A case of FK 506-induced leukoencephalopathy]

We reported a 15-year-old boy with an acute myelomonocytic leukemia and FK 506-induced leukoencephalopathy. He was received FK 506 for graft versus host disease occurred after peripheral blood stem cell transplantation. He, four weeks later, had generalized seizures and consciousness disturbance. The serum level of FK 506 was high (27.5 ng/ml). His brain MRI showed abnormal high intensity areas in the frontal and parietal white matter lesions on T2-weighted images. Neuropathological studies revealed the destruction of myelin sheeths and axons in the cerebral white matter corresponded with abnormal lesions on MRI. There were calcification and mineralization in the small vessel walls of the cortex and white matter. Osteopontin immunoreactivity was detected in the endothelial cells of small vessels. These findings suggest that the vascular damage was involved in the FK 506-induced leukoencephalopathy.     

Progressive enlargement of a mass lesion in late cerebral radionecrosis

The progressive enlargement of a mass lesion in late cerebral radionecrosis (LCR) was studied using a surgical specimen from a woman’s irradiated brain. Using immunohistochemical (IHC) staining on paraffin-embedded sections, expression of tumor necrosis factor-alpha (TNF??), interleukin (IL)6, Flk-1, and vascular endothelial growth factor (VEGF) was semi-quantitatively evaluated in the necrotic area and areas distant and adjacent to the necrotic area. High immunoreactivity for TNF??, IL6, and VEGF in regions distant to the necrotic core were strongly associated with inflammatory cell density, hyalinized vessels, and vascularization. Ghost cells stained with glial fibrillary acidic protein (GFAP), Ki-M1P, KP-1, ubiquitin-C-terminal hydrolase 1, and fibrinoid necrosis were observed in the necrotic area and adjacent regions. These results suggest that necrotic factors, inflammatory reaction, and angiogenetic factors act temporally and spatially through radiation-induced vascular endothelial cell damage to contribute to the progressive enlargement of an enhancing mass lesion in LCR.     

A morphologic study of the vasculature of malignant gliomas using thick celloidin sections and alkaline phosphatase stain

The combination of 100 microm thick celloidin sections and alkaline phosphatase (AP) enzyme histochemistry of the vascular endothelium offers a greatly enhanced, 3D morphologic perspective and reveals intricate details of the vasculature of brain. A study of tumor specimens obtained at craniotomy from 6 patients with glioblastomas, 1 with anaplastic oligodendroglioma and 1 with juvenile pilocytic astrocytoma was undertaken using this technique. Five of the 6 glioblastomas, the anaplastic oligodendroglioma and the low-grade astrocytoma specimen showed uniform staining of afferent tumor blood vessels. In the glioblastomas, newly formed vessels formed dense, festooned networks at the advancing edges of the tumor. Feeding arteries entered the tumor at the junction between the edge of the tumor and adjacent brain or meninges and proceeded to form striking, coiled vessels and smaller branches. The density of both small arteries and veins was greatly increased within the tumor although there was much variability. Disordered arborization, arteriole to venous and arteriole to arteriole shunts were observed, leading to a situation where arteries connected directly to veins. In necrotic areas, there were often no AP-stained vessels. In many places, arterioles and capillaries were lacking. Numerous AP-negative veins of various sizes drained the tumors. Glomeruloid proliferations were presumptively identified as focal stain smudges or clusters of capillaries arising from nearby vascular channels. Increased alkaline phosphatase staining and/or focal new vessels were seen outside necrotic areas. The pilocytic astrocytoma and the oligodendroglioma showed less dense vascularity and no formation of the focal festoons of vessels shown by the glioblastomas. This technique may be useful for the study of tumor angiogenesis and to evaluate vascularity in experimental and human brain tumors after various therapies.     

Evaluation of regional cerebral blood flow in patient with atypical senile dementia with asymmetrical calcification

We report an 83‐year‐old woman with atypical senile dementia with Fahr‐type calcification. Brain computed tomography demonstrated asymmetrical calcification predominant in the basal ganglia on the right side and pronounced diffuse cortical atrophy in the frontotemporal areas. The patient was clinically diagnosed with diffuse neurofibrillary tangles with calcification. Brain single photon emission computed tomography findings revealed that cerebral blood flow was reduced on the right side, as compared with the left side, in widespread areas. Hemispheric asymmetry in both calcification and cerebral blood flow suggests a relationship between calcification and vascular changes.     

Matrix Gla protein is associated with coronary artery calcification as assessed by electron-beam computed tomography

Matrix Gla protein (MGP) is an extracellular matrix protein with wide tissue distribution. It has been demonstrated that the expression of MGP is detected not only in the normal blood vessels but also calcified atherosclerotic plaques, and that MGP deficient mice develop extensive arterial calcification. MGP is thought to be a regulator of vascular calcification. A recent clinical study demonstrates the association between polymorphisms of the MGP gene and increased risk of myocardial infarction. However, there are no reports of the relationship between serum MGP levels and coronary artery calcification (CAC). We evaluated the severity of CAC using electron-beam computed tomography (EBCT), and measured serum MGP levels by enzyme-linked immunosorbent assay in 115 subjects with suspected coronary artery disease. CAC scores were correlated with traditional risk factors, such as age, gender, hyper-tension, diabetes, hyperlipidemia and smoking. The serum MGP levels were lower in patients with CAC than in those without CAC (p<0.001). As the severity of CAC increased, there was a significant decrease in serum MGP levels. Serum MGP levels (U/L) were 116.7 +/- 20.3, 104.9 +/- 19.2, 95.2 +/- 15.2 and 82.2 +/- 19.7, (medians 115.5, 105.0, 94.8, and 81.9) for the subjects with normal (CAC score=0), mild (CAC score=1 to 99), moderate (CAC score=100 to 400), and severe (CAC score >400) coronary calcification, respectively. We found that serum MGP levels are inversely correlated with the severity of CAC. These data suggest a possible role for MGP in the development of vascular calcification.     

Excitotoxic lesioning of the rat basal forebrain with S-AMPA: consequent mineralization and associated glial response

Regional depositions of calcium within the basal ganglia, cortex, cerebellum, and white matter and at perivascular sites have been observed in several pathological conditions. These generally indicate signs of ongoing apoptosis or necrotic processes, whereby the activation of glutamate receptors causes a rise in intracellular calcium levels leading to mineralization of neurons, and ultimately to cell death. The selective degeneration of cholinergic neurons in the basal forebrain is a major neuropathological component of Alzheimer's disease, and may result in abnormal deposition of calcium. In experimental models, selective lesions of the basal forebrain can be induced by intraparenchymal infusions of excito- or immunotoxins targeting cholinergic neurons. Excitotoxic lesions are often accompanied by calcium deposition within affected areas. In a previous study we also noted the presence of unusual deposition in areas close to the site of injections following unilateral S-AMPA-induced lesions of the basal forebrain (T. Perry, H. Hodges, and J. A. Gray, 2001, Brain Res. Bull. 54, 29-48). In this paper, we have characterized these deposits histologically and evaluated the microglial (CD11b) and astrocytic (GFAP) responses at 8 and 16 weeks following lesioning of the nucleus basalis magnocellularis with S-AMPA. The resulting deposits were heterogeneous in morphology and composed primarily of calcium. Small granular deposits were detected around blood vessels, whereas larger calcospherites were situated within the parenchyma. These deposits were more widely dispersed at 16 weeks postlesioning, affected neighboring nuclei, and displayed a progressive increase in size and frequency of occurrence. However, calcification within these regions was differentially associated with microglial and astrocytic reactivity at the two time points. Both microglial and astrocytic responses were pronounced at 8 weeks, whereas at 16 weeks, astrocytic reactivity prevailed and the microglial response was markedly attenuated. Importantly, the pattern of reactivity for microglia detected at 8 weeks was specifically localized to vulnerable nucleated areas prior to their substantial accumulation of calcium deposits, which was clearly evident by 16 weeks. We suggest that the initial microglial response could be used as a selective predictor of tissue necrosis and subsequent calcification, and that astrocytes, which form a glial scar in the affected tissues, may contribute toward the buildup of calcium deposits. The functional relevance of these findings is discussed.     

Intracranial vascular calcification with extensive white matter changes in an autopsy case of pseudopseudohypoparathyroidism

We herein report an autopsy case of a 69‐year‐old man with pseudopseudohypoparathyroidism. The patient suffered from mental retardation and spastic tetraparesis and had all the features of Albright's hereditary osteodystrophy with a normal response to parathyroid hormone in the Ellsworth–Howard test. Computed tomography demonstrated symmetrical massive brain calcification involving the bilateral basal ganglia, thalami, dentate nuclei and cerebral gray/white matter junctions, which was consistent with Fahr's syndrome. Magnetic resonance imaging revealed extensive white matter changes sparing the corpus callosum. Severe ossification of the posterior longitudinal ligament of the cervical spine was also demonstrated. A neuropathological examination revealed massive intracranial calcification within the walls of the blood vessels and capillaries with numerous calcium deposits. The calcium deposits aligned along the capillaries, and deposits in the vessel wall at the initial stage were confined to the border between the tunica media and adventitia. The vascular calcification in the basal ganglia continuously spread over the surrounding white matter into the cortex. The area of vascular calcification in the white matter was very well correlated with the area of the attenuated myelin staining. Axonal loss, myelin sheath loss and gliosis were observed in the white matter with severe vascular calcification. We should recognize the continuous area of vascular calcification and its correlation with extensive white matter changes as possible causes of neuropsychiatric symptoms in pseudopseudohypoparathyroidism with Fahr's syndrome.     

Rhabdomyolysis as the presenting manifestation of calciphylaxis

A 43-year-old woman was admitted with progressive leg pains and weakness and was found to have rhabdomyolysis. Prior to this admission the patient had hypercalcemia, but this returned to normal following treatment with calcitonin. During the hospitalization, she developed the syndrome of calciphylaxis consisting of necrotic skin and muscle associated with vascular calcification. This is the first case report of rhabdomyolysis caused by calciphylaxis in a patient without chronic renal failure.     

Brain vascular changes in Cockayne syndrome

Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are caused by deficient nucleotide excision repair. CS is characterized by cachectic dwarfism, mental disability, microcephaly and progeria features. Neuropathological examination of CS patients reveals dysmyelination and basal ganglia calcification. In addition, arteriosclerosis in the brain and subdural hemorrhage have been reported in a few CS cases. Herein, we performed elastica van Gieson (EVG) staining and immunohistochemistry for collagen type IV, CD34 and aquaporin 4 to evaluate the brain vessels in autopsy cases of CS, XP group A (XP‐A) and controls. Small arteries without arteriosclerosis in the subarachnoid space had increased in CS cases but not in either XP‐A cases or controls. In addition, string vessels (twisted capillaries) in the cerebral white matter and increased density of CD34‐immunoreactive vessels were observed in CS cases. Immunohistochemistry findings for aquaporin 4 indicated no pathological changes in either CS or XP‐A cases. Hence, the increased subarachnoid artery space may have caused subdural hemorrhage. Since such vascular changes were not observed in XP‐A cases, the increased density of vessels in CS cases was not caused by brain atrophy. Hence, brain vascular changes may be involved in neurological disturbances in CS.     

Matrix Gla-protein: the calcification inhibitor in need of vitamin K

Among the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification. Its pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in the vasculature. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. With the aid of conformation-specific antibodies MGP species in both tissue and the circulation have been detected in the healthy population, and significant differences were found in patients with cardiovascular disease (CVD). Using ELISA-based assays, uncarboxylated MGP (ucMGP) was demonstrated to be a promising biomarker for cardiovascular calcification detection. These assays may have potential value for identifying patients as well as apparently healthy subjects at high risk for CVD and/or cardiovascular calcification and for monitoring the treatment of CVD and vascular calcification.     

Mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS) with prominent degeneration of the intestinal wall and cactus-like cerebellar pathology

A 67-year-old woman had frequent subacute ileus, hearing difficulty, muscle atrophy and stroke-like episodes. Computed tomography revealed multiple low-density areas, which did not correlate with the vascular supply, in the cerebral cortex. She had metabolic disturbance comprising lactic acidosis and elevated pyruvate level. Her skeletal muscle biopsy specimen showed ragged-red fibers, and mitochondrial DNA analysis revealed a point mutation at position 3243, findings consistent with MELAS. Examination of her small intestine revealed a necrotic zone and numerous abnormal large mitochondria in the smooth muscle cells, vascular media and endothelium, and intestinal ganglion cells. The cerebral cortex showed multiple microcystic necrotic foci in cerebral cortex. Cactus-like pathology resembling the changes associated with Menkes’ kinky hair disease and torpedoes were observed in the cerebellar Purkinje cells. The intestinal dysmotility due to MELAS and cerebellar changes were presumed to be associated with a disturbance of copper metabolism. Received: 8 October 1999 / Revised, accepted: 18 January 2000     

Association of mast cells with calcification in the human pineal gland

Increased pineal calcifications and decreased pineal melatonin biosynthesis, both age related, support the notion of a pineal bio-organic timing mechanism. The role of calcification in the pathogenesis of pineal gland dysfunction remains unknown but the available data document that calcification is an organized, regulated process, rather than a passive aging phenomenon. The cellular biology and micro-environmental conditions required for calcification remain poorly understood but most studies have demonstrated evidence that mast cells are strongly implicated in this process. The aim of the present study was to examine the phenotype of mast cells associated with early stages and with the progressive development of calcification in the human pineal gland. The study was performed on pineal samples of 170 fetuses and children whose brains were autopsied and diagnosed during 1998-2002. The representative cerebral and pineal specimens were stained with haematoxylin and eosin or the von Kossa staining technique and for the distribution of mast cell tryptase, mast cell chymase, histamine H4 receptor and vascular network using biotinylated Ulex europaeus agglutinin. Tryptase mast cells were found in all stages of pineal gland development independently of the presence of local tissue lesions. All of them were always localized in the close vicinity of the blood vessels and expressed immunoreactivity to histamine H4 receptor antibody. Immunolocalization of mast cells by chymase antibody (and following dual immunostaining with both chymase and tryptase antibodies) demonstrated that these cells were few in number and were located in the subcapsular region of the gland. In our study, all functional mast cells that underwent activation and were co-localized with deposits of calcium did not contain chymase. All of them were stained with tryptase and represent the MC-T phenotype. Tryptase mast cells and extracellular tryptase were often associated with areas of early and more advanced stages of calcification. Our results lead to the conclusion that the tryptase mast cells play a major role in the pineal calcification process as sites where this process starts and as a source of production of numerous biologically active substances including tryptase that participate in calcification.     

Regression of white matter hypodensities with age in Aicardi–Goutierés syndrome: a case report

Background Aicardi–Goutierés syndrome (AGS) is a severe and progressive familial encephalopathy that is characterized by acquired microcephaly, intracranial calcification, white matter lesions, and chronic lymphocytosis with elevated levels of interferon-α in the cerebrospinal fluid. Although the degree of calcification and the severity of brain atrophy are variable, typically, the brain lesions appear to progress on successive examinations.Case report We report a 7-year-old male patient who showed relative regression of white matter lesions with nonprogression of basal ganglia calcification and atrophy on follow-up magnetic resonance imaging and computed tomography scans.Results Magnetic resonance spectroscopy findings were normal. This, to our knowledge, is the first case report, which describes relative regression of the white matter changes in AGS.     

Factors influencing tumour cell and vascular proliferation in glioblastoma

Introduction:  This project examines the factors that influence tumour cell and vascular proliferation in glioblastomas.
Hypothesis:  Necrosis is a major factor inducing tumour cell and vascular proliferation in glioblastomas.
Material and methods:  5 µm paraffin sections from 10 cases of glioblastoma containing areas of normal brain, viable tumour and necrosis were stained with H&E, reticulin and by immunocytochemistry for GFAP, Ki-67, CD34 for blood vessel endothelium, a combined Ki-67/CD34, and CD68 for macrophages and microglia. Tumour cell proliferation in Ki-67 preparations was measured in relation to (a) distance from necrosis and (b) proximity to blood vessels. The density of blood vessels was related to the distance from necrosis, and the presence of macrophages was related to the distance from necrosis and to the proximity to blood vessels. These measurements were effected by an automated computer quantification algorithm and by field-specific ocular quantification.
Results:  The mean tumour proliferation index (PI) was 6.49% (±4.95), with a two-fold increase in tumour cell PI to 12.36% ± 5.82 ( P  ≤ 0.001) in the vicinity of blood vessels. The density of blood vessels was increased in the vicinity of areas of necrosis. Macrophages were distributed throughout the tumour, but were increased around areas of necrosis and around blood vessels. No relationship between tumour cell proliferation and necrosis was detected.
Conclusions:  Tumour cell proliferation is concentrated around blood vessels in glioblastomas. Blood vessel proliferation, but not tumour cell proliferation, is related to areas of necrosis and the presence of macrophages in glioblastomas. Targeting of blood vessel proliferation and macrophages within glioblastoma may present a therapeutic strategy for treatment of these devastating tumours.     

A prospective study of patients with CT detected pallidal calcifications.

In a prospective study pallidal calcification was detected in 30 of 1478 (2%) adult patients, on CT brain scans. In 8 cases (26%), the calcifications were detected either years after, or during the course of, conditions known to cause basal ganglia calcification, including AIDS in four cases. Eight patients (three with AIDS) had disturbances of calcium and phosphorus metabolism. It was concluded that: a) pallidal calcification is not uncommon and aetiological factors may be recognised more often than previously reported; b) AIDS is emerging as a significant cause of pallidal calcification in young adults, and c) in AIDS and other conditions, abnormal calcium and phosphate metabolism may act in conjunction with local vascular changes.     

Angiomatous variant of pleomorphic xanthoastrocytoma in a patient with a 20-year history of epilepsy

The angiomatous variant of the pleomorphic xantho-astrocytoma (PXA) is a morphological subtype of PXA that is characterized by the presence of large numbers of tiny blood vessels with variable wall thicknesses. A case of an angiomatous variant of PXA occurring in the temporal lobe of a 43-year-old man is presented. The patient had a 20-year history of seizures. Considering the clinical course and intra-operative electro-encephalography findings, it appears that this tumor was the epileptic focus in this patient and that it had been present for 20 years. Histopathologically, various degenerative changes, such as microcystic changes, calcification and hyaline thickening of vessel walls were seen in the tumor. In particular, obvious vascularity in the tumor and secondary vascular degenera-tion should be related to gradual growth and benign clinical course of an angiomatous variant of PXA.     

Altered angioarchitecture in selected areas of brains with Alzheimer's disease

Summary It was the aim of this study to determine, qualitatively and quantitatively, alterations in the blood vessels of brains removed postmortem from patients with Alzheimer's disease (AD), and to compare these findings with the appearance of cerebral blood vessels in a group of individuals without brain disorders. Celloidin sections of brain tissue from four cerebral areas, pre-frontal (Brodmann's area 9), basal forebrain, sensorimotor, and hippocampus, were subjected to an alkaline phosphatase reaction to facilitate the evaluation of the vascular distribution. The vascular density in five sections was determined by counting the number of vascular intersections with a microscopic test grid of 100 squares; ten fields per section were examined in this manner. Analysis of 16 AD and 6 control brains, showed that there was a striking and statistically significant reduction in the vascular net density specifically in the basal forebrain region and the hippocampus of AD brains. In addition, vessels in the AD brains exhibited extensive topographical changes, such as kinking and looping. These results indicate that modifications in vascular density are present in AD brains with a marked regional specificity.Supported in part by the St. Louis Alzheimer's Disease and Related Disorders Association and the Department of Community Medicine. St. Louis University Medical Center     

Bilateral basal ganglia calcifications visualised on CT scan.

Thirty-eight cases of basal ganglia calcification imaged on computed axial tomography were reviewed. Most cases were felt to represent senescent calcification. The possibility of a vascular aetiology in this group is discussed. A less common group of patients was identified with calcification secondary to abnormalities in calcium metabolism or radiation therapy. Three cases of basal ganglia calcifications were detected in juvenile epileptic patients receiving chronic anticonvulsants. These cases may be related to abnormalities in calcium metabolism and alkaline phosphatase activity. Clinical evidence of basal ganglia abnormality was generally absent demonstrating the preservation of neuronal pathways in most cases.     

ET-A在脑血管畸形血管中表达的实验研究

目的探讨内皮因子受体A（ET-A）mRNA在脑血管畸形血管中的差异性表达。方法对14例脑血管畸形和8例正常脑血管标本分别提取总RNA。应用逆转录-聚合酶链反应的方法检测ET-A mRNA的表达，然后行DNA电泳鉴定，并进行光密度扫描，半定量计算ET-A mRNA的表达。结果在脑血管畸形血管中ET-A mRNA表达水平较正常脑血管中明显下降（P〈0．05）。结论脑血管畸形血管与正常脑血管中ET-A mRNA表达有差异性，为研究其在病理情况下的作用作了前期工作。