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PubMed2001

Convection-enhanced delivery in intact and lesioned peripheral nerve.

OBJECT: Although the use of multiple agents is efficacious in animal models of peripheral nerve injury, translation to clinical applications remains wanting. Previous agents used in trials in humans either engendered severe side effects or were ineffective. Because the blood-central nervous system barrier exists in nerves as it does in the brain, limited drug delivery poses a problem for translation of basic science advances into clinical applications. Convection-enhanced delivery (CED) is a promising adjunct to current therapies for peripheral nerve injury. In the present study the authors assessed the capacity of convection to ferry macromolecules across sites of nerve injury in rat and primate models, examined the functional effects of convection on the intact nerve, and investigated the possibility of delivering a macromolecule to the spinal cord via retrograde convection from a peripherally introduced catheter. METHODS: The authors developed a rodent model of convective delivery to lesioned sciatic nerves (injury due to crush or laceration in 76 nerves) and compared the results to a smaller series of five primates with similar injuries. In the intact nerve, convective delivery of vehicle generated only a transient neurapraxic deficit. Early after injury (postinjury Days 1, 3, 7, and 10), infusion failed to cross the site of injury in crushed or lacerated nerves. Fourteen days after crush injury, CED of radioactively-labeled albumin resulted in perfusion through the site of injury to distal growing neurites. In primates, successful convection through the site of crush injury occurred by postinjury Day 28. In contrast, in laceration models there was complete occlusion of the extracellular space to convective distribution at the site of laceration and repair, and convective distribution in the extracellular space crossed the site of injury only after there was histological evidence of completion of nerve regeneration. Finally, in two primates, retrograde infusion into the spinal cord through a peripheral nerve was achieved. CONCLUSIONS: Convection provides a safe and effective means to deliver macromolecules to regenerating neurites in crush-injured peripheral nerves. Convection block in lacerated and suture-repaired nerves indicates a significant intraneural obstruction of the extracellular space. a disruption that suggests an anatomical obstruction to extracellular and, possibly, intraaxonal flow, which may impair nerve regeneration. Through peripheral retrograde infusion, convection can be used for delivery to spinal cord gray matter. Convection-enhanced delivery provides a promising approach to distribute therapeutic agents to targeted sites for treatment of disorders of the nerve and spinal cord.

Albumins↗
PubMed1992

Morphological study of amyloid fibrils and preamyloid deposits in the brain with Alzheimer's disease.

In addition to the ultrastructural study of amyloid fibrils, amyloid fibrils and preamyloid in the brain which had the fine ultrastructure of a well-preserved neuropil were examined using methenamine silver stain by light and electron microscope. In serial sections, amyloid fibrils in extracellular spaces continued directly to the capillaries. Using methenamine silver stain, silver granules were deposited at the amyloid fibrils and in extracellular spaces forming diffuse plaques. Many silver granules in the extracellular spaces seemed to strain preamyloid surrounding the capillaries. These findings to indicate that the capillaries have an important role in the formation of amyloid fibrils at least in some senile plaques.

Alzheimer Disease↗
PubMed1991

On the question of a subdural space.

The structure of the meninges, with particular attention to the architecture of the inner portions of the dura mater and the arachnoid mater, has been reviewed in reference to the probable existence of a "subdural" space. The dura is composed of fibroblasts and large amounts of extracellular collagen. The innermost part of the dura is formed by the dural border cell layer. This layer is characterized by flattened cells with sinuous processes, extracellular spaces containing an amorphous material, and the presence of junctions between its cells. The dural border cell layer is continuous with the inner (meningeal) portions of the dura and may be attached to the underlying arachnoid by an occasional cell junction. The arachnoid consists of an outer part, the arachnoid barrier cell layer, and an inner portion, the arachnoid trabeculae which bridge the subarachnoid space. Arachnoid barrier cells are electron-lucent, closely apposed to each other, and joined by many cell junctions; in this layer there is little extracellular space and essentially no intercellular material. Arachnoid trabecular cells cross the subarachnoid space in a random manner, have extracellular collagen associated with their flattened processes, and form structures of variable shapes and sizes. There is no evidence of an intervening space between the arachnoid barrier cell layer and the dural border cell layer that would correlate with what has been called the subdural space. When a tissue space is created in this general area of the meninges it is the result of tissue damage and represents, in most instances, a cleaving open of the dural border cell layer. In this situation, extracellular spaces in the dural border cell layer are enlarged, cell junctions are separated, and it is probable that cell membranes are damaged. A survey of reports describing the morphology of the inner and outer capsule of so-called subdural hematomas in humans reveals that dural border cells are found in both parts of the capsule. Also, experimental infusion of blood into this portion of the meninges in animals frequently dissects open the dural border cell layer. These data support the view that what has been called a subdural hematoma is most frequently a lesion found within the layer formed by dural border cells. It is suggested that the so-called subdural space is not a "potential" space since the creation of a cleft in this area of the meninges is the result of tissue damage. In this respect it shares no similarities with legitimate potential spaces (i.e., serous cavities) found at other locations in the body.(ABSTRACT TRUNCATED AT 400 WORDS)

Arachnoid↗
PubMed1993

Hyaluronic acid and hyaluronic acid-binding proteins in brain extracellular matrix.

Hyaluronic acid (HA) plays the main structural role in the formation of brain extracellular matrix (ECM). The extracellular space appears empty by electron microscopy because HA is readily dissolved during the preparation of tissues for ultrastructural studies. The HA-binding proteins so far identified in brain ECM are versican, aggrecan and the glial HA-binding protein. Versican is a large fibroblast proteoglycan preferentially expressed in embryonic cartilage at the time of mesenchymal condensation. Glial HA-binding protein (GHAP) is probably a proteolytic product of versican corresponding to its HA-binding amino-terminal domain. It is mainly a white-matter protein, suggesting that the proteinase responsible for its cleavage from versican is normally activated in this location. Versican is found in both white matter and gray matter, where it forms pericellular coats around large neurons. Aggrecan, the aggregating proteoglycan of mature cartilage, co-localizes with versican in this location. In white matter, the localization of GHAP and versican is identical to that of the glial fibrillary acid protein, suggesting that both proteins are produced by astrocytes. An important difference between GHAP and versican is that GHAP but not versican is released from the tissues by hyaluronidase digestion, which suggests that versican is anchored to the cell membranes lining the extracellular space. GHAP was localized at the ultrastructural level in the granule cell layer of rat cerebellum, the only region of gray matter that is positive for GHAP in this species. Rats were perfused with aqueous fixatives containing cetylpyridinium chloride or tannic acid to prevent the solubilization of HA. GHAP is found throughout the extracellular space, the synaptic clefts being a notable exception. GHAP appears late in development, and the same is true for versican, the characteristic perineuronal coats first becoming apparent in the third postnatal week. It is suggested that a marked change occurs in the structure of brain ECM when HA-binding proteins first appear, and that the change is similar to that observed in prechondrogenic mesenchyme, i.e., reduction of the extracellular space and cell aggregation.

Animals↗
PubMed2000

Repair in the rat lens after threshold ultraviolet radiation injury.

PURPOSE: To investigate the development and recovery of lens damage after in vivo close-to-threshold exposure to ultraviolet B radiation. METHODS: One eye of young, female Sprague-Dawley rats was exposed to 5 kJ/m2 narrowband ultraviolet radiation (UVR) (lambda(max) = 302 nm) for 15 minutes. Groups of rats were killed 1, 7, and 56 days after exposure. The structure of the exposed and nonexposed lenses was examined with light microscopy, scanning electron microscopy, transmission electron microscopy, freeze-fracture, fluorescent membrane staining, and Fourier transform analysis. RESULTS: One day after UVR exposure the lens surface had flakelike opacities. Seven days after exposure, the lens surface appeared opaque and corrugated, and the equatorial cortex had small opacities. At 56 days postexposure, the surface and equator appeared clear, but the cortex had a subtle shell-shaped opacity. At 1 day postexposure, apoptotic cell death occurred in the lens epithelium, but the cortical fibers were normal. At 7 days postexposure, the epithelium and the fibers between the 10th and 40th growth shell below the capsule contained extracellular spaces of different sizes. After 56 days, the epithelial layer appeared normal, and the extracellular spaces had disappeared; but abnormal fibers were found between the 60th and 100th growth shell below the capsule. Fibers above and below the damaged growth shells appeared fully normal. CONCLUSIONS: A close-to-threshold dose of UVR causes cataract, which is largely reversible. The UVR exposure leads to apoptosis in the lens epithelium, and after a latency period of several days, lens fibers are abnormal. Extracellular spaces develop in the epithelium and fibers. Within several weeks after exposure, the epithelium fully recovers and new fibers develop normally. The originally affected fibers are repaired. However, this repair is incomplete, leaving a small zone of enhanced light scattering in the equatorial cortex.

Animals↗
PubMed2000

Apparent diffusion coefficient and MR relaxation during osmotic manipulation in isolated turtle cerebellum.

The apparent diffusion coefficient (ADC) and relaxation times of water were measured by magnetic resonance imaging (MRI) in the isolated turtle cerebellum during osmotic cell volume manipulation. The aim was to study effects of cell volume changes, a factor in ischemia and spreading depression, in isolation from considerations of blood flow and metabolism. Cerebella were superfused at 12-14 degrees C with solutions ranging from 50-200% normal osmolarity. Hypotonic solutions, which are known to cause cell swelling, led to reductions of ADC and increases of T(2), while hypertonic solutions had the opposite effect. This supports the concept that ADC varies with the extracellular space fraction and, combined with published data on extracellular ion diffusion, is consistent with fast or slow exchange models with effective diffusion coefficients that are approximately 1.7 times lower in intracellular than in extracellular space. Spin-spin relaxation can be affected by osmotic disturbance, though such changes are not seen in all pathologies that cause cell swelling.

Animals↗
PubMed1996

Contrast media as extracellular fluid space markers: adaptation of the central volume theorem.

We present some theoretical observations on the pharmacokinetics of the conventional intravascular radiographic and gadolinium chelate MR contrast agents. These agents may be viewed from a physiological perspective as extracellular fluid (ECF) space markers. It can be shown that the passage of such agents through the body may be described by a variant of the "central volume theorem", if the central volume is taken to be that of the entire extracellular fluid. A consequence is that, in a manner akin to nuclear medicine techniques utilizing technetium-99m diethylene triamine pentacetic acid (DTPA), measures of glomerular filtration rate (GFR) related to total ECF volume rather than to the normal body surface area may be obtained from direct or indirect measurements of iodine or gadolinium plasma levels. Typical measurements are presented. A simple means is also described of generating curves of the fraction of contrast medium excreted from the body, applicable to both patients with normal and with abnormal renal function.

Biomarkers↗
PubMed1992

Lanthanum tracer and freeze-fracture studies suggest that compartmentalisation of early bone matrix may be related to initial mineralisation.

In adult bone the calcified matrix and enclosed osteocytes are separated from the extracellular space by a continuous layer of bone lining cells. It thus appears that bone matrix is compartmentalised and, as such, may constitute a 'milieu intérieur' which is different from the general extracellular space. Since adult bone matrix is compartmentalised and matrix vesicles also form a microcompartment, it is conceivable that compartmentalisation, in early osteogenesis, may be a requirement for the initial events of the mineralisation process. We have therefore conducted an ultrastructural, tracer, and freeze-fracture study to determine the stage in which bone matrix becomes compartmentalised and also to find out whether there are tight junctions between osteoblasts. The results show that in early nonmineralised stages and in incipient mineralisation, lanthanum penetrates all intercellular spaces and the newly forming bone matrix which is rich in matrix vesicles and collagen. With the progression of mineralisation, when all matrix vesicles appear mineralised and calcification is 'spreading' to the surrounding matrix, lanthanum is restricted to intercellular spaces and conspicuous macular tight junctions are present between osteoblasts. We suggest that matrix vesicles act as microcompartments for calcification when the early bone matrix is in continuity with the surrounding extracellular space. In later stages, when lanthanum fails to penetrate the matrix, matrix vesicles may no longer be necessary because the bone matrix itself is compartmentalised, thus allowing for localised changes in composition that might favour mineral deposition.

Animals↗
PubMed1994

Protective effect of oxygen and heliox breathing during development of spinal decompression sickness.

A rat model of spinal decompression sickness (DCS) allows study of spinal cord function for at least 3 h after decompression to 1 atm abs (101 kPa) after an exposure to air at 3.8 atm abs (385 kPa) for 1 h. During these 3 h, spinal evoked potentials (SEPs) elicited by peroneal nerve stimulation may be reduced or disappear, and histologic lesions in the spinal cord are observed. Three groups of animals were given either air, oxygen, or heliox (80/20) to breathe at 1 atm abs for 3 h after decompression. Both oxygen and heliox breathing impeded the development of DCS significantly as judged by the mortality of the animals and disappearance of the SEPs. The effect of heliox seemed to be superior to that of oxygen. The latency time from stimulation to the first SEP peak increased significantly during both air and oxygen breathing, whereas no significant increase was seen during heliox breathing. Histologic examination of the spinal cords of animals breathing air, oxygen, or heliox (80/20) showed focal lesions in the white and gray matter. In the white matter, degenerated myelin sheaths as well as expanded extracellular spaces compatible with bubble formation were seen. In the gray matter, perikaryal degeneration was observed. The extracellular space in the white matter was increased in all decompressed animals compared with controls (P < 0.01). Oxygen and heliox breathing caused a smaller increase in extracellular space as compared with air-breathing animals (P < 0.05) and (0.10 > P > 0.05), respectively. It is concluded that breathing of oxygen or heliox (80/20) at 1 atm abs has a preventive effect on the development of DCS when compared with air breathing; the effect of heliox seems to be superior to that of oxygen.

Air↗
PubMed1987

Spatial response properties of acoustically responsive neurons in the superior colliculus of the ferret: a map of auditory space.

Extracellular single-unit recordings were made from auditory neurons in the superior colliculus of ferrets anesthetized with either a neuroleptic or a combination of barbiturate with paralysis. The response properties of these neurons were studied using white-noise bursts presented under free-field conditions in an anechoic chamber. Auditory neurons were found throughout the intermediate and deep layers of the superior colliculus. All neurons were spontaneously active, the rates of discharge varying from 0.1 to 61.1 spikes X s-1. Although the spontaneous discharge interspike-interval histograms for many units approximated to exponential distributions, the histograms of 44% had clear secondary peaks, indicating more than one preferred interval, and could not be modeled by a simple process. Most neurons (50%) responded only at stimulus onset, whereas 12% exhibited sustained discharges and 38% gave onset responses followed by a period of silence or reduced activity and then a period of elevated discharge, which was not apparently related to stimulus offset. Neurons with multipeaked response patterns were concentrated in the stratum griseum profundum. The latencies from arrival of the stimulus at the ear to the onset of neural activity ranged from 6 to 49 ms and decreased with increasing stimulus intensity. Although responsive to sounds over a large region of space, most neurons had clearly defined best positions at which the strongest response was obtained. The response declined as the speaker was moved away from this position, and nearly all units had peaked response profiles. The spatial tuning varied between different neurons, but most were more sharply tuned in elevation than in azimuth. Increasing the stimulus intensity did not, in general, alter the best positions of these neurons, but usually resulted in a broadening of the receptive fields, although other units became more sharply tuned. The best positions of auditory neurons varied systematically in azimuth from 20 degrees into the ipsilateral hemifield to 130 degrees into the contralateral hemifield as the electrode was moved from the rostrolateral to the caudomedial end of the superior colliculus. The best positions shifted in elevation along a rostromedial to caudolateral axis from 60 degrees above to 50 degrees below the visuoaural plane.(ABSTRACT TRUNCATED AT 400 WORDS)

Acoustic Stimulation↗
PubMed2002

Synaptic and nonsynaptic ictogenesis occurs at different temperatures in submerged and interface rat brain slices.

To investigate the temperature sensitivity of low-Ca2+-induced nonsynaptic and low-Mg2+-induced synaptic ictogenesis under submerged and interface conditions, we compared changes of extracellular field potential and extracellular potassium concentration at room temperature (23 +/- 1 degrees C; mean +/- SD) and at 35 +/- 1 degrees C in hippocampal-entorhinal cortex slices. The induction of spontaneous epileptiform activity under interface conditions occurred at 35 +/- 1 degrees C in both models. In contrast, under submerged conditions, spontaneous epileptiform activity in low-Mg2+ artificial cerebrospinal fluid (ACSF) was observed at 35 +/- 1 degrees C, whereas epileptiform discharges induced by low-Ca2+ ACSF occurred only at room temperature. To investigate the different temperature effects under submerged and interface conditions, measurements of extra- and intracellular pH and extracellular space volume were performed. Lowering the temperature from 35 +/- 1 degrees C to room temperature effected a reduction in extracellular pH under submerged and interface conditions. Under submerged conditions, temperature changes had no significant influence on the intracellular pH in presence of either normal or low-Mg2+ ACSF. In contrast, application of low-Ca2+ ACSF effected a significant increase in intracellular pH at room temperature but not at 35 +/- 1 degrees C under submerged conditions. Therefore increasing intracellular pH by lowering the temperature in low-Ca2+ ACSF may push slices to spontaneous epileptiform activity by opening gap junctions. Finally, extracellular space volume significantly decreased by switching from submerged to interface conditions. The reduced extracellular space volume under interface conditions may lead to an enlarged ephaptic transmission and therefore promotes low-Mg2+- and low-Ca2+-induced spontaneous epileptiform activity. The results of the study indicate that gas-liquid interface and total-liquid submerged slice states impart distinct physiological parameters on brain tissue.

Animals↗
PubMed1985

Membrane specializations in mammalian lens fiber cells: distribution of square arrays.

Fragments of intact rat, pig and bovine lenses and isolated membranes from bovine lenses were examined by freeze-fracture-etch electron microscopy employing samples ultra-rapidly frozen in the absence of fixatives or cryoprotectants. Complementary replicas of the bovine outer cortex clearly display small patches of square arrays (6.6 nm repeat) as structures distinct from gap junctions in the same membranes. In the outer cortex square arrays appear in single membranes where the extracellular space is not thinned, whereas gap junctions, as in other tissues, only occur where the extracellular space is greatly attenuated. Square arrays in the middle cortex appear as patches of varying size surrounded by smooth membrane fracture faces. Within the undulating membranes of tongue-and-groove interdigitations in the inner cortex and nucleus, the square arrays are extensive and are located specifically on the regions which have convex curvature toward the cytoplasm. Square crystalline regions alternate with non-crystalline regions within each membrane of an undulating pair. Across the extracellular space, crystalline regions are matched with non-crystalline regions, thus making it unlikely that the square array participates in intercellular communication. Because the undulations occur in isolated membranes following urea washing to remove cytoplasmic and extrinsic membrane proteins, the square arrays probably play a crucial role in the formation of the undulations and in the maintenance of membrane curvature. X-ray diffraction experiments show reflections from the crystalline square array for all twenty of our preparations of isolated membranes. These x-ray experiments indicate that the square arrays observed by freeze-fracture are abundant in lens fiber cell membranes.

Animals↗
PubMed1984

Vascular membrane permeability during hypoxia.

Extracellular space measurements using radioisotope markers (35S-sulphate and 14C-sorbitol) and ultrastructural examination of lanthanum distribution have been carried out on two vascular tissues (aorta, portal vein) exposed to normoxic and hypoxic media to see if hypoxia is associated with membrane damage. Extracellular space values did not change significantly with hypoxia of up to 60 min duration. Lanthanum remained distributed in the extracellular space in both normoxic and hypoxic specimens. These findings suggest that hypoxia may not be associated with increased vascular membrane permeability to lanthanum, as has been reported by some workers to occur with more severe metabolic deprivation.

Animals↗
PubMed1987

Influence of the rate of ventricular enlargement on the ultrastructural morphology of the white matter in experimental hydrocephalus.

The influence of the rate of ventricular enlargement on the morphology of hydrocephalic white matter was studied and correlated with previous studies of water content. Different rates of ventricular enlargement were obtained in two groups of cats by opening either the calvaria or the calvaria and the dura mater before injecting kaolin into the cisterna magna. Animals from each group underwent in vivo fixation of brain 2, 3, and 6 weeks after hydrocephalus was induced. Specimens of white matter were taken 1, 2, and 3 mm lateral to the ependymal surface of the lateral ventricles, imbedded, and examined using transmission electron microscopy. The ultrastructural changes associated with ventricular enlargement varied with the model used and the duration of hydrocephalus. Marked expansion of the extracellular space extending 2 mm lateral from the ependyma was found in the craniectomy-durectomy preparations examined 2 to 3 weeks after kaolin injection. Time-matched craniectomy preparations had less enlargement of the extracellular space that was confined to the white matter immediately adjacent to the ventricle. Marked glial reaction was observed in these areas in the early craniectomy preparations. When studied 6 weeks after hydrocephalus induction, both models had less expansion of the extracellular spaces compared to early observations. Glial reaction was found in both models, but was greater in the craniectomy model. The correlation of these morphological findings with the rate of ventricular enlargement and earlier studies of water content are discussed.

Animals↗