Cortical selective vulnerability in motor neuron disease: a morphometric study.

Neuroimaging and neuropsychological studies have revealed that the primary motor cortex (PMC) and the extramotor cortical areas are functionally abnormal in motor neuron disease (MND, amyotrophic lateral sclerosis), but the nature of the cortical lesions that underlie these changes is poorly understood. In particular, there have been few attempts to quantify neuronal loss in the PMC and in other cortical areas in MND. We used SMI-32, an antibody against an epitope on non-phosphorylated neurofilament heavy chain, to analyse the size and density of SMI-32-positive cortical pyramidal neurons in layer V of the PMC, the dorsolateral prefrontal cortex (DLPFC) and the supragenual anterior cingulate cortex (ACC) in 13 MND and eight control subjects. There was a statistically significant reduction in the density of SMI-32-immunoreactive (IR) pyramidal neurons within cortical layer V in the PMC, the DLPFC and the ACC in MND subjects compared with controls [t (19) = 2.91, P = 0.009; estimated reduction 25%; 95% CI = 8%, 40%]. In addition, we studied the density and size of interneurons immunoreactive for the calcium-binding proteins calbindin-D(28K) (CB), parvalbumin (PV) and calretinin (CR) in the same areas (PMC, DLPFC and ACC). Statistically significant differences in the densities of CB-IR neurons were observed within cortical layers V (P = 0.003) and VI (P = 0.001) in MND cases compared with controls. The densities of CR- and PV-IR neurons were not significantly different between MND and control cases, although there were trends towards reductions of CR-IR neuronal density within the same layers and of PV-IR neuronal density within cortical layer VI. Loss of pyramidal neurons and of GABAergic interneurons is more widespread than has been appreciated and is present in areas associated with neuroimaging and cognitive abnormalities in MND. These findings support the notion that MND should be considered a multisystem disorder.

Subdural hematoma (SDH): assessment of macrophage reactivity within the dura mater and underlying hematoma.

OBJECTIVES: Macrophages are an inherent component of the dura mater, and can be characterised in cases of subdural hematoma (SDH) by their progressive and varying accumulation within areas of damage. Gross and histological methods used to determine the age of SDH are inexact. These are in part due to the active nature of such lesions and the diverse manner in which trauma victims respond to injury. Correct diagnosis has obvious medico-legal implications. However, there is as yet no specific diagnostic method that allows the age of SDH to be reliably determined. This study investigated the progressive and orderly pattern of reactivity of resident and infiltrating dural macrophages that occurs in response to injury associated with SDH. MATERIALS: 26 postmortem cases of traumatic SDH were examined with survival times (onset of trauma to death) ranging from a few hours and up to 31 days. METHODS: Macrophage reactivity associated with the dura mater and the underlying hematoma was determined using CD68 and MHC class II immunohistochemistry and the qualitative and quantitative findings compared with the presence of iron detected using conventional Perl's Prussian blue method. RESULTS: The results show that CD68 and MHC class II are differentially expressed within the dura mater and hematoma in SDH, and that the expression of MHC class II is markedly upregulated in the inner aspect of the dura mater within the initial 24 hours following injury. CD68 expression can be detected quantitatively in the hematoma, 24-48 hours after SDH, and within the dura following this period. Linear regression analysis further revealed a significant and positive association between the expression of MHC class II or CD68 antigens and the progressive survival of SDH up to 31 days post-injury, which was not seen with Perl's histochemical method. The expression of MHC class II antigen was a distinguishing, and quantifiable feature particularly localized within the inner aspect of the dura from a very early stage in the progression of SDH. Widespread, diffuse and cellular MHC class II reactivity was particularly noted within the inner aspect of the dura mater in cases of SDH with survival > 10 days. Since only a proportion of this widespread immunoreactivity was accounted for by macrophages (considering CD68 immunoreactivity), a large component of this activity was more likely to be due to the reorganisation and activation of fibroblasts within inner dural layers (dural border layer), known to upregulate expression of MHC class II molecules. CONCLUSIONS: The expression of CD68 and MHC class II antigens provides a more informative picture of the progression of pathology associated with SDH, and may be used in conjunction with other clinicopathological factors, in further investigations that attempt to date SDH according to defined histopathological characteristics.

Ubiquitin-only intraneuronal inclusion in the substantia nigra is a characteristic feature of motor neurone disease with dementia.

Two types of ubiquitinated inclusions have been described in motor neurone disease (MND). (1) Skein or globular ubiquitinated inclusions in the motor neurones (more frequently in the lower motor neurones). This is a characteristic feature of all motor neurone disease categories. (2) Dot-shape or crescentric ubiquitinated inclusions in the upper layers of cortex and dentate gyrus described in cases of motor neurone disease with dementia (DMND). We investigated the substantia nigra (SN) in MND cases; two cases of motor neurone disease inclusion body (MND-IB) dementia, six cases of DMND, 14 cases of MND (including one case from Guam and two cases of familial SOD1 mutation), four cases of Parkinson's disease (PD), and 10 cases of age-matched normal controls. SN and spinal cord sections were stained with ubiquitin (alpha-synuclein, tau, PGM1, SMI-31 and SOD1 antibodies). The neuronal density in SN was quantified by using a computer-based image analysis system. Four out of six DMND cases showed rounded ubiquitin positive inclusions with irregular frayed edges, associated with neuronal loss, reactive astrocytosis and a large number of activated microglia cells. These inclusions are negative with antibodies to (alpha-synuclein, tau, SMI-31 and SOD1). The SN in cases from MND-IB dementia and MND showed occasional neuronal loss and no inclusions. The ubiquitin-only inclusions in SN of DMND cases are similar (but not identical) to the ubiquitinated inclusions described previously in the spinal cord of MND cases and are distinct from Lewy bodies (LBs). The degeneration of SN is most likely a primary neurodegenerative process of motor neurone disease type frequently involving the DMND cases. MND disease is a spectrum and multisystem disorder with DMND located at the extreme end of a spectrum affecting the CNS more widely than just the motor system.

The role of matrix metalloproteinase genes in glioma invasion: co-dependent and interactive proteolysis.

Matrix metalloproteinases (MMPs) are cation-dependent endopeptidases which have been implicated in the malignancy of gliomas. It is thought that the MMPs play a critical role in both metastasis and angiogenesis, and that interference with proteases might therefore deter local tumor dissemination and neovascularization. However, the attempt to control tumor-associated proteolysis will rely on better definition of the normal tissue function of MMPs, an area of study still in its infancy in the central nervous system (CNS). Understanding the role of MMP-mediated proteolysis in the brain relies heavily on advances in other areas of molecular neuroscience, most notably an understanding of extracellular matrix (ECM) composition and the function of cell adhesion molecules such as integrins, which communicate knowledge of ECM composition intracellularly. Recently, protease expression and function has been shown to be strongly influenced by the functional state and signaling properties of integrins. Here we review MMP function and expression in gliomas and present examples of MMP profiling studies in glioma tissues and cell lines by RT-PCR and Western blotting. Co-expression of MMPs and certain integrins substantiates the gathering evidence of a functional intersection between the two, and inhibition studies using recombinant TIMP-1 and integrin antisera demonstrate significant inhibition of glioma invasion in vitro. Use of promising new therapeutic compounds with anti-MMP and anti-invasion effects are discussed. These data underline the importance of functional interaction of MMPs with accessory proteins such as integrins during invasion, and the need for further studies to elucidate the molecular underpinnings of this process.

Specificity and sensitivity of betaAPP in head injury.

INTRODUCTION: Beta-amyloid precursor protein (betaAPP) expression has been found in traumatic brain injury, hypoxia, ischemia and infection which affect axonal transport. Although betaAPP is a sensitive marker for detecting axonal damage, it has become non-specific for a particular type of injury. The aim of this study was to identify a difference in the pattern, distribution and intensity of betaAPP expression in head injury compared to hypoxic/ischemic insults. MATERIALS AND METHODS: Thirteen primary head injury and 12 primary hypoxic/ischemic cases were selected. The anterior and posterior parts of corpus callosum, internal capsule (basal ganglia), middle cerebellar peduncles (cerebellum) and pons were examined and stained immunohistochemically for betaAPP antibody. A computerized system of image analysis was used to examine the intensity (strength of staining) and density (area fraction) of betaAPP. RESULTS: Significant differences were observed in the overall intensity and density of betaAPP expression (p < 0.05) and in all 5 brain regions in cases of head injury compared to the hypoxic/ischemic group (p < 0.05). Positive staining for betaAPP was found in all regions in all cases of head injury, however, 4 out of 12 cases of hypoxia/ischemia were positive for betaAPP. One case expressed positivity in all 5 regions, 2 cases exhibited positivity in the pons alone, with only 1 case exhibiting immunoreactivity in the posterior corpus callosum and internal capsule. Differences in the pattern of betaAPP expression identified a predominantly granular pattern with a dirty background seen in hypoxia/ischemia, while fusiform swellings, beaded and thick filaments with clear background were observed in head injury. CONCLUSION: There are differences in the pattern, distribution and intensity of betaAPP in head injury compared to hypoxia/ischemia. These could be due to pathophysiological differences. The results may be helpful in differentiating head injury from hypoxia in medicolegal cases.

Cyclin-dependent kinase-5 is associated with lipofuscin in motor neurones in amyotrophic lateral sclerosis.

We have studied the distribution of cyclin dependent kinase-5 (cdk-5) within spinal cord in sporadic and two superoxide dismutase type 1 (SOD1) familial cases of amyotrophic lateral sclerosis (ALS). Although most neurofilament accumulations in ALS motor neurones did not appear to contain high levels of cdk-5, intense cdk-5 immunoreactivity was observed in perikarya of degenerating neurones in many ALS cases. Here, cdk-5 co-localised with lipofuscin. Co-localisation of cdk-5 with lipofuscin was also observed in some aged non-affected controls although this labelling was less intense than the ALS cases. The biogenesis of lipofuscin is believed to be linked to oxidative stress and oxidative stress and free radical damage have been suggested to be part of the pathogenic process of ALS, possibly involving apoptotic mechanisms. cdk-5 has recently been associated with apoptosis. These observations suggest a role for cdk-5 in the pathogenesis of ALS.

Iatrogenic cerebrospinal fluid fistula to the pleural cavity: case report and literature review.

The authors observed one case of an iatrogenic subarachnoid-pleural fistula secondary to the resection of an upper lobe carcinoma of the lung. The clinical presentation was characterized by a sudden deterioration of mental status and level of consciousness immediately after the removal of the thoracotomy chest tube. The diagnosis was substantiated by the demonstration of pneumocephalus by a computed tomographic scan of the head and by the identification of a left T5 nerve root fistula by a postmyelographic computed tomographic scan. The excellent anatomical definition achieved by this modality emphasizes its usefulness in the identification and therapeutic management of these lesions. Operative treatment consisted of the suture ligature of the nerve root and a chest drain. The postoperative course was uneventful, and the outcome was excellent, with the only finding of sensory loss in the T5 nerve root territory. A review of the literature disclosed 11 similar cases, with some differences in the choice of the most appropriate diagnostic procedure and significant differences in the therapeutic options, which were related to the various mechanisms of injury.

Wegener granulomatosis with meningeal involvement.

The clinical, radiographic, and neuropathologic features of the case of a 41-year-old man with Wegener granulomatosis presenting with neurologic symptoms are correlated. CT and MR scans of the head demonstrated extensive meningeal thickening and enhancement. The importance of considering this diagnosis, confirmed by antineutrophil cytoplasmic autoantibodies, is emphasized.

Ascending pharyngeal artery-internal jugular vein fistula complicating radical neck dissection.

Arteriovenous fistulae of the ascending pharyngeal artery (AP) and internal jugular vein (IJ) are rare. Only two spontaneous AP-IJ fistulae have been described previously, both of which presented with pulsatile tinnitus. A unique case of an AP-IJ fistula developing after radical neck dissection is described in which the clinical presentation was identical to that of a carotid-cavernous fistula.

Adverse effects of anabolic steroids in athletes.

The effects of anabolic steroid use on athletic performance and the adverse effects associated with the use of anabolic steroids are reviewed. Anabolic steroids increase protein synthesis in skeletal muscles and reverse catabolic processes. Because of these properties, some athletes use anabolic steroids in an attempt to improve their athletic performance. However, studies indicate that increases in muscle mass and strength during anabolic steroid administration are observed only in athletes who already are weight-trained and who continue intensive training while maintaining high-protein, high-calorie diets. Adverse effects attributed to anabolic steroid use occur frequently. Serious adverse effects include hepatic and endocrine dysfunction; cardiovascular and behavioral changes also are reported. Some of the adverse effects associated with the use of these agents are irreversible, particularly in women. The use of anabolic steroids to improve athletic performance has become prevalent. However, the reported benefits are tempered by numerous adverse reactions.