involve at least three major neural elements. (1) Parvocellular division of the red nucleus (RNpc); (2) cerebellothalamic fibers passing through the red nucleus, and, (3) nigrostriatal fibers. These three elements were destroyed stereotaxically in areas remote from the VMT area separately and/or in various combinations, and correlation between the site of lesions and tremor was made. Lesion-induced tremor appeared only when the three elements were destroyed. A possible, particular role of the RNpc in the production of the spontaneous tremor is discussed.

The value of testing for unmyelinated fibre, sensory neuropathy in diabetic impotence.

Measurement of thermal thresholds provides a means of assessing neurological deficit and in particular of recognising a neuropathic process affecting unmyelinated and small myelinated fibres of the peripheral nerve. These groups of fibres cannot be tested by nerve conduction studies but are particularly susceptible to disease in diabetes. Thresholds for thermal sensation on the sole of the foot were measured in 33 men presenting with erectile dysfunction. All 15 men with erectile dysfunction, which had been considered on clinical grounds to be neuropathic, had abnormal thermal thresholds. Diabetics with non-neuropathic erectile dysfunction had normal results. Whereas tests of unmyelinated sensory fibre function were abnormal in all those with neuropathic erectile dysfunction, electrophysiological measurement of the bulbocavernosus reflex was normal in five of nine men with diabetic neuropathic impotence.

Diffuse visual field loss in chronic open-angle and low-tension glaucoma.

We examined 37 eyes of 37 patients with chronic open-angle glaucoma and 24 eyes of 24 patients with low-tension glaucoma. All patients had a scotoma confined to the upper or lower hemifield. Eyes with open-angle glaucoma showed twice as much loss of sensitivity in the spared hemifield as compared to eyes with low-tension glaucoma. These differences were statistically significant.

The effect of temporal parameters on subjective sensations evoked by electrical tooth stimulation.

The effect of stimulus duration and frequency on subjective sensations evoked by electrical tooth stimulation was studied in 12 subjects. The sensory responses were classified using 5 equi-sensation categories (perception threshold, prepain, pain threshold, moderate pain, intense pain). Both continuously increasing and randomised stimuli were applied. A comparison was made with the activation thresholds of intradental A- and C-fibres in the cat. The mean threshold of intradental A-fibres was lower than the perception threshold at all pulse durations. Perception threshold decreased with increasing stimulus frequency. Current intensities which evoked prepain at a stimulus frequency of 1 Hz were rated as pain at 20 Hz. At supraliminal pain levels the effects of summation were more marked. High-frequency stimulation produced intense pain sensations at intensities well below the activation thresholds of pulpal C-fibres in the cat. We conclude that both perception and pain thresholds and supraliminal pain are modified by temporal summation, and that activation of different pulpal fibre populations is not responsible for production of prepain and pain sensations.