Prevention and reversal of defective axonal transport and motor nerve conduction velocity in rats with experimental diabetes by treatment with the aldose reductase inhibitor Sorbinil.

This investigation was designed to determine whether the aldose reductase inhibitor Sorbinil prevented the development of or reversed defects of nerve conduction and axonal transport in streptozotocin-diabetic rats. Untreated diabetes of either 3 or 6 wk duration caused a fall in sciatic motor nerve conduction velocity (MNCV) of 6-9 m/s (P less than 0.001) and significantly reduced the accumulation of axonally transported choline acetyltransferase activity against a 24-h sciatic nerve crush. These functional defects were associated with accumulation of sorbitol and depletion of myo-inositol in the sciatic nerve. Treatment with Sorbinil (25 mg/kg/day, p.o.) throughout the period of diabetes prevented the development of all these abnormalities in both 3- and 6-wk diabetic groups. In a second study, three groups of rats were subject to 3 wk untreated diabetes followed by Sorbinil treatment (as above) for 1, 2, or 3 wk to determine whether the abnormalities expected from 3 wk of untreated diabetes could be reversed. One week of treatment significantly elevated both MNCV and choline acetyltransferase accumulation (P less than 0.05). The longer treatments progressively ameliorated these defects such that the group that received Sorbinil for the second 3 wk of a 6-wk diabetic period gave values that were similar to controls and to diabetic rats that had been given Sorbinil throughout their diabetes. Sorbitol accumulation was markedly reduced by only 1 wk of Sorbinil treatment, but the normalization of myo-inositol levels required 2 wk of treatment. These findings indicate that Sorbinil treatment in diabetic rats prevented and reversed both Sorbitol accumulation and depletion of nerve myo-inositol in the sciatic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological effects of selective opioid agonists on spontaneous and evoked neuronal activity in the dentate gyrus of the hippocampus in vivo.

The mechanism by which endogenous opioid peptides regulate neuronal excitability in the dentate gyrus of the hippocampus remains unclear. We studied the neurophysiologic responses to various receptor-selective opioids, given both iontophoretically and systemically, in anesthetized rats. Single unit action potentials and field potential recordings were taken from electrophysiologically classified dentate granule cells (DGCs) or dentate interneurons (INTs). The mu receptor agonist ([D-Ala2, NMe-Phe4, Gly-ol]-Enkephalin (DAMGO)) increased the responsiveness of DGCs to perforant path stimulation, although it did not induce spontaneous activity in DGCs. We did not see this facilitation with systemic morphine sulfate (MS). However, both DAMGO and MS produced similar, primarily inhibitory, effects on INTs. The responsiveness of an individual INT tended to be related to the cell's location in the dentate gyrus, and to a lesser degree, to its baseline spontaneous discharge frequency. U-50488H, a selective kappa receptor agonist, had little effect on either DGCs or INTs. Our results suggest that mu selective opioids have a complex neuropharmacology in this region involving interaction among different types of INTs to produce an effect on the principal output cells.

Subclavian artery approach for insertion of intra-aortic balloon.

Subperiosteal clavicular resection for access to the subclavian artery is described. In those patients requiring intra-aortic balloon placement in the nonsurgical setting, such an approach provides a reasonably benign alternative when aortoiliac atherosclerosis prevents the usual retrograde femoral placement. Little morbidity or functional compromise is associated with clavicular wedge resections, and the anatomic availability of a large artery without the need for major surgical maneuvers in these gravely ill patients is a distinct advantage.

Isolated, unruptured sinus of Valsalva aneurysm: serendipitous detection and correction.

Reaction of an isolated, unruptured sinus of Valsalva aneurysm is described. Detection was serendipitous in a patient with previous surgical resection and grafting of significant aortic coarctation. The philosophy and importance of proceeding with elective resection in these progressive lesions is emphasized.

Site-selective acute desensitization following local administration of opioid in the hippocampus.

Electrophoretic administration of the mu selective opioid agonist [D-Ala2, NMe-Phe4, Gly-ol]-Enkephalin (DAMGO) in the dentate gyrus of the hippocampus acutely produces a marked increase in the responsiveness of dentate granule cells to perforant path stimulation. This can be measured by an increase in the primary population spike (PS) amplitude and by disinhibition in the paired-pulse (PP) paradigm. Concomitantly, the spontaneous single unit activity of interneurons is usually inhibited. We have observed that after prolonged (usually 10-20 min) local (electrophoretic) administration of DAMGO, a second, late effect is noted, suggesting acute desensitization. There is a loss of the disinhibition seen in the PP paradigm while the primary PS shows only some increased variability in response to stimulation. Furthermore, in a time course parallel to the loss of disinhibition, single cell activity initially inhibited by DAMGO appears to lose its responsiveness. Pretreatment with kappa or delta opioid agonists, or with GABA agonists and antagonists, does not affect the development of this desensitization suggesting selective involvement of the mu receptor. We further propose a regional specificity within the hippocampus since we are unable to detect evidence of desensitization to opioid in CA1 using the same techniques.

Longitudinal study of cognitive abilities and academic achievement.

Assessment was made of the effectiveness of a battery of cognitive tests administered in kindergarten in the prediction of sixth grade achievement in reading comprehension, spelling, language usage, and arithmetic. Cognitive abilities included several factors of intelligence, visual perception and visual sequential memory, visual-motor integration, and auditory perception and auditory sequential memory. Measures of prior learning were also included. Subjects were 58 children in a suburban public school district. A criterion for predictive utility for correlation coefficients was established, and simple correlation coefficients for various kindergarten measures and sixth grade achievement ranged from the criterion of .35 to .69. In partial correlations with the effects of ability to understand ideas expressed in words removed, correlation coefficients for various cognitive measures and achievement tests ranged from the criterion of .35 to .63. Combinations of kindergarten measures having optimal multiple correlations with later school achievement generally approached or exceeded .70. These findings are discussed and suggestions are made for further research.

Electrophysiological effects of Mu-selective opioids on hilar neurons in the hippocampus in vivo.

Although mu-selective opioids have been shown to produce dramatic effects on neurons within the CA1 and dentate regions of the rat hippocampus, little is known regarding their effects on neurons within the hilus, a region of potential importance in several disease states. We studied the neurophysiologic responses of hilar neurons recorded extracellularly to electrophoretic [D-Ala2, NMe-Phe4, Gly-ol]-enkephalin (DAMGO) and systemic morphine (MS) in anesthetized rats. We found that hilar cells could be readily divided into two categories, based on their pattern of spontaneous activity and response to perforant path stimulation. Cells that discharged in a bursting-type pattern formed a homogeneous group electrophysiologically. The response of these cells to opioids was dependent on route of administration, with the spontaneous activity of all cells tested increasing following electrophoretically administered DAMGO, and remaining unchanged in response to systemic MS. Cells that discharged in a non-bursting pattern showed some electrophysiologic variation, as well as some differential response to opioids. However, the spontaneous activity in the majority of non-bursting cells increased following electrophoretic administration of DAMGO. In these cells, MS produced similar, although usually less dramatic, effects. Comparison with intracellular data suggests that the bursting cells in our study correlate most closely with hilar "mossy cells," while the non-bursting action potentials were recorded from other cells, primarily putative interneurons. We conclude that mu-selective opioids produce excitation of mossy cells, probably through an indirect mechanism, with the primary site of action occurring on cells in the granule cell layer. This regional excitation may help to mediate the effects of locally administered mu-selective opioids within the dentate gyrus.

Reversal of deficits in axonal transport and nerve conduction velocity by treatment of streptozotocin-diabetic rats with myo-inositol.

This study examined the effects of myo-inositol treatment on the deficits of motor nerve conduction velocity and of axonal transport of choline acetyltransferase in rats with streptozotocin-induced diabetes. Motor nerve conduction velocity was measured in seven groups of male rats. Two groups formed nondiabetic controls; one survived for 3 and the other for 6 weeks, then motor nerve conduction velocity was again measured and the accumulation of choline acetyltransferase activity proximal to a 24-h sciatic nerve constriction was estimated. The other five groups were rendered diabetic and subjected to similar measurements. Two diabetic groups were untreated and survived 3 or 6 weeks. The other three groups received myo-inositol for 1, 2, and 3 weeks, respectively, commencing 21 days after induction of diabetes. These groups survived for 4, 5, or 6 weeks, respectively. In all groups surviving for longer than 3 weeks an interim measurement of motor nerve conduction velocity was made 21 days after the start of the experiment (immediately before onset of treatment in the treated groups). In these groups a third measurement was made on the day before death. At death, choline acetyltransferase accumulation was measured and the remainder of the sciatic nerves was assayed for sorbitol and myo-inositol. In the two untreated diabetic groups we found reduced motor nerve conduction velocity, a deficit in the accumulation of choline acetyltransferase proximal to the sciatic nerve constriction, and a marked build-up of nerve sorbitol and a depletion of nerve myo-inositol. All three treated groups showed a reversal of this myo-inositol depletion without a reduction in the nerve sorbitol content.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of defects of axonal transport and nerve conduction velocity by oral administration of myo-inositol or an aldose reductase inhibitor in streptozotocin-diabetic rats.

The effects of orally-administered myo-inositol have been compared with those of an aldose reductase inhibitor on acute neurological defects in experimentally diabetic rats. Three groups of streptozotocin-treated diabetic rats (50 mg/kg, IP) together with three groups of age-matched controls (saline, IP) were compared. One pair of groups (control and diabetic) were untreated for 3 weeks, another pair of groups received daily oral myo-inositol (667 mg/kg) and the third pair received an aldose reductase inhibitor (ICI 105 552; 50 mg . kg-1, day-1, orally). The untreated diabetic group showed statistically significant deficits in accumulation, proximal to 24 h sciatic nerve constrictions, of choline acetyltransferase activity by comparison with untreated controls (2.8 +/- 0.4 versus 5.1 +/- 0.4 nmol acetylcholine . h-1 . nerve-1; p less than 0.001). The untreated diabetic rats also showed a fall in motor nerve conduction velocity of 6.2 +/- 0.7 m/s which was statistically significant (p less than 0.001). Treatment of the diabetic group with myo-inositol prevented the development of both defects of axonal transport and conduction velocity; both measurements were similar to those of the myo-inositol treated control rats. Likewise the diabetic rats which received aldose reductase inhibitor showed prevention of both defects. Nerves from untreated diabetic rats showed marked sorbitol accumulation and a statistically significant reduction in myo-inositol content by comparison with the untreated controls (sorbitol, 1.56 +/- 0.22 versus 0.8 +/- 0.01 and myo-inositol, 1.47 +/- 0.10 versus 2.3 +/- 0.10 nmol/mg; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Allergy and the gut.

There have frequently been doubts as to the relevance of food allergy, in particular as far as the involvement of the intestinal tract is concerned. Several studies, however, have confirmed the existence of allergic reactions in the gut, with an estimated prevalence of about 1-2% in adults. Clinical symptoms are unspecific and include nausea, vomiting, abdominal pain, cramping and diarrhea. Intestinal mast cells, as well as intestinal eosinophils, have been shown to be involved in the pathogenesis of food-allergy-related enteropathy. In addition to classical IgE-dependent degranulation, further agonists have been demonstrated for mast cell activation, for example IL-4. The methods used to confirm the diagnosis of intestinal allergy are still insufficient. Until now, blinded oral challenge procedures with food antigens have been accepted as the 'gold standard' in diagnosing food allergy, although these tests have practical problems. Therefore, new test systems have been developed, such as endoscopic provocation tests, that may improve diagnostic procedures. Elimination diet still presents the main basis of therapy. Aspects to be focused on in the future are the role fo IgE-independent allergic mechanisms in intestinal allergy, the impact of cross-reactivity with other allergens and the relationship to other inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, celiac disease and irritable bowel syndrome.

Axonal transport and nerve conduction and their relation to nerve polyol and myo-inositol levels in spontaneously diabetic BB/D rats.

This study examined orthograde axonal transport of choline acetyltransferase activity and motor nerve conduction velocity in insulin-treated diabetic and nondiabetic rats of the BB/D strain. In the same animals sciatic nerve contents of glucose, fructose, sorbitol, and myo-inositol were measured to determine whether any functional defects coexisted with polyol pathway activity or myo-inositol depletion. There were no differences between controls and diabetics in conduction velocity or the accumulation of choline acetyltransferase activity proximal to a 24-h sciatic nerve constriction. The latter finding implies no defect of axonal transport of the enzyme. At death the control rats were normoglycemic (mean blood glucose, 6.2 +/- 0.3 mmol/L) and the diabetic rats were moderately hyperglycemic (mean blood glucose, 18.1 +/- 1.3 mmol/L). The sciatic nerves of the diabetic rats showed marked elevation of glucose levels, moderate fructose accumulation and slight sorbitol accumulation. However, the myo-inositol levels were similar to those of control nerves. The findings suggest that, in BB rats with the degree of insulin treatment used here, myo-inositol levels were normal and that this co-existed with nerve conduction and axonal transport measurements which were similar to controls.

Slow orthograde axonal transport of radiolabelled protein in sciatic motoneurones of rats with short-term experimental diabetes: effects of treatment with an aldose reductase inhibitor or myo-inositol.

This study examined the effect of streptozotocin diabetes of 5 weeks duration on the profile of slow orthogradely transported radiolabelled protein in rat sciatic motoneurones. The diabetic rats showed a retardation of the tail of the slow-component profile. This selective retardation was unaffected by treatment with an aldose reductase inhibitor, although this treatment reduced the accumulation of sorbitol and prevented the depletion of myo-inositol in the sciatic nerves of the treated diabetic rats. Other groups, treated with myo-inositol, had normal or elevated sciatic nerve myo-inositol levels in the presence of accumulated sorbitol. The axonal transport profiles from both control and diabetic myoinositol-treated groups gave normal tail velocities but an altered shape such that retardation of the tail of the profile may have been present in both. The study concludes that rats with 5 weeks streptozotocin diabetes show retardation of the velocity of the most slowly transported proteins in sciatic motoneurones, and that this defect is not linked to the polyol pathway.

The regrowth of right atrial noradrenergic nerves after 6-hydroxydopamine in genetically diabetic mice; effects of insulin treatment.

1 This study examined the rate of repletion of right atrial noradrenaline levels after a single dose (100 mg/kg i.p.) of 6-hydroxydopamine (6-OH Da) in diabetic and non-diabetic mice of the C57 BL/KS db/db strain. 2 In mice which received no 6-OH Da there was no significant difference, in endogenous noradrenaline levels, between diabetic and non-diabetic animals. The depletion of noradrenaline 24 h after 6-OHDa was slightly more profound in the diabetic mice than in non-diabetic controls. Thereafter the rate of repletion of noradrenaline was more rapid in the diabetic group. 3 The normal noradrenaline content was reinstated in diabetic mice between 7 and 10 days after 6-OHDa. In the non-diabetic group levels similar to those found in untreated mie were not reinstated until 14 days after 6-OHDa. 4 Ten days after 6-OHDa right atria from diabetic mice were markedly more responsive to stimulation of the intramural noradrenergic nerves than were preparations from non-diabetic mice. 5 A group of diabetic mice was treated with insulin (10 m Units/g daily) for 6 weeks. The right atria from these animals, examined 10 days after 6-OHDa, were similar in their responses to noradrenergic nerve stimulation to the preparations from the non-diabetic mice. 6 All these groups of atria gave similar responses to exogenous noradrenaline. These findings indicate that regrowth of noradrenergic terminals after 6-OHDa was more rapid in diabetic mice than in either insulin-treated diabetic mice or non-diabetic mice.