Pericapillary arteriovenous malformations angiographically manifested as cerebral venous malformations.

Cerebral venous malformations have been diagnosed by angiographic features and are considered to be a benign anomaly. However, ample evidence indicates that stroke or similar symptomatology occurs in patients harboring a cerebral vascular malformation that was diagnosed angiographically as a venous malformation. The purpose of the study is to confirm the presence of a pericapillary arteriovenous malformation in these patients by analyzing the clinical history and surgical findings and correlating them with histological features. Thirteen patients were included in this study. Each patient fulfilled four criteria: 1. the patient was neurologically symptomatic; 2. the angiographic diagnosis was a venous malformation; 3. at operation, shunting arterioles (50-100 microns) were found to contribute to the malformation; and 4. histologically, a mixture of venous channels and arterioles with arterioles directly connected to venules was found. Based on the above findings, the malformation present in the 13 patients can be termed a 'pericapillary arteriovenous malformation'. Its angiographic distinction from the cerebral venous malformation requires technological advancement in the capability of magnifying images of arterioles and venules, along with improvement in image resolution.

Alzheimer's disease underlies some cases of complex partial status epilepticus.

Alzheimer's disease is a known risk factor for seizures, and age older than 60 years is a recognized risk factor for poor outcome from convulsive and nonconvulsive status epilepticus. The authors suspect that there may be a causal relationship between dementia pathology and the development and maintenance of refractory seizures. They report two selected patients with complex partial status epilepticus whose presentation and clinical course provide partial support for this hypothesis. Their methods include case reports with clinical, EEG, imaging, and pathologic correlations. The patients were 70 and 85 years of age. Both had central and peripheral brain atrophy on imaging studies (with some regions that were affected more than others), left temporal seizure foci corresponding to areas of greatest cortical atrophy, and early presentation with inhibitory epileptic symptoms (aphasia), with evolution to complex partial status epilepticus. Pathologic confirmation of Alzheimer's disease was obtained in one patient who had not been diagnosed previously. It involved maximally the cortex underlying the seizure focus. A diagnosis of probable Alzheimer's disease was established in the other patient. Alzheimer's disease may be causal in some cases of complex partial status epilepticus. Additional observations in support of this hypothesis are needed.

Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion in the rat pup.

Our studies examined the hypothesis that the distribution of cerebral injury after a focal ischemic insult in the immature rat pup is associated with the regional distribution of nitric oxide synthase (NOS) activity and that differences in the vulnerability to ischemia between pup and adult might be related to differences in cofactor availability. We measured NOS activity in well-defined regions prone to become either core or penumbra in controls and at different times (end of occlusion, 0.5 h, and 24 h reperfusion) after middle cerebral artery occlusion (MCAO) from the right and left hemispheres in a 14- to 18-day-old rat pup filament model. Three groups of corresponding isoflurane sham controls were also included. "Core" NOS activity for combined right and left hemispheres ranged from 113% to 217% more than "penumbral" regions in control and sham groups. In the three MCAO groups, marked decreases in ischemic core and penumbral NOS activity were seen; however, core NOS remained higher than penumbral regions bilaterally. The effects of cofactor addition (10 microM tetrahydrobiopterin, 3 microM flavin adenine dinucleotide, and 3 microM flavin mononucleotide) on NOS activity were similar in "core" and "penumbral" regions in control and sham groups. However, after 24 h MCAO, cofactor addition preferentially increased NOS activity in the ischemic hemisphere. Co-factor addition in the pup also had a greater effect on enhancing NOS activity in all regions compared with the adult. Greater NOS activity in core regions in the rat pup, as in the adult, could in part, explain the increased vulnerability of that region to ischemia. NOS activity also can be influenced by the availability of cofactors and this effect may be greater in the immature animal.

Ornithine decarboxylase activity in vitro in response to acute hypoxia: a novel use of newborn rat brain slices.

In fetal as well as newborn rats, acute hypoxic exposure results in significantly elevated brain ornithine decarboxylase (ODC) activity, polyamine concentrations, and ODC mRNA. The interpretations of these in vivo hypoxic-induced changes, however, are complicated by maternal confounding effects. To test the hypothesis that acute hypoxia will also increase ODC activity in vitro, we developed a brain slice preparation which eliminates such maternal effects. Sections of whole cerebrum, approximately 300-500 microns thick, were made from 3- to 4-day old Sprague-Dawley rat pups. The slices were equilibrated for 1 h in artificial cerebrospinal fluid (ACSF) continuously bubbled with 95% O2/5% CO2, prior to induction of hypoxia. We induced hypoxia by changing the oxygen concentration to 40%, 30%, 21%, 15%, 10%, or 0% O2, all with 5% CO2 and balance N2. In the normoxic control brain slices, low but stable basal ODC activity persisted for up to 5 h post-sacrifice. Slices in ACSF treated with bovine serum albumin (BSA), or both BSA and fetal bovine serum (FBS), however, showed stable ODC activity values 2- to 3-fold higher than slices in ACSF alone, for up to 5 h. In response to acute hypoxia (i.e., 15, 21, and 30% O2), ODC activity was elevated 1.5- to 2-fold above control values between 1 and 2 h after initiation of hypoxia. Qualitative light and electron microscopic examination of the neonatal brain slices following 2 h hypoxic exposure suggested that the great majority of cells did not show severe hypoxic damage or necrosis. It was concluded that: (1) in neonatal rat brain slices in vitro, stable ODC activity values approximating the whole brain ODC activity seen at sacrifice, can be maintained for several hours; (2) the in vivo hypoxic-induced increase in ODC activity can be approximated in vitro; (3) the neonatal rat brain slice preparation may be an alternative to other methods for studying hypoxic-induced ODC enzyme kinetics, or other brain enzymes, without maternal confounding effects; and (4) ODC activity may be an indicator of active metabolism within the newborn brain slice both in normoxia and hypoxia.

Pilot study of monoclonal antibody localization in subcutaneous and intracranial lung tumor xenografts after proton irradiation.

The purpose of this study was to determine if proton irradiation can increase the localization of radiolabeled monoclonal antibodies (MAb) in subcutaneous (s.c.) or intracranial (i.c.) human lung tumors xenotransplanted in athymic rats. Rats with carcinoembryonic antigen (CEA)-expressing (NCI-H441) tumors were irradiated using 3 different proton time-dose regimens, followed by 111In-ZCE025, an anti-CEA MAb, which was injected 2 hr after the last dose of irradiation, and the animals were euthanized 3 days later for biodistribution and other assays. Proton irradiation at 10 gray (Gy) as a single dose or in 2 Gy fractions given on 5 consecutive days increased the uptake of 111In-ZCE025 into s.c. tumors by 292% and 182%, respectively, compared to nonirradiated controls. No enhancement in radiolabeled MAb delivery was seen after hemibrain irradiation in animals with i.c. tumors. Histopathological examination of both implantation sites showed a viable poorly differentiated adenocarcinoma with a decrease in blood vessel density, a decrease in mitotic activity, and an increase in areas of necrosis following irradiation as compared with adjacent nonirradiated tissue. CEA expression was generally maintained in vivo in that the marker was detectable in the tumor, plasma, and cerebrospinal fluid. Oxygen radical production by peripheral blood cells from s.c. and i.c. tumor-bearing rats exhibited strikingly different patterns of responsiveness. I.c. injected animals were 24% lighter than their s.c. injected counterparts, but no neurological signs of tumor progression were noted. The results indicate that proton irradiation can be used effectively to increase the delivery of radiolabeled MAb to s.c. implanted human lung tumor xenografts. However, in order to accomplish this in the brain, other radiation time-dose schedules and treatments may be needed.

Extrarenal angiomyolipoma with melanocytic and hibernoma-like features.

Angiomyolipoma is a tumor commonly occurring in the kidney, but occasionally found in extrarenal sites. Retroperitoneal angiomyolipoma with unusual features presenting in a 39 year old woman with hypertension is reported in this paper. Tumor fat was inconspicuous, and present largely as hibernoma-like microvesicular lipid. Tumor cells also demonstrated positivity for HMB-45 and S-100 protein, and by electron microscopy showed occasional cytoplasmic striated granules indistinguishable from stage II premelanosomes. However, electron microscopy and immunocytochemistry also confirmed the presence of a substantial myogenous component in the tumor, establishing the diagnosis of angiomyolipoma. The implications of these findings, and the role of immunocytochemistry and electron microscopy in the diagnosis of this tumor are discussed.

Tumor necrosis factor-alpha augments radiation effects against human colon tumor xenografts.

Recent reports indicating that tumor necrosis factor-alpha (TNF-alpha) can augment the lethal effects of radiation against certain tumor cell lines prompted us to investigate whether this premise holds true for human colon tumor xenotransplants. Nude mice implanted s.c. with LS174T adenocarcinoma cells (day 0) were randomized into 4 groups: 1) no treatment; 2) TNF-alpha at 1 x 10(4) units/i.v. injection on days 1, 4, 8, and 10; 3) radiation at 4 Gy delivered on days 2, 5, 9, and 11; and 4) TNF-alpha + radiation administered using the same time-dose schedules as for groups 2 and 3. A decrease in tumor growth was obtained with radiation, but not TNF-alpha, as a single modality. However, significanty slower tumor growth was observed with TNF-alpha + radiation when compared to radiation alone. Blood and spleen cells from animals receiving both modalities exhibited the highest oxidative burst capacity. Histopathological evaluation showed large areas of necrosis in animals treated with radiation and with combined radiation + TNF-alpha, and only small areas of necrosis in animals treated with TNF-alpha alone. Necrosis in TNF-alpha-treated animals was not significantly larger than in controls. Irradiation of LS174T cells in culture generally decreased soluble TNF-alpha receptor and carcinoembryonic antigen in cell supernatants, but TNF-alpha was not detectable, regardless of radiation. The results show that pretreatment with TNF-alpha can significantly enhance the effects of radiation against human colon tumor xenografts and that the mechanisms of action may be related to increased oxygen radical production when both agents are administered and/or to induction of apoptosis by TNF-alpha. This data provides support for further investigations using TNF-alpha as an adjunctive agent in the radiotherapy of colon and other cancers.

Primitive cerebral tumor with rhabdoid features: a case of phenotypic rhabdoid tumor of the central nervous system.

The rhabdoid tumor (RT) was first described as an aggressive neoplasm of unknown histogenesis affecting the kidneys of infants and young children, but has since been reported in all ages and in many other primary sites, including the central nervous system. It has been shown, however, that the histologic and cytologic features of RT can be mimicked by many other tumors of known histogenesis. For this and other reasons it remains controversial whether cases of putative extrarenal RT represent the same histogenetic entity as RT of the kidney (RTK), another entity or entities, or merely a diverse collection of unrelated tumors sharing a common morphologic phenotype. The present paper describes a lethal primary cerebral tumor in a 26-month-old Hispanic boy that was composed predominantly of cells exhibiting the "classic" rhabdoid phenotype by light microscopy. Immunocytochemical and ultrastructural studies disclosed features of primitive neuroglial differentiation not seen in RTK. The findings in this case, as well as evidence from other studies, would seem to support the notion that primary RT of the brain may in fact constitute a morphologic and clinicopathologic entity. However, that entity likely represents a distinctive type of neuroglial neoplasm, more closely related to other primitive brain tumors than to RTK.

Meningioma with chordoid features.

Meningioma is a relatively common intracranial tumor, occurring most frequently in adults, and is capable of a wide variety of growth patterns. We describe a meningioma in a child that had a peculiar chordomalike appearance. The pathologic findings and distinction from chordoma are discussed.

An anatomic basis for recurrence after Morton's neuroma excision.

Dissections of the common digital nerve and its branches were performed in the second and third web spaces in five fresh-frozen cadaveric feet. Plantarly directed nerve tetherings, which were histologically demonstrated to be nerve branches, were consistently present along the course of each common digital nerve. These plantarly directed nerve branches were found in highest concentration in the distal aspect of the common digital nerve proximal to the bifurcation into the proper digital branches. The presence of these nerve branches may contribute to the high incidence of Morton's neuroma recurrence either due to traumatic neuroma formation in the branches or to failure of proximal retraction of the more distally resected nerve stump.

Endogenous peptide YY is dependent on jejunal exposure to gastrointestinal contents.

Peptide YY (PYY), a homolog of pancreatic polypeptide, has been shown to be released after stimulation of colonic mucosa with bile and fatty acids. In this study proximal jejunal and biliary involvement in the regulation of circulating PYY and the distribution of PYY-containing cells in rat intestine was evaluated. Six rats underwent proximal jejunal bypass, six rats had Roux-en-Y cholangiojejunostomies, and six sham-operated rats were used as controls. Three months after surgery feeding studies using either a mixed meal or a pure fat meal were performed in unanesthetized animals and venous blood was collected for plasma PYY radioimmunoassays. After the feeding studies, fresh specimens were taken from multiple areas of the intestine for immunohistochemical analysis. The surgical procedures did not significantly affect basal PYY plasma levels. Both mixed and fat meals significantly increased circulating PYY in control animals. Exclusion of the proximal jejunum resulted in inhibition of postprandial PYY release. The PYY response in rats with Roux-en-Y cholangiojejunostomies was blunted after a mixed meal and delayed after a fat meal. The incidence of PYY-containing cells increased along the functional gut in all rats. The bypassed jejunum in both experimental groups of animals contained fewer PYY-staining cells than sham-operated rats. Our results suggest that the exclusion of a segment of proximal jejunum from gastrointestinal continuity in rats leads to an inhibition of postprandial PYY release. PYY release may be controlled in part by stimulatory neural and/or endocrine signals originating from the proximal jejunum.

Pericyte degeneration and thickening of basement membranes of cerebral microvessels in complex partial seizures: electron microscopic study of surgically removed tissue.

Complex partial seizures are associated with alterations in regional cerebral blood flow in abnormally spiking foci, as shown by positron emission tomography and single photon emission computed tomography, with an increase in flow ictally and a decrease interictally. Alterations of vasoregulation during ictal periods have also been described in animal seizure models. An electron microscopic study on human brain tissue from seven patients undergoing resections for the treatment of intractable complex partial seizures was performed to examine ultrastructural changes of the microvasculature and their locations within the microvessel wall. Biopsies were obtained intraoperatively from temporal lobe regions with electrocorticographically detected abnormal spiking and from regions without abnormality on electrocorticograms (control samples) removed as part of the therapeutic resection. A total of 539 microvessels from three regions were evaluated: spiking mesial temporal lobe, spiking lateral temporal cortex, and nonspiking (control) cortex. Evidence of pericyte degeneration (aggregates of cellular debris within the basement membrane) was noted in the majority of spiking area microvessels (76.7% in spiking mesial temporal cortex; 69.8% in spiking lateral temporal cortex) as compared with 37.8% of control microvessels (P less than 0.0005). Morphometric studies revealed a significant increase in total wall thickness, pericyte-basement membrane unit thickness, pericyte cytoplasmic density, basement membrane density, and basement membrane thickness in microvessels from spiking (mesial and lateral temporal cortex), as compared to control areas (P less than 0.01). No statistically significant difference was noted in pericyte coverage or pericyte or endothelial mitochondrial densities between microvessels in spiking and control regions. This study shows degeneration of pericytes, cells thought to play an essential role in microvascular hemodynamics, and thickening of microvessel walls in abnormally spiking brain regions in patients with intractable complex partial seizures. The pericyte degeneration and basement membrane thickening in abnormally spiking areas may explain alterations in vasoregulation, by a decrease in the microvascular compliance and in cross-capillary diffusion.

Radiation-induced cerebral aneurysms.

The association between vasculopathy and radiation is well recognized. Generalized arterial disruption and subsequent stenosis and occlusion is most often described. Additional vascular phenomenon, such as pseudoaneurysm formation, aneurysmal dilatation and aneurysmal rupture, are less common. We document a case of a cerebral aneurysm formation and rupture in the field radiated for cerebral neoplasm.

Electrophysiological and biochemical characterization of a continuous human astrocytoma cell line with many properties of well-differentiated astrocytes.

Astrocytes comprise about 25% of the cellular volume of the brain, and their main function is to maintain homeostasis of the neuronal environment. These cells are commonly identified on the basis of their membrane electrical properties and the presence of specific proteins. We have characterized the human astrocytoma cell line designated UC-11MG and have shown these cells have many of the traits of differentiated astrocytes. Many of the UC-11MG cells have a large resting membrane potential, averaging -74 mV. The slope of the Em vs log [K]o cuve was 58.5 mV per decade [K]o. The cells were inexcitable when exposed to brief depolarizing current pulses. The astrocytoma traits are virtually identical to those previously reported for normal astrocytes. The astrocytoma cells also express glutamine synthetase activity which is considered specific to astrocytes among brain cells. Previous work had also demonstrated the presence of other astrocyte markers glial fibrillary acidic protein and S-100 protein in the UC-11MG cells. The steady-state ion transport properties of Na+, Cl-, and K+ were also characterized in these cells, and the rates of efflux were found to be similar to those in other astrocytes, with the major difference being the presence of a second kinetic compartment in the UC-11MG cells. From this work, we conclude that the UC-11MG cell line displays prominent features associated with differentiated astrocytes, and may provide an excellent model system for the study of human astrocytes.

The relationship between the capillary structure and hemorrhage in gliomas.

A 48-year-old man was admitted with the sudden onset of symptoms of stroke caused by hemorrhage in an oligodendroglioma. Despite surgery and antiedema treatment, the patient died. Histological evaluation revealed an oligodendroglioma with calcified capillaries of the retiform type. To further investigate this phenomenon, a total of 160 gliomas were reviewed: 90 glioblastomas multiforme, 30 oligodendrogliomas, and 40 astrocytomas. Sufficient data were available for clinical evaluation in 100 cases. Of these, 5% (two oligodendrogliomas and three glioblastomas multiforme) were related to clinically significant hemorrhages. Of the remaining cases, microhemorrhages were found in 53.0% of the glioblastomas, in 56.7% of the oligodendrogliomas, and in 10.0% of the astrocytomas. In each case reviewed, the capillaries were assigned to one of three groups: axial, retiform, or glomeruloid. Statistical analysis revealed a significant association between hemorrhages and retiform capillaries in all three types of tumors, except that in oligodendrogliomas the statistical significance held true when calcification of the capillaries was also present. Glomeruloid-type capillaries were only weakly associated with hemorrhages, and no association was found for axial capillaries. A large-scale prospective study is necessary to more precisely assess the role of each of the three types of capillaries in hemorrhages of gliomas. Based on data available so far, patients with glial tumors with retiform capillaries, confirmed on biopsy, should be carefully monitored to exclude possible intratumoral hemorrhage.

Concanavalin A and Lens culinaris agglutinin binding patterns in normal and neoplastic sebaceous epithelium.

Formalin-fixed, paraffin-embedded tissue sections of normal skin, sebaceous hyperplasia, nevus sebaceus, sebaceous adenoma, and sebaceous carcinoma were studied by means of biotinylated and FITC conjugated concanavalin A (Con A) and Lens culinaris agglutinin (LCA). At relatively high concentrations of these lectins, all cutaneous epithelial cells were stained. As the concentration of LCA was lowered, there was a corresponding decrease in the intensity of staining of all epithelial cells. With lowered concentrations of Con A, staining of sebaceous epithelium remained strongly positive, while staining of other epithelia decreased in a manner similar to that seen for LCA. These staining patterns were seen in normal and neoplastic tissues. Both Con A and LCA are known to bind to alpha-D-mannopyranosyl and alpha-D-glucopyranosyl residues of glycoproteins and glycolipids. The difference in staining of sebaceous epithelial cells by Con A and LCA suggests that the binding of these lectins is not determined strictly by the presence of alpha-D-mannopyranosyl or alpha-D-glucopyranosyl residues, but is modified by side-chain substitution on the monosaccharides and/or by the oligosaccharide which contains the particular monosaccharide. Whichever event is operative, a saccharide moiety is present on the surface of mature sebaceous cells which has a strong affinity for Con A.

Immunocytochemical binding to neurons of serum from spinocerebellar degeneration patients.

Antineural antibodies have been described in sera of patients with neurodegenerative disorders. We looked for the presence of those antibodies in the sera of patients with spinocerebellar degeneration. Serum IgG from four patients with familial spinocerebellar degeneration showed strong binding to cerebral cortical neurons, Purkinje cells, and dorsal root ganglia of normal human tissue sections stained with the peroxidase antiperoxidase (PAP) method at serum dilution of 1:500. No binding to neuroglia cells or cells of the granular layer of the cerebellum was seen. Sera from four immediate, asymptomatic relatives (son or sibling) showed only moderate binding to Purkinje cells and to dorsal root ganglia, but not to cortical neurons. Sera from seven patients with neurological diseases other than spinocerebellar degeneration and from five healthy subjects showed no binding to neural elements. The findings may be of value in the diagnosis and screening of patients suspected of having spinocerebellar degeneration; however, the significance of these antineural antibodies in the pathogenesis of spinocerebellar degeneration is uncertain and awaits further studies.

Binding of serum IgA of multiple myeloma to normal peripheral nerve.

Serum from a 60-year-old man with multiple myeloma (monoclonal IgA-lambda) and peripheral sensorimotor neuropathy showed immunohistochemical binding to normal human endoneurium in dilutions up to 1:6000 (IgA = 1 mg/dl). The binding was shown to be specific for IgA-lambda and it was negative for IgA-kappa, IgG and IgM. Absorption of the serum with peripheral myelin eliminated the myelin immunostaining. Peptic digestion of the serum failed to eliminate immunostaining of the endoneurium. Immunoblot analysis revealed reactivity of the monoclonal IgA with 58,000, 43,000 and 18,500 dalton components of human nerve endoneurium. Sera from two patients with monoclonal IgA without peripheral neuropathy, from one patient with peripheral neuropathy and lung cancer, from one patient with stroke and from six normal subjects failed to stain myelin in sections of peripheral nerves or to react in immunoblots at comparable serum concentrations. Axonal staining was seen with some of the control sera. The relationship of the findings to the pathogenesis of peripheral neuropathy in multiple myeloma is discussed.