Expression and localization of VEGF-C and VEGFR-3 in glioblastomas and haemangioblastomas.

Primary human brain tumours account for approximately 2% of all cancers. High levels of expression of vascular endothelial growth factor-A (VEGF-A), a potent angiogenic factor, are linked to poor prognosis. In contrast, the potential role in human brain tumour biology of newer VEGF family members, VEGF-C and VEGF-D, both of which are lymphangiogenic factors, is poorly understood. In the present study, the expression of all VEGFs (VEGF-A, -B, -C, and -D) and their receptors (VEGFR-1, -2, and -3) has been assessed in 39 primary human brain tumours. The well-established findings were confirmed with VEGF-A. Surprisingly, however, VEGF-C and VEGF-D, as well as VEGFR-3, were expressed in some tumour types such as haemangioblastomas and glioblastomas, despite their lack of lymphatic vessels. VEGF-C and VEGFR-3 transcripts were localized to the tumour palisade around necrotic areas in glioblastomas and were evenly distributed throughout haemangioblastomas. VEGF-C protein was localized by immunohistochemistry to the palisade layer in glioblastomas. More than 50% of VEGF-C-positive cells also expressed the intermediate-stage inflammatory macrophage marker CD163; however, a significant proportion of VEGF-C-positive cells were CD163-negative. These data demonstrate the presence of molecules, primarily described as regulators of lymphangiogenesis, in normal human brain and brain tumours that are devoid of lymphatics. Their localization in macrophages points to a role in tumour-associated inflammation.

Sudden, unexpected death due to undiagnosed frontal glioblastoma in a schizophrenic patient.

The incidence of sudden death due to undiagnosed primary intracranial tumor is low in forensic autopsy. We report a case of a 48-year-old white male, known to be a schizophrenic patient for several years, and in whom a medico-legal autopsy disclosed a large, previously undiagnosed, bilateral frontal glioblastoma infiltrating the genu of corpus callosum. We emphasize the importance of performing complete autopsy, including a thorough neuropathological examination, in all cases of sudden unexpected death, especially in those cases in which no extracerebral cause of death had been established and whose clinical history was primarily of a psychiatric nature.

Neuropathology of a case of dopa-responsive dystonia associated with a new genetic locus, DYT14.

Detailed autopsy findings are reported for a patient with dopa-responsive dystonia genetically related to the dopa-responsive dystonia locus DYT14 on chromosome 14q13. Substantia nigra and locus ceruleus showed a normal abundance of severely hypomelanized dopaminergic neurons and no Lewy body. In the nigra, the reduction of melanin pigment was found to be asymmetric between the two sides and uneven within neurons, and the lateral aspect of the nigra appeared more affected than the medial, in a pattern similar to the neuronal loss in PD. Dopa-responsive dystonia has a unique neuropathologic signature that seems to be independent of its genotype.

[Transthoracic transvertebral approach for resection of an anteriorly located, calcified meningioma. Case report]. / Abord transthoracique transvertébral pour résection d'un méningiome calcifié de situation antérieure. A propos d'un cas.

We report the case of a 61-year-old woman, who developed progressive paraparesia over a period of 8 months. Conventional X-rays of the thoracic spine showed an intra-spinal calcified lesion at T10. On CT-scan and MRI, the lesion appeared anterior to the cord, thus making a posterior approach hazardous. Total resection of this calcified meningioma was achieved through a right transthoracic transcorporeal approach, under close monitoring of the somatosensory evoked potentials. Despite a delayed pseudomeningocele formation requiring an additional thoracotomy, outcome after 7 years is excellent with no residual neurological deficit. No recurrence was seen on a CT-scan performed two years after the surgery. Calcified anterior meningiomas of the spine are rare lesions. Surgical outcome has been unfavorable for a long time in relation with posterior or postero-lateral approaches. Although anterior transthoracic procedures are routinely performed for extradural spinal lesions, this approach is rarely used for intradural lesions. A calcified anterior spinal thoracic meningioma should be managed like the more frequent calcified thoracic disk hernia, despite the increased risk of cerebrospinal fluid effusion requiring subsequent repair.

Early fatal pontocerebellar hypoplasia in premature twin sisters.

We report clinical, neuroradiological and neuropathological findings of monozygotic twin sisters born at 30 weeks' gestation, with pontocerebellar hypoplasia (PCH) similar but not identical to type 2 PCH. They presented with hypertonia, jitteriness, spontaneous and provoked myoclonic jerks (hyperekplexia), apnoeic episodes, and progressive microcephaly. They died at 7 weeks of age from respiratory failure.

Proximal myotonic myopathy: clinical, electrophysiological and pathological findings in a family.

Proximal myotonic myopathy (PROMM) is an autosomal dominant muscle disorder characterized by proximal weakness, myotonia, muscle pain and cataract. It resembles Steinert myotonic dystrophy (MD), but weakness is proximal, without facial muscle involvement, and the chromosome 19 CTG trinucleotide repeat expansion characteristic of MD is not present. We describe a further family with PROMM. Affected members complained of weakness of lower limbs or of myotonia. EMG revealed diffuse myotonic discharges. Muscle histology showed dystrophic abnormalities. The PROMM phenotype varies, even in the same pedigree, and may mimic MD or limb-girdle muscle dystrophy. EMG is particularly useful, since it may disclose myotonic discharges even in the absence of overt myotonia. Thus far it is not known whether PROMM is a single entity, or if it represents a heterogeneous group of disorders. This question will probably soon be settled through genetic analysis.

[Inflammatory and infectious manifestations of the nervous system]. / Manifestations inflammatoires et infectieuses du système nerveux.

The Central Nervous System is the site of a wide variety of inflammatory and infectious diseases. Some disease entities have been in the focus of interest in recent years and progress has been achieved in our understanding of some chosen domains. We will review recent progress in our knowledge about transmissible spongiformes encephalopathies and AIDS-associated lesions, and briefly discuss cerebral vasculitis, granulomatous diseases and the most frequent infections by parasites.

Cerebral vasculitis during FK 506 treatment in a liver transplant patient.

The immunosuppressive agent FK 506 is widely used in liver transplant patients. Neurotoxicity is a major complication of its use. We report progressive and irreversible neurologic complications occurring in a 39-year-old woman who underwent liver transplantation and was treated with FK 506. Neuropathologic examination revealed multiple vasculitic lesions. The possibility of an FK 506-mediated toxic effect on the cerebral vessels is suggested.

Dysembryoplastic neuroepithelial tumour as a cause of coma.

Dysembryoplastic neuroepithelial tumour (DNT), a non-evolutive intracranial cortical lesion, is generally associated with epileptic seizures principally among youths. A case of a DNT which presented with uncommon clinical features, characterized by severe intracranial hypertension and progressive blindness warranting emergency surgery, is documented. In addition to the classical radiological and neuropathological features characteristic of DNTs there was a large haemorrhagic cystic haematoma as a result of repeated dissections and/or ruptures of the abnormal vessels in areas, explaining some of the atypical clinical symptoms. Therefore the need for a regular, careful clinical and radiological follow-up of cases with cystic DNTs is strongly recommended.

Adhesion molecules in HIV-related and idiopathic polymyositis: immunohistochemical studies.

Idiopathic polymyositis (IPM) and HIV polymyositis (HIV-PM) are considered to be related autoimmune diseases whose target is skeletal muscle. They have been associated to a T cell-mediated and MHC-I-restricted cytotoxic phenomenon, but both etiology and physiopathology remain incompletely understood. Their histological hallmarks are mononuclear leukocyte infiltrates as well as necrosis, degeneration, and regeneration of muscle fibers. In the present study, we have investigated the immunohistochemical expression of cell adhesion molecules, cytokines, and leukocyte surface antigens in biopsies of HIV-PM and IPM patients. The aim was to better define factors involved in lymphocyte recruitment and in inflammatory changes seen in PM. Notable upregulation of ICAM-1 and TNF-alpha was detected on capillary and venular endothelia and on inflammatory cells, whereas no significant VCAM-1 and ELAM-1 expression was present. LFA-1, the main ICAM-1 counter-receptor, was found to be highly expressed on lymphocytes and monocytes, especially at the vicinity of damaged fibers. The majority of infiltrating cells were CD8+CD45 RO-T cells, which are thought to have memory capacities. These findings suggest that in IPM and HIV-PM, enhanced ICAM-1 and LFA-1 expression possibly induced by TNF-alpha, may regulate the homing process of selected lymphocyte clones in muscle tissue. Lymphocyte proliferation and differentiation into memory subsets may further potentiate tissue-restricted homing capabilities.

Synovial cyst and degeneration of the transverse ligament: an unusual cause of high cervical myelopathy. Case report.

A case of cystic degeneration of the transverse ligament located posteriorly to the dens and causing compression to the lower medulla and upper cervical spinal cord is reported. The clinical, pathological, and radiological findings are described and compared to the literature to characterize this syndrome more fully. The advantages of a posterolateral surgical approach are stressed.

Decreased nitric oxide production accounts for secondary arteriolar constriction after retinal branch vein occlusion.

PURPOSE: After retinal branch vein occlusion (BVO), the arteriole crossing the occluded territories is often constricted. This constriction persists up to several weeks and is correlated with the development of extended territories of nonperfused capillaries. These are results of an investigation supporting the hypothesis that decrease in the production of nitric oxide (NO) accounts for the observed arteriolar constriction. METHODS: Preretinal [NO] was measured using an NO microprobe in the anesthetized miniature pigs, before and during the first 4 hours after experimental branch vein occlusion. Modifications of arteriolar diameter were correlated to preretinal [NO] changes. The retinal arteriolar sensitivity to constitutive NO was checked by applying preretinal puff injections of nitro-L-arginine (L-NA) after both systemic hypoxia and branch vein occlusion. RESULTS: Two hours after branch vein occlusion there was a 73.7 +/- 4% decrease in preretinal [NO] and a simultaneous 25.4 +/- 3.4% decrease in the diameter of the arteriole in the affected territory. Both persisted for at least 4 hours after branch vein occlusion. Applying a puff of L-NA to an arteriole previously dilated by systemic hypoxia induced a vasoconstriction. However, no arteriolar constriction was observed when a puff was applied to an arteriole after branch vein occlusion. CONCLUSIONS: These results show that experimental branch vein occlusion induces in the affected retina an impairment in the release of constitutive NO and an arteriolar constriction, which, in turn, contributes to the development of hypoxia in tissue and neuronal swelling and death in the inner retina.

Discrepancies between HMPAO and ECD SPECT imaging in brain tumors.

Among several brain radiopharmaceuticals for SPECT imaging, 99mTc complexes of HMPAO and ECD are the most widely used. They are considered to be equal in their capacity to reflect regional cerebral blood flow; but discrepancies between HMPAO and ECD brain uptake have been reported in stroke patients. This paper reports our observations regarding discrepancies between HMPAO and ECD SPECT in 14 of 23 patients with suspected brain tumors or presumed metabolic cerebral abnormalities. We obtained similar conflicting results, namely focal HMPAO hyperactivities and isoactive ECD SPECT. The majority of these discrepancies were found in patients with brain tumors (10 of 13 patients), while only 4 of the 10 remaining patients with nontumoral process showed similar discrepant results. The physiopathology behind these observations is discussed here, and it is likely to be related to the specific response to cellular metabolic disorders rather than to perfusion disturbances.

Mitochondrial anomalies in a Swiss family with autosomal dominant myoglobinuria.

We report on a Swiss family in which 10 individuals of both sexes in 4 successive generations suffered from myoglobinuria, precipitated by febrile illness. It is the second family described with autosomal dominant inheritance of myoglobinuria. Four individuals suffered acute renal failure, which in two was reversible only after dialysis. In a recent case, a mitochondrial disorder was suspected because of an abnormal increase in lactate levels during an exercise test and because of a subsarcolemmal accumulation of mitochondria in a muscle biopsy, associated with a lack of cytochrome C oxidase in some muscle fibers. No mutation in the mitochondrial DNA was identified. Along with the inheritance pattern, these findings suggest that the myoglobinuria in this family is caused by a nuclear-encoded mutation affecting the respiratory chain.

A panencephalopathic type of Creutzfeldt-Jakob disease with selective lesions of the thalamic nuclei in 2 Swiss patients.

Creutzfeldt-Jakob disease (CJD), a subacute spongiform encephalopathy, is generally included among the group of human and animal diseases which is transmissible by a non-conventional agent, the prion, whose expression is conditioned by the host's genome. The process leading to neuropathological changes is still unknown. We report the neuropathological findings in 2 cases of the "panencephalopathic" variant of CJD, which is relatively common in Japan, but extremely rare in Europe and North America. When compared with the classical form this variant is characterized by a relatively long clinical course with persistent vegetative state and primary involvement of the white matter presenting in the form of demyelination and gemistocytic gliosis. The selective involvement of certain thalamic nuclei is a particular pathological feature in both our cases. There was practically complete neuronal loss with diffuse gliosis of the anteroventral (AV) and dorsomedial (DM) nuclei, while the neuronal loss in the pulvinar remained moderate: the other nuclei were apparently spared. A similar involvement of the thalamus has been reported in fatal familial insomnia, a recently described prion disease in which these lesions are predominant. A comparable distribution has also been observed in other degenerative neurological diseases such as Steele-Richardson-Olszewski disease, Alzheimer disease, and thalamic dementia (selective thalamic atrophy or with multisystemic degeneration). The AV and DM nuclei, commonly referred to as "limbic thalamus" represent phylogenetically the most recent thalamic structures and would appear to play an important role in the superior functions in man as memory, attention and awareness. In our cases thalamic lesions are selective, bilateral, and symmetric, not explained by Wallerian degeneration. These lesions may be due to the primary pathogenetic properties of the infectious agent. The rapid clinical evolution in a persistent vegetative state could be consequential to precocious and severe disfunction of the limbic thalamus.

[Early alterations in release of nitrogen monoxide by the retinal after experimental venous occlusion]. / Altérations précoces dans le relâchement du monoxide d'azote par la rétine après occlusion veineuse expérimentale.

PURPOSE: We present hereby some results indicating that there is a significant decrease in the release of NO by the retina immediately after branch-venous occlusion (BVO). METHODS: Using an NO microprobe we measured (NO) in the preretinal vitreous of miniature pigs before and two hours aRer bvo. Conventional and electronic microscopy were performed on the affected retina. RESULTS: At the retinal surface (NO) was reduced to 25% of the previous value two hours after BVO, at the same time significative oedema of the inner retina was observed. CONCLUSIONS: Immediately after BVO there is a significative decrease in the amount of NO released by the affected retina, parallel to the first evidences of an oedema of the inner retinal layers.

[Morphology of early retinal lesions after experimental venous occlusion]. / Morphologie des lésions rétinennes précoces après occlusion veineuse expérimentale.

PURPOSE: Study of early hystological lesions after experimental branch venous occlusion (BVO) in miniature pigs. MATERIALS AND METHODS: The retina was taken 1, 2, 4, 6 and 8 hours after BVO with green argon laser for examination with conventional and electronic microscopy. RESULTS: 1 hour after occlusion an extracellular focal oedema is observable in the ganglion cells optic nerve fibers and cells of inner plexiform layer; 2 hours after occlusion there is also an extracellular oedema of the external plexiform layer as intracellular oedema of the inner nuclear layer, 4 hours after occlusion the extracellular oedema is more diffuse especially in the ganglion cells, inner nuclear and optic nerve fibers layers. Cytoplasmic vacuolisation, nuclear pycnosis and ruptured cell membrane layers are observed; 8 hours after occlusion both intra and extracellular oedema are observable throughout the inner retina. CONCLUSIONS: After BVO histological lesions are found within one hour only following the occlusion, apoptosis and cell necrosis are present as soon as 4 hours after experimental BVO.

The clinical, molecular, and pathological characterisation of a family with two cases of lethal perinatal type 2 Gaucher disease.

It has recently been emphasised that a subset of patients with type 2 Gaucher disease die in the neonatal period. This report describes an Afghani family with two conceptuses having severe, prenatally detected Gaucher disease. Mutational analysis showed that the family carried a known complex allele which included mutations at amino acids L444P, A456P, and V460V. Although glucocerebrosidase RNA was present, an affected fetus had virtually no glucocerebrosidase cross reactive material on western analyses. The severe clinical course and pathology observed in these patients resemble that of the null allele Gaucher mouse, and suggest that the absence of glucocerebrosidase activity results in early death.