Astrogliosis and impaired aquaporin-4 and dystrophin systems in idiopathic normal pressure hydrocephalus.

AIMS: Idiopathic normal pressure hydrocephalus (iNPH) is one subtype of dementia that may improve following drainage of cerebrospinal fluid (CSF). This prospective observational study explored whether expression of the water channel aquaporin-4 (AQP4) and the anchoring molecule dystrophin 71 (Dp71) are altered at astrocytic perivascular endfeet and in adjacent neuropil of iNPH patient. Observations were related to measurements of pulsatile and static intracranial pressure (ICP). METHODS: The study included iNPH patients undergoing overnight monitoring of the pulsatile/static ICP in whom a biopsy was taken from the frontal cerebral cortex during placement of the ICP sensor. Reference (Ref) biopsies were sampled from 13 patients who underwent brain surgery for epilepsy, tumours or cerebral aneurysms. The brain tissue specimens were examined by light microscopy, immunohistochemistry, densitometry and morphometry. RESULTS: iNPH patients responding to surgery (n = 44) had elevated pulsatile ICP, indicative of impaired intracranial compliance. As compared to the Ref patients, the cortical biopsies of iNPH patients revealed prominent astrogliosis and reduced expression of AQP4 and Dp71 immunoreactivities in the astrocytic perivascular endfeet and in parts of the adjacent neuropil. There was a significant correlation between degree of astrogliosis and reduction of AQP4 and Dp71 at astrocytic perivascular endfeet. CONCLUSIONS: Idiopathic normal pressure hydrocephalus patients responding to CSF diversion present with abnormal pulsatile ICP, indicative of impaired intracranial compliance. A main histopathological finding was astrogliosis and reduction of AQP4 and of Dp71 in astrocytic perivascular endfeet. We propose that the altered AQP4 and Dp71 complex contributes to the subischaemia prevalent in the brain tissue of iNPH.

Reactive changes in the adolescent porcine spine with disc degeneration due to endplate injury.

Degenerative and reactive structural alterations occurring after experimentally-induced disc degeneration were evaluated using a porcine model. A cranial perforation was made through the L4 vertebral endplate into the nucleus pulposus. Three months later, the lumbar intervertebral disc and adjacent vertebrae were dissected, fixed in formalin and further processed for histopathological analyses. The results showed that there were nucleus pulposus fragments, rather than a distinct border between the nucleus and annulus fibrosus. The central lamellae were distorted and delamination of the outer anterior layers was observed. Blood vessels emerged from the adjacent tissue, penetrated the annulus and branched into the residues of the nucleus. Nerve fibres accompanying the blood vessels could be recognized in the disc within the connective scar tissue. The epiphyseal cartilage plates in the vertebrae were hypertrophic in several areas and there was bone formation directed towards the centre of the vertebral body and the disc. Hypertrophic hyaline cartilage, newly formed bone and scar tissue filled the injury canal. A slight chronic inflammatory reaction was evident along vascular buds. The reactive changes dominated over the degenerated features in the operated disc. Physiological loading enhanced the infiltration of various tissue types characterizing immature cartilage formation. Prominent neovascularisation of the central parts of the disc is likely to be of key importance in turning the degenerative features of the remaining tissue into reactive healthy structures.

A new model for diffuse brain injury by rotational acceleration: I model, gross appearance, and astrocytosis.

Rapid head rotation is a major cause of brain damage in automobile crashes and falls. This report details a new model for rotational acceleration about the center of mass of the rabbit head. This allows the study of brain injury without translational acceleration of the head. Impact from a pneumatic cylinder was transferred to the skull surface to cause a half-sine peak acceleration of 2.1 x 10(5) rad/s2 and 0.96-ms pulse duration. Extensive subarachnoid hemorrhages and small focal bleedings were observed in the brain tissue. A pronounced reactive astrogliosis was found 8-14 days after trauma, both as networks around the focal hemorrhages and more diffusely in several brain regions. Astrocytosis was prominent in the gray matter of the cerebral cortex, layers II-V, and in the granule cell layer and around the axons of the pyramidal neurons in the hippocampus. The nuclei of cranial nerves, such as the hypoglossal and facial nerves, also showed intense astrocytosis. The new model allows study of brain injuries from head rotation in the absence of translational influences.

A new model for diffuse brain injury by rotational acceleration: II. Effects on extracellular glutamate, intracranial pressure, and neuronal apoptosis.

The aim of this study is to monitor excitatory amino acids (EAAs) in the extracellular fluids of the brain and to characterize regional neuronal damage in a new experimental model for brain injury, in which rabbits were exposed to 180-260 krad/s2 rotational head acceleration. This loading causes extensive subarachnoid hemorrhage, focal tissue bleeding, reactive astrocytosis, and axonal damage. Animals were monitored for intracranial pressure (ICP) and for amino acids in the extracellular fluids. Immunohistochemistry was used to study expression of the gene c-Jun and apoptosis with the terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) technique. Extracellular glutamate, glycine, and taurine increased significantly in the hippocampus within a few hours and remained high after 24 h. Neuronal nuclei in the granule layers of the hippocampus and cerebellum were positive for c-Jun after 24 h. Little immunoreactivity was detected in the cerebral cortex. c-Jun-positive neuronal perikarya and processes were found in granule and pyramidal CA4 layers of the hippocampus and among the Purkinje cells of the cerebellum. Also some microglial cells stained positively for c-Jun. TUNEL reactivity was most intense at 10 days after trauma and was extensive in neurons of the cerebral cortex, hippocampus, and cerebellum. The initial response of the brain after rotational head injury involves brain edema after 24 h and an excitotoxic neuronal microenvironment in the first hour, which leads to extensive delayed neuronal cell death by apoptosis necrosis in the cerebral cortex, hippocampus and cerebellum.

Blast exposure causes redistribution of phosphorylated neurofilament subunits in neurons of the adult rat brain.

There is little information on threshold levels and critical time factors for blast exposures, although brain damage after a blast has been established both clinically and experimentally. Moreover, the cellular pathophysiology of the brain response is poorly characterized. This study employs a rat model for blast exposure to investigate effects on the neuronal cytoskeleton. Exposure in the range of 154 kPa/198 dB or 240 kPa/202 dB has previously been shown neither to cause visual damage to the brain, nor to affect the neuronal populations, as revealed with routine histology. Here, the brains were investigated immunohistochemically from 2 h to 21 days after blast exposure. A monoclonal antibody was used which detects only the phosphorylated epitope of the heavy subunit of the neurofilament proteins (p-NFH). This epitope is normally restricted to axons, that is, not demonstrable in the perikarya. Eighteen hours after exposure in the 240-kPa/202-dB range, p-NFH immunoreactivity accumulated in neuronal perikarya in layers II-IV of the temporal cortex and of the cingulate and the piriform cortices, the dentate gyrus and the CA1 region of the hippocampus. At the same time, the p-NFH immunoreactivity disappeared from the axons and dendrites of cerebral cortex neurons. The most pronounced immunostaining of neuronal perikarya was found in the hemisphere, which faced the blast source. The perikaryal accumulation of p-NFH was present also at 7 days but the neuronal perikarya had become negative at 21 days, at which time the axons again displayed p-NFH immunoreactivity. Exposure in the range of 154 kPa/198 dB caused similar, although less marked accumulation of p-NFH immunoreactivity in the neuronal perikarya. The findings are interpreted to show a dephosphorylation of NFHs in axons and dendrites and a piling up of p-NFHs in the perikarya due to disturbed axonal transport.

Neck injuries in car collisions--a review covering a possible injury mechanism and the development of a new rear-impact dummy.

A review of a few Swedish research projects on soft tissue neck injuries in car collisions is presented together with some new results. Efforts to determine neck injury mechanisms was based on a hypothesis stating that injuries to the nerve root region in the cervical spine are a result of transient pressure gradients in the spinal canal during rapid neck bending. In experimental neck trauma research on animals, pressure gradients were observed and indications of nerve cell membrane dysfunction were found in the cervical spinal ganglia. The experiments covered neck extension, flexion and lateral bending. A theoretical model in which fluid flow was predicted to cause the transient pressure gradients was developed and a neck injury criterion based on Navier-Stokes Equations was applied on the flow model. The theory behind the Neck Injury Criterion indicates that the neck injury occurs early on in the rearward motion of the head relative to the torso in a rear-end collision. Thus the relative horizontal acceleration and velocity between the head and the torso should be restricted during the early head-neck motion to avoid neck injury. A Bio-fidelic Rear Impact Dummy (BioRID) was developed in several steps and validated against volunteer test results. The new dummy was partly based on the Hybrid III dummy. It had a new articulated spine with curvature and range of motion resembling that of a human being. A new crash dummy and a neck injury criterion will be very important components in a future rear-impact crash test procedure.

Dorsal root ganglion nerve cells transiently express increased immunoreactivity of the calcium-binding protein S-100beta after sciatic nerve transection.

Transiently increased immunoreactivity of the calcium binding protein S-100beta was demonstrated in spinal ganglion nerve cells after sciatic nerve transection. Neuropeptide Y (NPY), normally not seen in these nerve cells, appeared concomitantly. The transiently elevated co-expression of S-100beta and NPY is proposed to reflect an increased demand of neurotrophic and neuroprotective compounds in reactive neurons, tentatively regulating calcium ions.

[Nerve cell damages in whiplash injuries. Animal experimental studies]. / Nervenzellschäden bei Schleudertraumen. Tierexperimentelle Untersuchungen.

Mechanical loading of the cervical spine during car accidents often lead to a number of neck injury symptoms with the common term Whiplash Associated Disorders (WAD). Several of these symptoms could possibly be explained by injuries to the cervical spinal nerve root region. It was hypothesised that the changes in the inner volume of the cervical spinal canal during neck extension-flexion motion would cause transient pressure changes in the CNS as a result of hydro-dynamic effects, and thereby mechanically load the nerve roots and cause tissue damage. To test the hypothesis, anaesthetised pigs were exposed to experimental neck trauma in the extension, flexion and lateral flexion modes. The severity of the trauma was kept below the level where cervical fractures occur. Transient pressure pulses in the cervical spinal canal were duly recorded. Signs of cell membrane dysfunction were found in the nerve cell bodies of the cervical spinal ganglia. Ganglion injuries may explain some of the symptoms associated with soft-tissue neck injuries in car accidents. When the pig's head was pulled rearward relative to its torso to resemble a rear-end collision situation, it was found that ganglion injuries occurred very early on in the neck motion, at the stage where the motion changes from retraction to extension motion. Ganglion injuries did not occur when pigs were exposed to similar static loading of the neck. This indicates that these injuries are a result of dynamic phenomena and thereby further supports the pressure hypothesis. A Neck Injury Criterion (NIC) based on a theoretical model of the pressure effects was developed. It indicated that it was the differential horizontal acceleration and velocity between the head and the upper torso at the point of maximum neck retraction that determined the risk of ganglion injuries.

Gel matrix vehicles for growth factor application in nerve gap injuries repaired with tubes: a comparison of biomatrix, collagen, and methylcellulose.

The repair of nerve gap injuries with tubular nerve guides has been used extensively as an in vivo test model in identifying substances which may enhance nerve regeneration. The model has also been used clinical nerve repair. The objective of this study was to compare three different gel matrix-forming materials as potential vehicles for growth factors in this system. The vehicles included a laminin containing extracellular matrix preparation (Biomatrix), collagen, and a 2% methylcellulose gel. The growth factor test substance consisted of a combination of platelet-derived growth factor BB (PDGF-BB) and insulin-like growth factor I (IGF-I). An 8-mm gap in rat sciatic nerve was repaired with a silicone tube containing each of the vehicles alone or with a combination of each vehicle plus PDGF-BB and IGF-I. At 4 weeks after injury, the application of the growth factor combination significantly stimulated axonal regeneration when applied in methylcellulose or collagen, but not in Biomatrix. A similar trend was present between the vehicle control groups. By 8 weeks after injury, nerves repaired with methylcellulose as a vehicle had significantly greater conduction velocity than either collagen or Biomatrix. It was concluded that a 2% methylcellulose gel was the best of the three matrices tested, both in its effects on nerve regeneration and flexibility of formulation.

Increased expression of xanthine oxidase and insulin-like growth factor I (IGF-I) immunoreactivity in skeletal muscle after strenuous exercise in humans.

The present study investigated the effect of 7 days of strenuous exercise on the quantity of xanthine oxidase and IGF-I in muscle. Fifteen male military trainees performed 1 week of terrain marching and warfare exercises. Muscle biopsies and blood samples were obtained prior to and after the week. After the week, the number of xanthine oxidase immunoreactive cells, identified as capillary endothelial cells and leucocytes, and the number of IGF-I immunoreactive cells, mainly vascular cells but also cells tentatively identified as satellite cells, were higher in the muscle (P < 0.05). Plasma creatine kinase activity was 650% higher after the week (P < 0.001) and the muscle content of hydroxyproline was elevated by 160% 2 months post-exercise (P < 0.05), both findings implying injury to the muscle. The present data provide a first observation of an elevated level of xanthine oxidase and IGF-I in human skeletal muscle after exercise. It is proposed that both substances increased as a result of cellular damage: xanthine oxidase because of the influence of immunomodulators, and IGF-I in association with regenerative processes. The increased expression of IGF-I in the muscle could, however, also reflect cellular growth in response to an elevated load on the muscle and the vascular bed.

Membrane leakage in spinal ganglion nerve cells induced by experimental whiplash extension motion: a study in pigs.

Nerve cells in the cervical and upper thoracic spinal ganglia were examined for possible plasma membrane leakage, as revealed by their ability to exclude a dye-protein complex, after experimentally induced whiplash in a pig model system. The rationale for this approach is found in the fact that the interstitium of spinal ganglia differs from most other parts of the nervous system in that it lacks a barrier, allowing blood constituents to gain access. The dye Evans blue, which rapidly conjugates with blood proteins, is found in the interstitium of normal spinal ganglia after intravenous injection, but it is excluded from the nerve cells and their enveloping satellite cells. In contrast, after a simulated whiplash extension trauma many of the nerve cells were stained, reflecting the inability of their plasma membranes to exclude the dye-protein complex. Morphometric measurements revealed that the highest frequency of cellular dye uptake was observed in the C4-C7 spinal ganglia (mean 16 - 18%; range 5-27%). The blood-nerve barrier of the adjacent nerve fascicles remained intact, with rare exception. Several factors are considered to contribute to the induction of these cell abnormalities in the spinal ganglia after an experimentally induced, simulated whiplash trauma in this pig model system.

Comparison among different approaches for sampling cerebrospinal fluid in rats.

Two approaches for time-resolved sampling of cerebrospinal fluid (CSF) in rats were compared regarding performance, reproducibility, and extent of the inevitable trauma caused by the implantation of a sampling tube. Several parameters were checked to evaluate the injury: blood cell contamination of CSF; concentrations in CSF of the cytosolic proteins neuron-specific enolase (NSE) and S-100 (chiefly present in astrocytes); blood-brain barrier leakage of a dye-protein complex; viability of nervous tissue cells as assessed by dye exclusion; light and electron microscopy. In one sampling method, a tube was forced epidurally into the cisterna magna via a hole in the calvarium, consistently damaging the meninges and the nervous tissue. When using the alternative sampling method, the tube was instead affixed to the posterior atlanto-occipital membrane and connected with the cisterna magna via a hole in the membrane. Such a procedure caused negligible damage. Both techniques induced an inflammatory response. We advocate the use of the second approach, i.e., to sample CSF via a hole in the atlanto-occipital membrane, as the method of choice due to its high reproducibility. It is fairly rapid, and associated with a negligible injury.

Helicobacter pylori interacts with heparin and heparin-dependent growth factors.

The pathogenic bacterium Helicobacter pylori, which causes active, chronic type B gastritis and peptic ulcer disease, and increases the risk for development of gastric cancer, could tentatively interfere with growth factors and growth factor receptors of importance for the gastroduodenal mucosa, e.g. heparin-binding FGFs (fibroblast growth factors). H. pylori binds FGF with an extremely strong affinity (3.8 x 10(-12)M), and also heparan sulfate and heparin with higher affinity (Kd 9 x 10(-9)M) than FGFs bind to heparin (10(-8) - 10(-9)M). FGF receptors are also dependent on heparin for their activation. Heparan sulfate binding proteins (HSBP) are exposed on and shed from the surface of H. pylori, which often are localised close to the epithelial stem cells in the gastroduodenal glands. H. pylori could thus efficiently interfere with growth factors and growth factor receptors, tentatively resulting in disturbance of the delicate balance that control the renewal, maintenance and repair of the gastroduodenal mucosa. This mode of action has previously not been considered, but may constitute part of its pathogenic mechanisms. Such a dynamic mode of action of H. pylori may explain the reason for that infected victims may either suffer from gastrointestinal symptoms or lack clinical evidence of disease or discomfort.

A new approach for multiple sampling of cisternal cerebrospinal fluid in rodents with minimal trauma and inflammation.

A new approach was developed to minimize inevitable damage to nervous and meningeal tissue due to implantation of a sampling tube allowing multiple withdrawal of cerebrospinal fluid (CSF) from the cisterna magna in adult rats. A tube was secured on the atlanto-occipital membrane. Thereafter, a hole was cut through the membrane, allowing flow of CSF from the cisterna magna to the tube. CSF could be sampled repeatedly for at least 1 week. There was no blood-brain barrier damage. The pressure in the cisterna magna remained normal as did the estimated rate of CSF formation. Very few blood cells contaminated the CSF. There was very little evidence of inflammation. The nervous tissue was undamaged as shown by exclusion of a dye-protein complex. The CSF concentrations of the cytosolic neuronal protein neuron-specific enolase (NSE), and of the astrocyte protein S-100 were very low. The pattern of amino acids remained within normal limits. Scanning electron microscopy revealed that clot and reactive changes were restricted to the vicinity of the connecting hole. We conclude that our approach to positioning a tube on the atlanto-occipital membrane and then connecting it to the cisterna magna reproducibly and reliably enables 'atraumatic' multiple sampling of CSF.

Glutathione transferases of classes alpha, mu and pi show selective expression in different regions of rat kidney.

1. Glutathione transferases (GST) are mainly cytosolic and occur in multiple forms, which can be arranged in three distinct, structural classes. The different enzyme forms show distinct substrate specificities with electrophilic and genotoxic substances. The expression of the alpha subunits 1, 2 and 8, the mu subunits 3, 4 and 6, and the pi subunit 7 of GST in different parts of the rat kidney was determined immunohistochemically. 2. GST immunoreactivity was present predominantly in the nephron, collecting duct and urothelium. 3. A conspicuous finding was that subunits 1, 2 and 8 were localized to the proximal tubules, while the mu subunit 3 was demonstrable in epithelial tubular cells from the distal tubules to the urothelium. The immunoreactivity of subunits 4 and 6 could be visualized in epithelial cells from the ascending thin limb to the collecting ducts. Subunit 7 was found in the thin limb of the loop of Henle, and in scattered cells in the distal tubules. 4. The urothelial cells covering the papilla and the renal calyces showed immunoreactivity to GST subunits 2-4 and 6-8. 5. Thus, in the nephron the class alpha GSTs were selectively expressed in the proximal tubules and the class mu and class pi GST in the thin loop of Henle and distal tubules. The cells in the collecting ducts and the urothelium, which have a different ontogeny than the nephron, do not show any corresponding differential distribution of the GST classes. 6. Cells in a given location were in some cases found to be non-reactive with a given antiserum in an otherwise immunoreactive cell population, demonstrating a spatial variation in GST expression. The immunoreactivity to the different forms of GST was predominantly cytoplasmic but a nuclear localization could also be demonstrated. 7. The panel of antibodies to GST may tentatively be used as markers in localizing lesions in restricted parts of the nephrons and to elucidate dynamic alterations in the tubular system in response to physiological and toxic agents.

Peptide growth factors and myofibroblasts in capsules around human breast implants.

Peptide growth factors were mapped immunohistochemically for assessment of their presumed relation to the cells in capsules enveloping gel-filled, smooth-surfaced silicone mammary implants (12 capsules from 11 women). The implant capsules were dominated by fibroblast-like cells, but there were as well macrophages, inflammatory cells, and vascular cells. These cells expressed immunoreactivity for TGF-beta, IGF-II, IGF-I, and, to a lesser extent, PDGFB, NGF, and TNF-alpha. The numerous spindle-shaped cells in the contracted capsules displayed several distinct cytoplasmic actin bundles and fulfilled ultrastructural criteria for myofibroblasts. In contrast, myofibroblasts were recognized in low frequencies in the noncontracted capsules. Mature skin scar tissue did not show any peptide growth factor immunoreactivity, and myofibroblasts were absent. It is postulated that the low-grade chronic inflammatory foreign-body reaction, aggravated by mechanical stress and possible leakage of irritants, stimulates capsule cells to form peptide growth factors, reflecting that extended healing processes prevail in both noncontracted and contracted capsules. We propose that the local enrichment of peptide growth factors, beneficial for acute wound healing, in the chronically irritated tissue around implants provides trophic support for the contractile cells in the implant capsules.

Regenerating human nasal mucosa cells express peptide growth factors.

The goal of this study was to investigate if the distribution of peptide growth factors in the human nasal mucosa could be correlated to its maintenance and to repair processes. Biopsy specimens from clinically healthy humans, aged 6 months to 70 years, were investigated immunohistochemically. In the intact human nasal mucosa, only scattered basal epithelial cells and rare, randomly distributed cells in the lamina propria expressed peptide growth factor immunoreactivity. In contrast, in areas with deficient epithelial lining and infiltration of inflammatory cells, intense insulinlike growth factor I immunoreactivity was demonstrable in reactive epithelial cells, while adjacent, more differentiated cells were nonreactive. Vascular wall cells, fibroblasts, macrophages, and exocrine gland cells in the reactive nasal mucosa showed variable insulinlike growth factor I immunoreactivity and, at lower frequencies and intensities, immunoreactivity to insulinlike growth factor II, basic fibroblast growth factor, platelet-derived growth factor, and transforming growth factor beta, as did cells in the normally nonreactive exocrine glands. Macrophages and vascular smooth-muscle cells could in addition express platelet-derived growth factor immunoreactivity. Increased cell proliferation was recognized in reactive areas of the nasal mucosa specimens, ie, in those concomitantly showing distinct peptide growth factor immunoreactivity. We concluded that a complex pattern of peptide growth factor immunoreactivity is transiently expressed by reactive and regenerating nasal mucosal cells, contrasting with the nonreactive normal, differentiated cells. The close correlation between the appearance of peptide growth factors and the local repair and maintenance processes supports our working hypothesis that peptide growth factors are of functional importance for the nasal mucosa.

Immunohistochemical distribution of isoenzymes of glutathione transferase in adult rat adrenal gland before and after hypophysectomy.

The distribution of glutathione transferase subunits 1, 2, 3, 4, 7 and 8 in the different cells of the female and male rat adrenal and the effects of hypophysectomy on these isoenzymes were studied using immunohistochemical methods. All these glutathione transferase subunits, with the exception of subunit 1, were present in the adrenal. Each subunit showed, however, its own characteristic distribution pattern. After hypophysectomy, increased staining for these isoenzymes was generally observed, and this effect was also cell-specific. Staining for subunit 2 increased in intensity in the zona fasciculata and reticularis after hypophysectomy, whereas a decrease was observed in the zona glomerulosa. Staining for subunit 8 was increased in the borderline between the capsule and zona glomerulosa, as well as in medullary chromaffin cells after hypophysectomy. The Mu subunits 3 and 4 increased markedly in fascicular and reticular cells after hypophysectomy and staining for subunit 3 was also increased in the medullary cells. A slight, but more general, increase was observed for subunit 7. We conclude from these experiments that the increases in glutathione transferase subunits observed in the rat adrenal after hypophysectomy are due to increased protein synthesis and/or increased protein stability and not to a selective destruction of cells lacking, or with low levels of, the isoenzymes.

Immunoreactivities for epidermal growth factor (EGF) and for EGF receptors in rats with gastric ulcers.

The present study was aimed at assessing whether epidermal growth factor (EGF) and its receptors are present in the gastric mucosa during the healing of gastric ulcers. Immunohistochemical, immunochemical and functional studies were performed in rats after induction of ulcers in the oxyntic mucosa. Controls, which included non-operated and sham-operated animals, displayed only rare cells in the bottom of the oxyntic glands showing EGF-like immunoreactivity. Within one day after ulcer induction, a markedly increased number of chief cells in undamaged mucosa showed intense staining. Concomitantly, there was an increased immunoreactivity for EGF receptors in the mucous neck cells. Maximal immunostaining for both compounds was observed at 3 days after ulcer induction; augmented staining was still demonstrable after 3 weeks. RIA revealed significantly increased EGF concentration in the oxyntic mucosa three days after ulcer induction, and at this stage stimulated gastric acid secretion, measured in a parallel group of chronic fistula rats, indicated significant inhibition. The transient increases in EGF-like and EGF receptor immunoreactivities may stimulate gland cell proliferation. The local release of EGF-like substances may also serve to reduce gastric acidity and thereby promote ulcer healing.