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P C Blumbergs

Publications and source records attributed to P C Blumbergs.

At least 19 recordsLinked to original sources
PubMed2006

Increased substance P immunoreactivity and edema formation following reversible ischemic stroke.

Previous results from our laboratory have shown that neurogenic inflammation is associated with edema formation after traumatic brain injury (TBI). This neurogenic inflammation was characterized by increased substance P (SP) immunoreactivity and could be attenuated with administration of SP antagonists with a resultant decrease in edema formation. Few studies have examined whether neurogenic inflammation, as identified by increased SP immunoreactivity, occurs after stroke and its potential role in edema formation. The present study examines SP immunoreactivity and edema formation following stroke. Experimental stroke was induced in halothane anaesthetized male Sprague-Dawley rats using a reversible thread model of middle cerebral artery occlusion. Increased SP immunoreactivity at 24 hours relative to the non-infarcted hemisphere was observed in perivascular, neuronal, and glial tissue, and within the penumbra of the infarcted hemisphere. It was not as apparent in the infarct core. This increased SP immunoreactivity was associated with edema formation. We conclude that neurogenic inflammation, as reflected by increased SP immunoreactivity, occurs following experimental stroke, and that this may be associated with edema formation. As such, inhibition of neurogenic inflammation may represent a novel therapeutic target for the treatment of edema following reversible, ischemic stroke.

Animals↗
PubMed2006

Paranodal pathology in Tangier disease with remitting-relapsing multifocal neuropathy.

Pathological studies of a sural nerve biopsy in a man with Tangier disease presenting as a remitting-relapsing multifocal neuropathy showed abnormalities in the paranodal regions, including lipid deposition (65%) and redundant myelin foldings, with various degrees of myelin splitting and vesiculation (43%) forming small tomacula and abnormal myelin terminal loops (4%). The internodal regions were normal in the majority of myelinated fibres. Abnormal lipid storage was also present in the Schwann cells of the majority of unmyelinated fibres (67%). The evidence suggests that the noncompacted myelin region of the paranode is a preferential site for lipid storage in the myelinated Schwann cell, and that the space-occupying effects of the cholesterol esters leads to paranodal malfunction and tomacula formation as the pathological basis for the multifocal relapsing-remitting clinical course.

Adolescent↗
PubMed2006

Avian riboflavin deficiency: an acquired tomaculous neuropathy.

The finding of tomacula, focal areas of sausage-shaped hypermyelination in peripheral nerves, is reported for the first time in avian riboflavin deficiency. Day-old, meat-type chickens were fed a riboflavin-deficient diet (1.8 mg/kg) and were killed on postnatal days 6, 11, 16, and 21, while control chickens were fed a conventional diet containing 5.0 mg/kg riboflavin. Tomacula were found in sciatic and brachial nerves from day 11 onward, became more frequent and prominent with increasing time, and preceded the onset of segmental demyelination.

Animal Feed↗
PubMed2005

Early paranodal myelin swellings (tomacula) in an avian riboflavin deficiency model of demyelinating neuropathy.

INTRODUCTION: Disruption of the complex architectural and molecular organization of the paranodal region of myelinated peripheral nerve fiber may initiate the evolving time dependent process of segmental demyelination. In support of this notion was the finding of focal paranodal myelin swellings (tomacula) due to redundant folding of myelin sheaths, early in the time course of an avian riboflavin deficiency model of demyelinating neuropathy. METHODS: Newborn broiler meat chickens were maintained either on a routine diet containing 5.0 mg/kg riboflavin (control group) or a riboflavin-deficient diet containing 1.8 mg/kg riboflavin. Riboflavin concentrations in the liver were measured at postnatal day 11. Peripheral nerves were morphologically examined at days 6, 11, 16 and 21 using light and electron microscopy and teased nerve fiber techniques. RESULTS: Riboflavin-deficient chickens showed signs of a neuropathy from days 8 and pathological examination of peripheral nerves revealed a demyelinating neuropathy with paranodal tomacula formation starting on day 11. Paranodal tomacula consisted of redundant myelin infoldings or outfoldings, increased in size and frequency after day 11. After day 16, the paranodal swellings showed prominent degenerative changes accompanied by an increased frequency of myelinated fibers showing demyelination. CONCLUSION: Tomacula due to redundant myelin folds are generally considered a remyelination phenomenon, yet in this avian riboflavin deficiency model of demyelination, the paranodal tomacula occurred early in the course of demyelination.

Animals↗
PubMed2005

SUMO-1 marks subdomains within glial cytoplasmic inclusions of multiple system atrophy.

Conjugation of the small ubiquitin-like modifier, SUMO-1, to target proteins is linked to the regulation of multiple cellular pathways, including nucleocytoplasmic trafficking, cell cycle progression, the ubiquitin-proteasome system and apoptosis. Recently, the accumulation of SUMOylated proteins in pathological neuronal intranuclear aggregates has been found in several neurodegenerative diseases. The aim of our study was to examine SUMO-1 in the alpha-synucleinopathy diseases, Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). We conducted anti-SUMO-1 immunostaining of fixed brain tissue sections and smears of unfixed brain tissue homogenates of DLB and MSA cases. We found that oligodendroglial cytoplasmic inclusions, the alpha-synuclein-positive cytoplasmic aggregates that characterize MSA, exhibit robust punctate SUMO-1 immunostaining, marking discrete submicron-sized subdomains within the inclusion bodies. Lewy bodies in smears of DLB tissue homogenates showed similar SUMO-1-positive structures, although these were not detected in fixed tissue. In cell culture experiments, we found that the nuclear and perinuclear accumulation of SUMO-1 aggregates could be induced in glioma cells by chemical inhibition of proteasomal protein degradation.

Biomarkers↗
PubMed2005

Alpha B-crystallin is a major component of glial cytoplasmic inclusions in multiple system atrophy.

Multiple system atrophy (MSA) is characterized by the formation of oligodendroglial cytoplasmic inclusions (GCIs) consisting of alpha-synuclein filaments. AlphaB-crystallin, a small chaperone protein that binds to unfolded proteins and inhibits aggregation, has been documented in GCIs. We investigated the relative abundance and speciation of alphaB-crystallin in GCIs in MSA brains. We also examined the influence of alphaB-crystallin on the formation of cytoplasmic inclusions in cultured glial cells. Immunohistochemistry and confocal microscopy revealed alphaB-crystallin is a prominent component of GCIs, more abundant than in Lewy bodies in Lewy body dementia. One- and two-dimensional gel electrophoresis and mass spectrometric analysis of GCIs immunopurified from MSA brains indicated that alphaB-crystallin is a major protein component with multiple post-translationally modified species. In cultured C6 glioma cells treated with the proteasomal inhibitor, lactacystin, to induce accumulation of ubiquitinated proteins, a subset of cells showed increased cytoplasmic staining for alphaB-crystallin. Proteasome-inhibited cells transfected with GFP-tagged alpha-synuclein resulted in ubiquitin- and alphaB-crystallin-positive aggregates resembling GCIs in MSA brains. Our results indicate that alphaB-crystallin is a major chaperone in MSA, and suggest a role of the protein in the formation of inclusion bodies in glial cells.

Amino Acid Sequence↗
PubMed2003

SUMO-1 marks the nuclear inclusions in familial neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by progressive ataxia and neuronal nuclear inclusions (NIs), similar to the inclusions found in expanded CAG repeat diseases. NIID may be familial or sporadic. The cause of familial NIID is poorly understood, as no CAG expansion has been detected. We examined three cases, from two unrelated families, who had autosomal dominant NIID but normal CAG repeats in genes involved in polyglutamine neurodegenerative diseases. We found that NIs in all three cases were intensely immunopositive for SUMO-1, a protein which covalently conjugates to other proteins and targets them to the nuclear regions (nuclear bodies) responsible for nuclear proteasomal degradation. Electron microscopy demonstrated that SUMO-1 was located on the 10-nm fibrils of NIs. In cultured PC12 cells, we found that inhibition of proteasome function by specific inhibitors resulted in the appearance of SUMO-1-immunopositive nuclear inclusions. Our study suggests that recruitment of SUMO-1 modified proteins into insoluble nuclear inclusions and proteasomal dysfunction may be involved in the pathogenesis of NIs in familial NIID cases.

Adult↗
PubMed2003

alpha-Synuclein fibrils constitute the central core of oligodendroglial inclusion filaments in multiple system atrophy.

Multiple system atrophy (MSA) belongs to synucleinopathies and is characterized pathologically by oligodendroglial inclusions (GCIs) composed of 20- to 30-nm tubular filaments. alpha-Synuclein fibrils formed in vitro, however, range between 10 and 12 nm in diameter. To understand the relationship between alpha-synuclein and GCI filaments, we conducted structural analyses of GCIs in fixed brain sections and isolated from fresh-frozen MSA brains. In fixed brain sections, GCIs were composed of amorphous material-coated filaments up to 30 nm in size. The filaments were often organized in parallel bundles extending into oligodendroglial processes. In freshly isolated GCIs, progressive buffer washes removed amorphous material and revealed that GCI filaments consisted of 10-nm-sized central core fibrils that were strongly alpha-synuclein immunoreactive. Image analysis revealed that each core fibril was made of two subfibrils, and each subfibril was made of a string of 3- to 6-nm-sized particles probably alpha-synuclein oligomers. Immunogold labeling demonstrated that epitopes encompassing entire alpha-synuclein molecule were represented in the core fibrils, with the N-terminal 11-26 and C-terminal 108-131 amino acid residues most accessible to antibodies, probably exposed on the surface of the fibril. Our study indicates that GCI filaments are multilayered in structure, with alpha-synuclein oligomers forming the central core fibrils of the filaments.

Aged↗
PubMed2003

Brain damage in pigs produced by impact with a non-penetrating captive bolt pistol.

OBJECTIVE: To assess the effect of impact with a nonpenetrating captive bolt pistol in pigs by studying the resulting traumatic brain injury (TBI) and to compare the pathological changes with those found previously in the brains of sheep using a similar experimental paradigm. PROCEDURE: The unrestrained heads of six, anaesthetised, 7- to 8-week-old, Large White pigs were impacted in the temporal region with a nonpenetrating captive bolt pistol. Four hours postimpact, brains were perfusion-fixed with 4% paraformaldehyde. Coronal sections from six levels along the brain were cut and stained with haematoxylin and eosin and immunohistochemically for amyloid precursor protein, a sensitive marker of axonal injury (AI) in the brain after trauma. RESULTS: TBI in pigs was characterised only by very mild AI, whereas AI in sheep after captive bolt impact to the same head region was much more severe and widely distributed and often associated with vascular damage such as contusions, subarachnoid and intraparenchymal haemorrhage. CONCLUSIONS: TBI in pigs was much less severe than in sheep after non-penetrating mechanical impact of similar magnitude, confirming the importance of interspecies differences in determining an appropriate physical method of euthanasia.

Animal Welfare↗
PubMed2003

Mechanisms of unexpected death in tuberous sclerosis.

Tuberous sclerosis complex is a protean autosomal dominant disorder characterized by multifocal tissue lesions arising from defects in cellular migration, proliferation, and differentiation. It has an association with sudden death. In the current study, review of all cases of sudden death due to tuberous sclerosis was undertaken at the Forensic Science Centre in Adelaide, Australia from 1991 to 2001, in addition to an analysis of cases from the literature. There were two local cases where unexpected death had occurred in individuals with known tuberous sclerosis, involving a 31-year-old male (epilepsy), and a 24-year-old female (massive hemorrhage into a renal angiomyolipoma). Fatal mechanisms in cases of tuberous sclerosis may be associated with underlying cardiovascular, renal and cerebral abnormalities. Sudden death may be due to cardiac arrhythmia, epilepsy, and intra-tumoral hemorrhage with additional complications including cardiac outflow obstruction, obstructive hydrocephalus, aneurysm rupture, and spontaneous pneumothorax. An awareness of the highly variable tissue manifestations of tuberous sclerosis and the mechanisms that may be responsible for death is necessary to establish correctly the diagnosis in occult cases (possibly with molecular confirmation), and to chart accurately organ changes in individuals with established disease.

Adult↗
PubMed2002

Patterns of immunocytochemical staining for ferritin and transferrin in the human spinal cord following traumatic injury.

Normally Fe(2+) is strictly controlled within the central nervous system (CNS) because of its potential to react with oxygen and form free radicals.(1,2) Traumatic spinal cord injury (TSCI) leads to cell damage and haemorrhage, both of which may increase the pool of free iron.(3) The aim of this study was to examine the response to TSCI of the iron storage protein ferritin (Ft) and the iron transport protein transferrin (Tf). The study found a significant increase in Ft positive cells compared to controls and a significant correlation between the number of Ft positive cells and the severity of injury. Significantly fewer Tf positive cells were seen in the trauma cases compared to the control and there was no relation with the severity of injury. These observations suggest a disturbance in normal iron metabolism within the spinal cord following injury, with possible implications for free radical mediated secondary damage.

Adolescent↗
PubMed2002

Accuracy of sampling methods in morphometric studies of human sural nerves.

The aim of this study was to ascertain the minimum sample required to accurately measure the total number of myelinated fibres, mean myelinated fibre density (MFD), myelinated fibre diameter (Ds) and axonal diameter (Da) in morphometric studies of sural nerve biopsies. Measurements were obtained by sampling a single fascicle or systematic sampling of up to 50% of the total transverse fascicular area of two control and eighteen pathological sural nerves showing varying degrees of demyelination and axonal degeneration. MFD and fibre size were heterogeneous between fascicles in both control and pathological sural nerves, and morphometric results from one fascicle and systematic sampling of up to 50% of the total transverse fascicular area did not accurately represent the whole myelinated fibre population in the sural nerve. For accurate morphometric data it is necessary to quantitate all the myelinated fibres in the sural nerve.

Adult↗
PubMed2002

Traumatic brain injury.

Animal models have played a critical role in elucidating the complex pathogenesis of traumatic brain injury, the major cause of death and disability in young adults in Western countries. This review discusses how different types of animal models are useful for the study of neuropathologic processes in traumatic, blunt, nonmissile head injury.

Animals↗
PubMed2001

Excitotoxic model of post-traumatic syringomyelia in the rat.

STUDY DESIGN: A rat model was developed to elucidate the role of excitatory amino acids and spinal subarachnoid block in the genesis of post-traumatic syringomyelia. This excitotoxic model produces intramedullary cavities rather than the dilation of the central canal (canalicular syringomyelia) created by previous animal models. OBJECTIVES: To produce extracanalicular cysts in the rat spinal cord with quisqualic acid, a potent agonist of multiple excitatory amino acid receptors, and to compare the effects of excitotoxic injury only with that of excitotoxic injury and subarachnoid block with kaolin. SUMMARY OF BACKGROUND DATA: In post-traumatic syringomyelia, primary injury and excitotoxic cell death secondary to elevated levels of excitatory amino acids may initiate a pathologic process leading to the formation of spinal cavities. Subarachnoid block by arachnoiditis may promote enlargement of the cavities. METHODS: Three control rats received a unilateral injection of normal saline into the spinal cord, and another five rats received an injection of kaolin into the spinal subarachnoid space. Quisqualic acid was injected unilaterally into the spinal cord of 20 rats, and 13 additional rats received a unilateral injection of quisqualic acid into the spinal cord after injection of kaolin into the subarachnoid space. Histologic and immunocytochemical assessments were undertaken. RESULTS: In the control groups, no parenchymal cyst developed in any of the animals. Spinal cord cyst formation was observed in 16 of 19 animals in the quisqualic acid groups, but no cysts exceeding two segments in the length of the spinal cord developed in any of the rats. Much larger cavities were seen in 9 of 11 animals in the group with quisqualic acid and kaolin, and cysts exceeding two segments developed in all 9 of these (9/11; 82%). CONCLUSIONS: In post-traumatic syringomyelia, excitotoxic cell death occurring secondarily to elevated levels of excitatory amino acids may contribute to the pathologic process leading to the formation of spinal cord cysts. Subarachnoid block by arachnoiditis is likely to cause enlargement of the cavity.

Animals↗
PubMed2001

A novel method for correlating internal and external structure of individual myelinated nerve fibres.

A new method is described that enables longitudinal and cross sections of an individual nerve fibre to be cut at multiple specified sites along the fibre by the use of a unique marker system. In this way the internal structure of the fibre can be correlated with the external appearance. Individual myelinated nerve fibres are teased apart in epoxy resin and mounted onto a carbon-coated slide, and after orientation and marking of specific sites of interest are snap frozen to liberate the orientated and marked fibres for embedding on the surface of an epoxy resin block for subsequent longitudinal or transverse sectioning. This method is particularly useful for the correlative study of the myelin-axon relationships.

Axons↗