Detection of cathepsin S cysteine protease in human brain tumour microdialysates in vivo.

Microdialysis enables the chemistry of extracellular fluid in body tissues to be measured. Extracellular proteases such as the cysteine protease, cathepsin S (CatS), are thought to facilitate astrocytoma invasion. Microdialysates obtained from human brain tumours in vivo were subjected to cathepsin S activity and ELISA assays. Cathepsin S ELISA expression was detected in five out of 10 tumour microdialysates, while activity was detected in five out of 11 tumour microdialysates. Cathepsin S expression was also detected in microdialysate from the normal brain control although no activity was found in the same sample. While some refinements to the technique are necessary, the authors demonstrate the feasibility and safety of microdialysis in human astrocytomas in vivo. Characterisation of the extracellular environment of brain tumours in vivo using microdialysis may be a useful tool to identify the protease profile of brain tumours.

Cutaneous metastasis from glioblastoma.

A rare case of glioblastoma with isolated cutaneous metastasis adjacent to the scar site is described. Its pathogenesis and clinical significance are discussed.

Up-regulation of osteopontin and alphaBeta-crystallin in the normal-appearing white matter of multiple sclerosis: an immunohistochemical study utilizing tissue microarrays.

Tissue microarrays assembled from control and multiple sclerosis (MS) brain tissue have been used to assess the expression patterns and cellular distribution of two antigens, the proinflammatory cytokine osteopontin and the inducible heat shock protein alphaBeta-crystallin, which have previously been implicated in MS pathogenesis. Tissue cores were taken from paraffin-embedded donor blocks containing chronic active or chronic inactive plaques and normal-appearing white matter (NAWM) in seven MS cases, and white matter (WM) in five control cases. Expression patterns of both proteins were assessed against myelin density and microglial activation in the different tissue categories. Both proteins showed increased expression in all categories of MS tissue compared with control WM. The results indicate progressive up-regulation of expression of osteopontin with increased plaque activity, while elevation of alphaBeta-crystallin expression in MS tissue was independent of demyelination. In MS NAWM a significant correlation was observed between high levels of expression of osteopontin and alphaBeta-crystallin. Osteopontin expression was predominantly confined to astrocytes throughout MS tissues. alphaBeta-crystallin was expressed on astrocytes, oligodendrocytes and occasionally on demyelinated axons. Taken together, these data indicate a wider distribution of osteopontin and alphaBeta-crystallin in MS tissues than previously described and support their proposed role in MS pathogenesis.

Plasmacytoma: an unusual cause of a pituitary mass lesion. A case report and a review of the literature.

A sixty six year old female presented with headache and decreased hearing. Clinical examination confirmed the presence of impaired hearing on the left side. Visual fields were full to confrontation and corrected visual acuity was normal. CT scan of brain revealed a pituitary mass. Preoperative anterior pituitary function was normal. Transsphenoidal decompression was performed, and histology was that of a plasmacytoma. Post operative pituitary function was normal. The patient had no symptoms or signs of multiple myeloma and subsequent investigations revealed no evidence of the disease. One year after diagnosis a course of radiotherapy was administered for local tumour recurrence. During seven years of follow-up, no evidence of multiple myeloma has emerged. Only thirteen similar cases have been described. Four of these had evidence of multiple myeloma at presentation and six progressed to it during follow-up. In twelve patients cranial nerve deficits were recorded. In any cases where it was documented, preoperative anterior pituitary function was normal. In a number of cases histology was reported initially as being that of a non-functioning adenoma, the true diagnosis being discovered, either by electron microscopy findings or after the development of multiple myeloma. Plasma cell tumours of the pituitary area are rare and can present with symptoms and signs indistinguishable from non-functioning adenoma. Atypical symptoms such as cranial nerve involvement or unexpected preservation of anterior pituitary function should arouse suspicion.

Superficial siderosis of the central nervous system many years after neurosurgical procedures.

Recurrent haemorrhage into the subarachnoid space causes superficial siderosis, which clinically manifests as cerebellar ataxia, sensorineural hearing loss, and myelopathy. Two patients developed clinical, radiological, and biochemical evidence of superficial siderosis many years after surgery. One had two posterior fossa operations, a left temporal craniectomy, and radiotherapy for a presumed brain tumour before developing clinical evidence of superficial sidersosis 37 years later. The other had small bilateral subdural collections from recurrent shunt revisions following posterior fossa surgery for a Chiari malformation, and then developed deafness and ataxia. The first patient currently has the longest recorded delay between presumed subarachnoid bleeding and clinical manifestations of superficial siderosis. Both patients provide further evidence that superficial siderosis of the central nervous system, a progressive neurodegenerative vascular condition, may be a delayed complication of neurosurgical procedures.

CD83-positive dendritic cells are present in occasional perivascular cuffs in multiple sclerosis lesions.

Multiple sclerosis (MS) has a wide spectrum of clinical courses, characterized by multifocal central nervous system (CNS) damage, postulated to be mediated by CNS antigen-specific T cells. Dendritic cells (DC), the most potent antigen-presenting cell, play a pivotal role in the decision between T-cell activation or anergy. Monoclonal antibodies to CD1a (immature DC) and CD83 (mature DC) were used to screen lesions with evidence of recent demyelinating activity and chronic plaque and normal appearing white matter (NAWM) tissue sections from 12 MS cases by immunocytochemistry. No CD1a-positive cells were detected in the MS or control CNS tissue blocks investigated. CD83-positive cells were not detected in tissues from any of the control cases or in the majority of perivascular cuffs in the MS tissue sections. However; in eight of the MS tissue blocks with evidence of recent demyelination, and in one block each from chronic plaque and NAWM, small numbers of distinct CD83-positive cells were present within occasional perivascular cuffs. In one area only of MS NAWM were CD83-positive cells detected in the tissue parenchyma, in an area of intense immunological activity. DC in MS tissue may originate in the peripheral circulation as monocytes or immature DC and migrate to areas of plaque in response to signals received from CNS-produced chemokines.

Pathological abnormalities in the normal-appearing white matter in multiple sclerosis.

In established cases of multiple sclerosis (MS), the normal-appearing white matter (NAWM), as defined for magnetic resonance imaging (MRI), is abnormal in the majority of cases. The clinical significance of these NAWM abnormalities is the subject of debate, but there is strong correlation with degree and progression of disability. New lesions form in NAWM before blood-brain barrier breakdown, as evidenced by gadolinium enhancement. The pathological basis of these neuroimaging abnormalities is largely unknown. Definitive pathological studies on the NAWM are few and are often based on small numbers of samples and of cases. Despite a variety of MS NAWM pathological studies, major research questions, of importance to our understanding of basic pathogenetic mechanisms and consequent rational therapies, remain unanswered. These relate to the frequency and extent of oligodendrocyte/myelin and axonal abnormalities in MS NAWM, and to the cellular basis of very early MS lesions detected by neuroimaging. In a pilot study of MS NAWM, microglial activation was demonstrated in 9 of 10 MS cases. We are currently testing the hypothesis that microglial activation, as defined by altered phenotype and HLA-DR positivity, will act as a marker for oligodendrocyte/myelin and axonal pathology in MS NAWM.

Immunohistochemical evaluation of the post-translational processing of chromogranin A in human pituitary adenomas.

Chromogranin A (CgA), pancreastatin (PST), intervening-peptide (IP) and WE-14 antisera were employed to investigate the proteolysis of CgA in 50 pituitary adenomas. All non-functioning (NF) pituitary tumours (n = 28) exhibited CgA immunoreactivity. PST, IP and WE-14 immunostaining was observed in 85%, 89% and 67%, respectively. CgA, PST and IP immunostaining were comparable in the majority of NF tumours, while less intense WE-14 immunoreactivity was detected in a subpopulation of NF tumour cells. Approximately half of the functioning pituitary tumours expressed CgA immunoreactivity. Six of nine ACTH-secreting tumours displayed CgA and IP immunostaining; four of these tumours displayed PST immunoreactivity. WE-14 immunoreactivity was detected in one corticotroph tumour. Three of six growth hormone (GH) secreting tumours displayed CgA immunostaining, two exhibited PST and IP, and one exhibited WE-14 immunoreactivity. Clusters of WE-14 immunopositive cells were detected in one GH tumour. One of seven prolactinomas exhibited weak CgA immunostaining, while weak IP and WE-14 immunostaining was detected in an additional tumour. No PST immunostaining was detected in prolactinomas. Therefore CgA is a valuable marker of NF pituitary tumours, however it is a more sporadic marker of functioning adenomas. In general, the cellular pattern and intensities of CgA, PST and IP immunoreactivity were comparable in the majority of pituitary adenomas. In contrast, WE-14 immunostaining was observed in a subpopulation of tumour cells. The pathophysiological significance of the proteolysis of CgA to generate bioactive peptides in both NF and functioning pituitary adenomas remains to be established.

Discordant repeat size and phenotype in Kennedy syndrome.

Previous reports in the literature have described correlation of increasing repeat length with severity of the phenotype, in Kennedy syndrome. We describe male siblings with different repeat lengths, with lack of expression of the phenotype in the sibling with the longer repeat length. The phenotype was identical to motor neurone disease. There is variability of expression in Kennedy syndrome and repeat length even in siblings cannot be taken as a conclusive indicator of severity. CAG repeat length cannot be used to predict the natural history of Kennedy disease. The diagnosis of Kennedy syndrome should be considered in male patients presenting with atypical motor neurone disease.

Expression of bcl-2 oncoprotein in pituitary tumours: comparison with c-myc.

AIMS/BACKGROUND: Whereas the control of hormone secretion from pituitary adenomas has been studied in considerable detail, the molecular events underlying the development of these tumours are still poorly understood. Abnormalities of some oncogenes and tumour suppressor genes have been previously reported to occur at very low frequencies. The aim of the present study was to assess the possible expression of the bcl-2 oncoprotein and to compare it with that of c-myc in pituitary adenomas. METHODS: Monoclonal antibodies were used, along with microwave antigen retrieval and the avidin-biotin immunohistochemical method, to investigate expression of the oncoproteins bcl-2 and c-myc in 30 primary pituitary tumours from five broad diagnostic groups and in five normal pituitaries. RESULTS: Bcl-2 and c-myc immunoreactivities were detected in nine (30%) and eight (27%) tumour samples, respectively. Of the nine bcl-2 and eight c-myc positive tumours, seven were positive for both oncoproteins and included one of the four corticotrophinomas studied, four of seven prolactinomas, one of two somatotrophinomas, and one of four oncocytomas. All 13 null cell adenomas studied were negative for both bcl-2 and c-myc immunoreactivities. CONCLUSIONS: These results indicate that the bcl-2 and c-myc oncoproteins are expressed abnormally in over one quarter of pituitary tumours. Most these tumours co-expressed both oncoproteins. The genetic complementation of simultaneously deregulated bcl-2 and c-myc is implicated, through the regulation of apoptosis, in the pathogenesis of pituitary tumours.

Deficiency of respiratory chain complex I is a common cause of Leigh disease.

We reviewed the clinical features and etiologies of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of all pedigrees, and in 74% of the 19 pedigrees with pathologically proved Leigh disease. Isolated deficiency of respiratory chain complex I was found in 7 patients, though the complex was only assayed in 25 patients, making this the second most common biochemical abnormality after complex IV deficiency. Mutations at residue 8993 of mitochondrial DNA were found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate concentrations in the cerebrospinal fluid.

Focal myositis of the floor of mouth: report of two cases and review of the literature.

Focal myositis is an uncommon inflammatory myopathy of unknown cause affecting skeletal muscle. It may be mistaken on clinical evaluation for a malignant neoplasm. We describe two cases, both involving the mylohyoid muscle of the floor of the mouth. In each case excisional biopsy of a firm indurated mass revealed a focal lymphocytic and histiocytic infiltrate associated with degenerating and regenerating skeletal muscle fibers. No clinical or biochemical evidence of generalized muscle disease was seen at presentation or at 1-year and 7-year follow-up examination. The literature on focal myositis involving the head and neck region is reviewed.

Desmin myopathy with cardiomyopathy.

We report a case of abnormal desmin accumulation within the muscle of a 30-year-old female with a 2-year history of cardiomyopathy and axial muscle weakness. Serum creatine kinase was normal. A quadriceps muscle biopsy revealed pink hyaline inclusions, which stained for acid phosphatase and with PAS and were present in both fibre types. Electron microscopy showed these inclusions to consist of aggregates of irregularly arranged 6- to 15-nm-diameter filaments enmeshed within a central core of dense granulo-amorphous material. In other areas, the granulo-amorphous material lay as irregular patches within the sarcoplasm, mainly at the level of the "Z" band causing disruption of the sarcomere. Immunoelectron microscopy using colloidal gold showed that the dense amorphous material reacted strongly with desmin antisera and could, therefore, represent a defective or phosphorylated form of the protein.

A clinicopathological review of spinal ependymomas in Northern Ireland.

Of eighty-three tumours of ependymal origin diagnosed in the twenty years 1969-1988 in Northern Ireland, fifteen were located within the spine. Two were in children, 13 in young adults with a mean age of 33 years. 70% presented with back pain and 60% had weakness of the lower limbs. Survival was found to correlate well with histological grading (WHO classification). The mean time of survival for tumours graded 1/2 was six years; there were three long-term survivors of 13, 17 and 18 years; 90% of the patients survived 2.5 years.

Cutaneous remnants of the vitellointestinal duct: a clinico-pathological study of 19 cases.

The presence of cutaneous vitellointestinal duct remnants was confirmed histologically in 19 cases in the period 1970-1984. These lesions occurred mostly in males (16 males, 3 females), and 80% in children under the age of five years. One case was identified in an adult, suggesting that these lesions may in some cases cause little inconvenience, and that their true incidence is underestimated.