Structural specificity of sugar transport at the blood-nerve barrier.

The major component of D-glucose transfer across the membranous sites of the blood-nerve barrier (BNB) occurs via a facilitative mechanism at a rate greater than twice the rate of D-glucose metabolism by nerve. To characterize further properties of monosaccharide transport at the BNB, unidirectional transfer constant (K) values were determined in vivo in tibial nerve of anesthetized rats for radiolabeled mannitol, L-glucose, and a series of D-glucose analogs. K values(X 10(-4) mls-1 g-1) equaled 4.8 for 2-deoxy-D-glucose, 3.7 for D-glucose, 2.3 for 3-O-methyl-D-glucose, 1.4 for D-mannose, 0.6 for D-galactose, 0.2 for mannitol, and 0.19 for L-glucose. The rank order of ratios between K values of a D-hexose and D-glucose, which reflects the rank order of affinity of the system for individual sugars, was 2-deoxy-D-glucose greater than D-glucose greater than 3-O-methyl-D-glucose greater than D-mannose greater than D-galactose. The results demonstrate that the order of substrate affinity of the monosaccharide carrier at the BNB is similar to that at cerebral capillaries and at erythrocytes. At normal concentrations of plasma D-glucose, the contribution of simple passive diffusion to unidirectional D-glucose influx across the BNB equals 5%, which is greater than that at cerebral capillaries and reflects the greater permeability to hydrophilic nonelectrolytes of the endoneurial vasculature.

A compartmental analysis of solute transfer and exchange across blood-nerve barrier.

A three-compartment model was derived to analyze solute exchange among plasma, peripheral nerve epineurium, and endoneurium. The model was fit to measured tibial-nerve epineurial and endoneurial contents of [14C]sucrose after intravenous bolus injection of tracer in pentobarbital sodium-anesthetized rats. The transfer constant (K) for tracer at epineurial vessels approximated 1.1 X 10(-3) ml.s-1.g whole-nerve-1. K at the blood-nerve barrier (BNB) equaled 1.36-1.51 X 10(-5) ml.s-1.g endoneurium-1. The endoneurial uptake data were analyzed also by a simplified two-compartment model incorporating solute exchange between plasma and endoneurium. K at the BNB (1.46 X 10(-5) ml.s-1.g endoneurium-1), determined by multiple uptake time graphic analysis, was only threefold greater than K at the blood-brain barrier. The transfer constant at the perineurium alone was determined in situ and equaled (1 X 10(-6) ml.s-1.g endoneurium-1. Calculated permeability coefficients (X 10(-8) cm/s) equaled 3.2 at the perineurium, 23 at the endoneurial capillaries, and 3.2 at the brain vasculature. The results demonstrate that for hydrophilic nonelectrolytes 1) flux across the perineurium contributes significantly to solute uptake from plasma into the endoneurium; 2) although nerve capillaries are more permeable than brain capillaries, the tissues of the BNB function as a unit to markedly restrict solute diffusion into the endoneurium; and 3) a two-compartment analysis accurately describes hydrophilic solute transfer from plasma into peripheral nerve.

Sciatic nerve blood flow response to carbon dioxide.

Sciatic nerve blood flow (NBF) during hypercarbia was examined in unanesthetized decerebrate rats by means of laser Doppler flowmetry (LDF). During inspiration of gas mixtures containing no CO2, followed by either 5, 10 or 20% CO2, arterial pCO2 increased by 13, 18 and 68 mm Hg, respectively. Blood pressure (BP) and the LDF signal, which were measured continuously, increased for 30-40 s following the start of inhalation of CO2 and then decreased. Three min after the start of inhalation of 5 or 10% CO2, BP had returned to the baseline and the LDF signal was increased by 14 and 15%, respectively, compared with preinhalation values. In rats inspiring 20% CO2, systemic BP remained elevated 12% above the baseline and NBF was increased by 18%. The results indicate that dilatation of the vasa nervorum during hypercarbia is less than that at cerebral blood vessels. The nerve vasculature dilates maximally in response to 5% CO2, with a rise in NBF of about 1.1% per mm Hg increase in paCO2.

Permeability changes in blood-retinal barrier of galactosemic rats are prevented by aldose reductase inhibitors.

Permeability-surface-area products (PA) for sucrose at the blood-retinal barrier (BRB) were determined with quantitative in vivo techniques and compared in control rats, rats fed a 50% galactosemic diet, and rats fed a diet containing both galactose and the aldose reductase inhibitor sorbinil. The mean PA +/- SE for controls was 0.656 x 10(-5) +/- 0.13 ml.g-1.s-1 and increased by approximately 500% in galactose-fed animals to 3.13 x 10(-5) +/- 0.32 ml.g-1.s-1. Animals fed both galactose and sorbinil showed no significant difference from control animals (P greater than .05), with a PA of 0.91 x 10(-5) +/- 0.22 ml.g-1.s-1. No breach in the BRB to horseradish peroxidase was detected in any of the groups. These results demonstrate an increased permeability at the BRB to small molecules in galactosemic rats that is prevented by an aldose reductase inhibitor. This suggests that the retinal capillary basement membrane thickening seen in galactosemic rats is associated with an increased permeability of the BRB and that aldose reductase is implicated in its pathogenesis.

Assessment of the permeability of the blood-retinal barrier in hypertensive rats.

We assessed the permeability surface area products at the blood-retinal barrier and blood-brain barrier to sucrose (molecular weight, 340) and microperoxidase (molecular weight, 2000) following acute hypertension induced by metaraminol in Wistar-Kyoto rats (controls) and during chronic hypertension in spontaneously hypertensive rats. In acute hypertension, the permeability surface area product for sucrose was increased at the blood-retinal barrier and at the blood-brain barrier over control values (p less than 0.02), and the vessels became leaky to microperoxidase. In chronic hypertension, the permeability of the blood-retinal barrier to sucrose was increased over that in control animals (p less than 0.02), whereas the permeability of the blood-brain barrier was unaffected. Neither barrier leaked microperoxidase. These results indicate that the blood-brain barrier and the blood-retinal barrier are similarly affected in acute hypertension and that in chronic hypertension, the blood-brain barrier is unaffected whereas the blood-retinal barrier is rendered more permeable to small, but not large, solutes.

Quantitative assessment of the permeability of the rat blood-retinal barrier to small water-soluble non-electrolytes.

1. The passive permeability of the blood-retinal barrier (b.r.b.) to the water-soluble non-electrolytes, sucrose and mannitol, was determined using a multiple time point-graphical approach as has been used in the assessment of blood-brain barrier (b.b.b.) permeability. 2. The calculated permeability surface area product for the b.r.b. for sucrose was 0.44 (+/- 0.081 S.E. of mean) X 10(-5) ml g-1 s-1 (n = 20) and for mannitol was 1.25 (+/- 0.30) X 10(-5) ml g-1 s-1 (n = 18). These values are similar and comparable to those found for the capillaries in the brain (P greater than 0.05) and significantly different from zero (P less than 0.01). 3. Data on the concentrations of sucrose in different parts of the eye show that the permeability of the blood-retinal barrier, rather than the more permeable blood-aqueous barrier permeability, was being measured by our technique.

Transfer of nonelectrolytes from blood into peripheral nerve endoneurium.

Permeability-surface area (PA) products were determined for the transfer of seven nonelectrolytes across the blood-nerve barrier (BNB) of rat tibial nerve using a quantitative in vivo injection technique. PA values at the BNB for slowly penetrating nonelectrolytes such as urea, mannitol, L-glucose, and sucrose differed by less than threefold from values at the blood-brain barrier in the same animals. Permeability coefficients for transfer across the BNB were calculated assuming both endoneurial capillaries and perineurium contribute to solute flux into endoneurium. Total BNB surface area was determined as 175 cm2/g with morphometric techniques. Calculated permeability coefficients for slowly penetrating nonelectrolytes ranged from 7 X 10(-8) cm/s for sucrose to 4 X 10(-7) cm/s for urea and were directly proportional to solute lipid solubility as measured by the octanol-water partition coefficient. BNB permeability coefficients for sucrose, mannitol, L-glucose, and urea were within 60% of values at cerebral capillaries, of the same order of magnitude as values at aporous lipid membranes, and 100-1,000 times less than values at most nonneural capillaries, such as in skeletal muscle. These results demonstrate that the BNB markedly restricts the transfer of hydrophilic nonelectrolytes between plasma and endoneurium and that diffusion restriction of the BNB is comparable to that of the blood-brain barrier.

Altered blood-nerve barrier permeability to small molecules in experimental diabetes mellitus.

Permeability-surface area products (PA) were determined with a quantitative in vivo injection technique at the blood-nerve barrier of tibial nerve, and at the blood-brain barrier, in control and streptozotocin-induced diabetic rats. The PA product for [14C]mannitol at the blood-nerve barrier was increased by 100% in diabetic animals, 3.12 +/- 0.15 X 10(-5) ml X s-1 X g-1, compared with controls, 1.61 +/- 0.10 X 10(-5) ml X s-1 X g-1. In contrast, PA for [14C]mannitol at the blood-brain barrier was unaltered in the diabetic animals. Following intravenous injection, no leakage of microperoxidase across the perineurium or endoneurial vessels of diabetic rats could be demonstrated by morphological techniques. Nerve blood-space, as determined with intravenous [3H]inulin, and blood-nerve barrier surface area as determined by morphometric methods, did not differ in diabetic when compared to control animals. Thus, the calculated permeability coefficient for [14C]mannitol at the blood-nerve barrier was about 100% greater in diabetic nerve compared to control nerves. The increased permeability was accompanied by a 7% increase in nerve-water content and a 32% decrease in motor-nerve conduction velocity. The results demonstrate a specific vulnerability of nerve as compared to brain in an animal model of diabetes mellitus. Chronically altered permeability to small water-soluble molecules reduces the protective effect of salt impermeability at the blood-nerve barrier against nerve edema, and may be an important pathogenic mechanism in diabetic neuropathy.

Calcium in rat peripheral nerve during chronic alterations in plasma calcium.

The calcium content in desheathed tibial nerve was compared to that in cerebellum in rats fed diets containing either 0.01% (low), 0.67% (control) or 3.0% (high) Ca, for 8 weeks. For changes in concentration of plasma ionized Ca, 48% below and 35% above the control mean, percent change in endoneurial Ca content is linearly related, with a slope of 0.80, to percent change in plasma ionized Ca. A line with a slope of 0.21 describes the relation between percent change in cerebellum Ca and percent change in plasma ionized Ca. Plasma, cerebellum and nerve concentrations of Na, K and Cl were similar in the control compared with the two experimental groups of animals. The concentration of plasma Mg varied 20% below and 17% above the control mean, inversely with plasma Ca, but nerve and cerebellum Mg did not change from control values. The results of this study fail to demonstrate Ca homeostasis in rat peripheral nerve endoneurium during chronic hypo- and hypercalcemia. Endoneurial Mg, however, appears to be regulated.

The pathophysiology of penicillamine-induced myasthenia gravis.

The temporal course and pathophysiology of penicillamine-induced myasthenia gravis were studied in detail in a typical case. Our results suggest that this disorder and idiopathic autoimmune myasthenia gravis share the same essential pathophysiological features, including the presence of anti-acetylcholine receptor (AChR) antibody, serum-induced blockade of AChRs, antibody-mediated accelerated degradation of AChRs, and a resultant quantitative reduction in available junctional AChRs. An initial severe reduction in junctional AChRs was reversed and the patient recovered, both within 8 months of stopping penicillamine. Our data suggest that penicillamine probably produced myasthenia gravis by initiating a new autoimmune response rather than by enhancing ongoing autoimmunity.

Distribution of adrenergic innervation of blood vessels in peripheral nerve.

The distribution of adrenergic innervation of microvessels in the extrafascicular and endoneurial compartments of rat tibial nerve was examined with glyoxylic acid-induced and formaldehyde-induced histofluorescence methods. Periarterial and arteriolar adrenergic nerves were present in the epineurium-perineurium suggesting that blood flow in the extrafascicular connective tissue is under neurogenic influence. In contrast, blood vessels in the nerve endoneurium were not associated with histofluorescent nerve fibers. The absence of perivascular adrenergic innervation in the endoneurium suggests that regulation of vascular function within the endoneurium is not under neurogenic control.

Facilitated transport of glucose from blood into peripheral nerve.

D-Glucose is the major substrate for energy metabolism in peripheral nerve. The mechanism of transfer of glucose across the blood-nerve barrier is unclarified. In this study an in situ perfusion technique was utilized, in anesthetized rats, to examine monosaccharide transport from blood into peripheral nerve. Unidirectional influxes of D-[14C]glucose, L-[14C]glucose, and [14C]3-O-methyl-D-glucose across capillaries of the tibial nerve were measured at different perfusate concentrations of unlabelled D-glucose. The permeability-surface area product (PA) for D-[14C]glucose and [14C]3-O-methyl-D-glucose decreased, whereas the PA for L-[14C]glucose remained constant, as the perfusate concentration of D-glucose was increased. In the presence of no added unlabelled D-glucose in the perfusate, the PA for L-[14C]glucose equaled one-fifth the PA for D-[14C]glucose. These results demonstrate self-saturation, competitive inhibition, and stereospecificity of glucose transfer, and for the first time show a unidirectional facilitated transport mechanism for D-monosaccharides at capillaries of mammalian peripheral nerve. The data were fit to a model for facilitated transport and passive diffusion. The half-saturation constant and maximal rate of transport for the saturable component of D-glucose influx equaled 23 +/- 11 mumol X ml-1 and 6.6 +/- 3.2 X 10(-3) mumol X s-1 X g-1, respectively. The constant of nonsaturable glucose influx equaled 0.5 +/- 0.1 X 10(-4) s-1. At normal plasma glucose concentrations, the saturable component comprises about 80% of total D-glucose influx into nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic demyelinating polyneuropathy in systemic lupus erythematosus.

Mononeuritis multiplex and acute demyelinating polyneuropathy (Guillain-Barré syndrome) are well known in systemic lupus erythematosus (SLE). Chronic acquired demyelinating polyneuropathy has been reported rarely in SLE. Two young women had monophasic progressive weakness, areflexia, elevated CSF protein, and slow nerve conduction velocities as the first manifestation of SLE. Sural nerve biopsy in one patient revealed mild loss of myelinated fibers and an increased number of thinly myelinated fibers. Steroid therapy led to improvement in both patients. These patients demonstrate that chronic demyelinating polyneuropathy can be an unusual presentation of SLE, even preceding characteristic systemic disease by months.

Atypical CT findings in bacterial meningoencephalitis.

Computed tomography has become a valuable imaging modality in the evaluation and management of most intracerebral infections. We report two cases of intracranial infections with atypical CT findings, and attempt to correlate these findings with the pathophysiology.

Hereditary neuropathy with upper motor-neuron, visual pathway, and autonomic disorders.

A 42-year-old man had progressive distal weakness and muscle atrophy, stocking-type sensory loss, upper motor-neuron and visual pathway lesions, and dysautonomia. Electrodiagnostic tests revealed a generalized sensorimotor peripheral neuropathy that largely involved axons. Low recumbent and upright norepinephrine levels implied a peripheral autonomic defect. Sural nerve biopsy showed mild abnormalities of medium and small size fibers. The patient's mother and two brothers were also affected. Other causes of peripheral motor, sensory, and autonomic failure were eliminated. This kinship does not fit any generally accepted classification of hereditary neuropathies.

In vitro effects of amphotericin B on growth and ultrastructure of the amoeboflagellates Naegleria gruberi and Naegleria fowleri.

In vitro effects of the polyene antibiotic amphotericin B (AmB) on growth, viability, and ultrastructure of amoeboflagellates of the genus Naegleria were examined. The strains studied were the nonpathogenic Naegleria gruberi EG(B) and the Carter and TY strains of the pathogenic Naegleria fowleri. AmB was amoebicidal at all concentrations used (0.25, 0.50, and 1.0 mug/ml) when the drug was added to cultures in lag phase, as determined by viability testing, but was mainly inhibitory when added to log-phase cultures. The drug produced ultrastructural modifications at all concentrations (0.05 to 1.0 mug/ml). These changes included distortion of nuclear shape, increase in cytoplasmic membranes (both rough and smooth endoplasmic reticulum), decrease in number of food vacuoles, absence of pseudopod formation, mitochondrial abnormalities, increase in autophagic vacuoles, and blebbing of the plasma membrane. These alterations of amoebic ultrastructure became more pronounced with increased time in AmB and with increase in AmB concentration in the growth medium.