Human cerebral cysticercosis: immunolocalization of a sodium-dependent glucose cotransporter (SGLT) in larval and adult tapeworms.

Light microscopic immunocytochemistry was used to examine human brain cysticerci resected from the fourth ventricles of patients who had not been treated with anthelminthic drugs. Tissues were examined from 3 different patients undergoing surgery for treatment of hydrocephalus. A rabbit polyclonal antiserum to the peptide corresponding to amino acids 564-575 unique to the rabbit sodium-dependent, SGLT1 glucose cotransporter labeled with immunoperoxidase, localized immunoreactive SGLT epitopes. This antibody localizes SGLT1 in the apical brush borders of human enterocytes, but is negative in cytoplasm, as well as lateral and basal enterocyte membranes. Taenia solium neurocysticerci were SGLT positive; transporter protein was highly expressed on the surface microvilli of the external cyst wall. The well-developed network of small and larger osmoregulatory ducts within racemose larval cystcerci displayed high expression of SGLT cotransporter, consistent with a resorptive function for this system of tubules. Because water is cotransported with glucose molecules by the SGLT protein, its high expression in neurocysticerci may contribute to the expansive growth of these larvae in subarachnoid and intraventricular sites. The SGLT epitopes were also immunolocalized in gravid proglottids of Taenia saginata, indicating that cotransporter expression persisted in intestinal-dwelling, adult tapeworms. Cotransporter antibody was abundantly localized at the proglottid tegumentary surface and in the lateral osmoregulatory ducts, analogous to the SGLT localization in cysticerci. Furthermore, high expression of this cotransporter was seen in the branches of the uterus, suggesting that SGLT-mediated absorption of glucose and water has an important functional role within the reproductive system of adult tapeworms.

Responses of nitric oxide synthase expression in the gracile nucleus to sciatic nerve injury in young and aged rats.

Neuronal nitric oxide synthase (nNOS) is induced in dorsal root ganglion neurons following axotomy in young rats, and is also increased in the gracile nucleus neurons of intact aged rats. The present study examined the influence of sciatic nerve axotomy on nNOS expression in the gracile nucleus in young compared to aged rats. The unilateral transection of the sciatic nerve was performed in young (4 months) and old (24 months) Fischer rats. Sections of rat medulla obtained 14 days after axotomy were immunolabelled using a polyclonal antibody directed against nNOS and stained by nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry, a marker of nNOS activity. In young rats, unilateral axotomy produced increased NADPHd containing neurons in the rostral region and the caudal region of the ipsilateral gracile nucleus compared to the side with intact sciatic nerve. In old rats, the NADPHd containing neurons in the ipsilateral gracile nucleus were moderately increased by axotomy over the age changes seen in the contralateral side. Similar results were obtained with nNOS immunoreactivity in young rats, but more cells were seen with NADPHd staining compared to nNOS immunostaining in old rats. The results suggest that unilateral sciatic axotomy causes an increase in nNOS expression in the ipsilateral gracile nucleus of young rats, which is still seen in old rats as an increase over normal aging changes.

Sudden unexpected death associated with HHV-6 in an adolescent with tuberous sclerosis.

A 14-year-old female with tuberous sclerosis and history of seizures was found dead in bed at home 3 days after she had been assessed as doing well at a routine neurology clinic appointment. She had been treated with an antiepileptic drug, felbamate, for 36 months and had been seizure-free except for one seizure episode 5 months before death. Postmortem examination revealed cerebral edema, with uncal and tonsillar herniation, and pulmonary edema, consistent with seizure-induced apnea. Multiple microglial nodules with mature perivascular lymphocytic cuffing and diffuse infiltrates were identified around subependymal tuberous sclerosis giant cell nodules. Immunostaining and electron microscopy revealed human herpesvirus-6-infected macrophages, astrocytes, lymphocytes, and endothelial cells in the subependymal tuberous sclerosis lesions and choroid plexus. Subacute human herpesvirus-6 encephalitis is postulated to have precipitated a seizure and thus sudden unexpected death in epilepsy in this otherwise stable adolescent patient.

Sclerosing hyaline necrosis of the liver in Bloom syndrome.

Bloom syndrome is a rare autosomal recessive disorder characterized by normally proportioned but strikingly small body size, a characteristic facies and photosensitive facial skin lesion, immunodeficiency, and a marked predisposition to development of a variety of cancers. We describe here, we believe for the first time, pronounced sclerosing hyaline necrosis with Mallory bodies in the liver of a patient with Bloom syndrome. Mallory bodies are cytoplasmic eosinophilic inclusions, which are more common in visibly damaged, swollen hepatocytes in various liver diseases but are never found in normal liver. The possible pathogenesis of this finding in Bloom syndrome is discussed.

Intrachromosomal triplication of 2q11.2-q21 in a severely malformed infant: case report and review of triplications and their possible mechanism.

A female fetus with brain malformations, multicystic kidneys, absence of the right thumb, and a posterior cleft of palate was delivered at 32 weeks of gestation. Cytogenetic studies including FISH showed a novel intrachromosomal triplication of the proximal long arm of chromosome 2 (q11.2-q21), resulting in tetrasomy for this segment. The middle repeat was inverted. At least 11 patients with intrachromosomal triplications have been reported, mostly involving chromosome 15q. The mechanism involved in formation of these rearrangements is compatible with U-type exchange events among three chromatids.

Isolated leptomeningeal Castleman's disease with viral particles in the follicular dendritic cells.

To our knowledge, five cases of Castleman's disease involving only the central nervous system have been reported previously. We report a sixth case, which occurred in a 47-year-old woman with a 3-month history of headaches and a large superior frontal lobe mass on neuroimaging. Excisional biopsy revealed confluent lymphoid nodular areas with multiple well-developed germinal centers surrounded by concentrically layered proliferations of small B lymphocytes typical of Castleman's disease. Ultrastructural study found 100-nm virallike particles within follicular dendritic cells as well as intercellular spaces. These particles were suggestive of a D-type retrovirus. The patient underwent postoperative radiotherapy and was neurologically normal 3 months after surgery.

Cerebral toxoplasmosis and lymphoma in AIDS: perfusion MR imaging experience in 13 patients.

PURPOSE: To evaluate the perfusion magnetic resonance (MR) imaging characteristics of cerebral toxoplasmosis and lymphoma in patients with acquired immunodeficiency syndrome (AIDS). MATERIALS AND METHODS: Perfusion MR imaging was performed prospectively in 13 patients with AIDS who had contrast material-enhancing focal brain lesions (six with active lymphoma, five with toxoplasmosis, one with treated lymphoma in remission, and one with toxoplasmosis plus lymphomatoid granulomatosis). Regional cerebral blood volume (rCBV) was determined by using dynamic echo-planar MR imaging during bolus injection of a gadolinium chelate. RESULTS: The rCBV was decreased (44% +/- 24 [standard deviation] of rCBV in the contralateral regions) throughout the toxoplasmosis lesions and in the surrounding edema of both lesion types, whereas all active lymphomas displayed areas of increased rCBV (258% +/- 99). These differences were significant (P < .005). CONCLUSION: Reduced rCBV i toxoplasmosis lesions is probably due to a lack of vasculature within the abscess; increased rCBV in lymphomas is probably due to hypervascularity in foci of active tumor growth; and decreased rCBV in the edema is probably due to vasoconstriction associated with increased interstitial pressure. Perfusion MR imaging is a rapid, noninvasive tool that may allow differentiation between cerebral lymphoma and toxoplasmosis in patients with AIDS.

A single glucose transporter configuration in normal primate brain endothelium: comparison with resected human brain.

Cellular distribution of the Glut1 glucose transporter in normal primate brains was analyzed by immunogold electron microscopy. Two configurations of endothelial Glut1 glucose transporter (high and low density capillaries) have been found in resections of traumatically injured and epileptogenic human brain; the objective of the present study was to ascertain whether these same 2 capillary populations, expressing high and low glucose transporter densities, were the common configuration in normal brain. The relative numbers of Glut1 glucose transporter-associated gold particles on luminal and abluminal endothelial cell membranes were determined within the cerebral cortex of several normal, nonhuman primates. Low Glut1 densities were seen in brain endothelia of both the rhesus and squirrel monkey cortex, with slightly greater quantities of Glut1 in vervet monkey cortices. The Glut1 transporter was most highly expressed in the baboon cortex, approaching the concentrations seen in human brains. In the rhesus, squirrel, and vervet monkeys, Glut1 concentrations were greater on the abluminal than luminal capillary membranes. In contrast, mean luminal membrane Glut1 concentrations were greater in baboons, resembling the distribution seen in the human brain. Brain regional differences in transporter concentration were seen in comparing membrane densities in the baboon cortex (approximately 15 Glut1-gold particles per micrometer), hippocampus (approximately 12 Glut1 gold particles per micrometer), cerebellum (approximately 6 Glut1-gold particles per micrometer), and retinal microvasculature (approximately 20 Glut1-gold particles per micrometer). We conclude that a single, uniform Glut1 distribution characterizes brain capillaries of normal nonhuman primates, and hypothesize that the presence of high and low density glucose transporter endothelial cells (seen in human traumatic injury and seizure resections) represents a pathologic response to brain insult.

Glut1 glucose transporter in the primate choroid plexus endothelium.

The objective of the present study was to define the cellular location of the Glut1 glucose transporter in the primate choroid plexus. Immunogold electron microscopy indicated that Glut1 epitopes were associated primarily with choroid plexus endothelial cells. Digitized analyses of electron microscopic images provided quantitative estimates of the relative number of Glut1 glucose transporter epitopes on luminal and abluminal endothelial cell membranes within the choroid plexuses. We recorded a high density of Glut1 in the microvascular endothelium of primate choroid plexus, which was consistent in vervet monkeys (5-10 Glut1 gold particles per micrometer of endothelial cell plasma membrane), as well as in baboons (5-20 Glut1 gold particles per micrometer of capillary plasma membrane). In the baboon choroid plexus, we observed that perivascular cells (presumed to be pericytes) were also Glut1-positive, but with substantially reduced activity compared with endothelial cells. Occasional Glut1-immunogold particles were also seen in the basolateral membranes of the choroid plexus cuboidal cells. Light microscopic immunocytochemistry confirmed the abundance of Glut1 immunoreactivity in choroid plexus endothelial cells of vervet monkeys and baboons. A similar pattern was observed in surgically resected human choroid plexus, suggesting differences between primates, including humans and laboratory animals. The only difference was that erythrocytes within the human choroid plexus exhibited a florid Glut1-positive response, but were weakly immunoreactive in nonhuman primates. The observation of high glucose transporter densities in choroid plexus endothelial cells is consistent with the suggestion that choroidal epithelia and capillaries provide a metabolic work capability for maintaining ionic gradients and secretory functions across the blood-CSF barriers.

Interictal seizure resections show two configurations of endothelial Glut1 glucose transporter in the human blood-brain barrier.

Immunogold electron microscopy was used to analyze and quantify the Glut1 glucose transporter in brain tissue from five patients undergoing surgery for treatment of seizures. Samples were prepared from two different regions of each resection: (1) the most actively spiking epileptogenic site, and (2) the least actively spiking region, as indicated by intraoperative EEG monitoring. Two configurations of endothelial cell Glut1 were observed. About one half of the capillary profiles examined displayed abundant Glut1 immunoreactivity on both luminal and abluminal endothelial membranes. In the remainder of the profiles, reduced Glut1 labeling was seen, but adjacent erythrocyte membranes remained highly Glut1 immunoreactive, suggesting that reduced endothelial Glut1 reactivity was not attributable to method artifacts. Immunogold studies using antisera to human glial fibrillary acidic protein and human serum albumin demonstrated increased quantities of these two epitopes in the extravascular regions in which more EEG spiking activity had been demonstrated. These observations were consistent with the hypotheses that capillary integrity was more compromised, and gliosis was quantitatively increased, in the more actively spiking region of the resection. Altered glucose transporter activity in the blood-brain barrier was characterized by a bimodal Glut1 distribution in which the smaller (type B) endothelial cells displayed low Glut1 immunoreactivity, whereas adjacent (and even contiguous) larger (type A) endothelial cells showed 5- to 10-fold greater expression of membrane Glut1 transporter protein. Because this transporter facilitates glucose entry to the brain, small pericapillary volumes of brain tissue may have quite different concentrations of glucose. We hypothesize that in complex partial seizures and other forms of brain insult, an alteration of blood-brain barrier Glut1 glucose transporter activity is indicated by the appearance of these two subpopulations of endothelial cells. In comparison with previous studies of human brain capillaries in hemangioblastoma and brain injury, endothelial Glut1 density was apparently reduced (interictally) in affected temporal lobes of patients with complex partial seizures.

Fulminant demyelinating encephalomyelitis associated with productive HHV-6 infection in an immunocompetent adult.

Human herpesvirus 6 (HHV-6), the etiologic agent of roseola in young children, has been reported to be detectable in the brain of many neurologically normal adults, although regional localization to plaques of multiple sclerosis has also been demonstrated. Large amounts of this virus were present in multifocal demyelinating white matter lesions of fulminant encephalomyelitis with seizures in a 21-year-old woman with normal immune parameters. Brain biopsy after 3 weeks of neurologic deterioration revealed a viral etiology by light and electron microscopy; the virus was identified as HHV-6 by immunohistochemistry and by polymerase chain reaction (PCR) amplification in biopsy and autopsy specimens.

Adult-onset temporal lobe epilepsy associated with smoldering herpes simplex 2 infection.

A 40-year-old man with chronic genital herpes simplex infection developed partial complex temporal lobe seizures of insidious onset, with EEG and MRI evidence of a unilateral temporal lobe destructive, atrophic process. Extensive workup did not reveal an infectious etiology. Three years of escalating number and severity of daily seizures with memory loss led to temporal lobectomy. Histologic study revealed active, low-level viral infection in the resected hippocampus and temporal lobe cortex, with immunohistochemical evidence for infection by herpes simplex 2, principally in neurons. In situ hybridization confirmed the presence of herpes simplex virus in neurons. Anticonvulsant-resistant seizure episodes began to recur several times daily soon after surgery, but the addition of acyclovir to the treatment regimen resulted in a substantial reduction in seizure occurrence, maintained for the subsequent 2.5 years.

Congenital insensitivity to pain and anhidrosis with mitochondrial and axonal abnormalities.

Hereditary sensory and autonomic neuropathy type IV, or congenital insensitivity to pain with anhidrosis (CIPA), is a rare clinical disorder with only 32 cases reported in the literature. There has been no consistent pathophysiologic defect of the sensory nerve detected by light microscopic examination, but a frequent finding of decreased small myelinated fibers and a uniform finding of decreased unmyelinated fibers by ultrastructural analysis has been reported. Muscle biopsy in a 2-year-old boy with congenital insensitivity to pain with anhidrosis indicated lipid droplet accumulation and reduced cytochrome C oxidase histochemically on light microscopy. Electron microscopic study showed almost absent small unmyelinated nerve axons within the muscle, increased microfilaments, and decreased microtubules in axons, some abnormally enlarged mitochondria, and normal-appearing motor endplates. Biochemical analysis of muscle mitochondrial enzyme function revealed cytochrome c oxidase function to be reduced to 35% of normal, with normal function of the other mitochondrial enzymes.

Glut1 glucose transporter activity in human brain injury.

The principal glucose transporter at the blood-brain barrier (BBB) is the Glut1 isoform, and transporter density is believed to be an index of cerebral metabolic rate. In the present study, glucose transporter expression was studied in tissue resected 7-8 h after acute traumatic brain injuries in 2 patients. Light microscopic immunochemistry indicated a zone of complete loss of the Glut1 glucose transporter isoform in microvessel endothelial cells adjacent to sites of small vessel injury, concentrically surrounded by a narrow zone of variable Glut1, and distally surrounded by capillaries with typically immunoreactive endothelia in nondisrupted parenchyma. Variably reactive capillaries displayed alternating sectors of greatly reduced and highly reactive Glut1 density, suggesting a high density and low density of transporter activity in contiguous endothelial cells. Quantitative electron microscopic immunogold analyses demonstrated that the transporter was predominantly localized to the luminal and abluminal endothelial membranes, with lesser reactivity in cytoplasm; pericyte Glut1 was minimally above background levels. In endothelial sectors with reduced Glut1 transporter immunoreactivity, the luminal:abluminal ratio of Glut1 epitòpes was less than unity; while it is greater than unity in highly reactive endothelial cells. The number of Glut1-immunoreactive sites per micrometer of capillary membrane was not significantly different from previous reported Glut1 density in seizure resections, and about 2- to 3-fold higher than in human red cells. In the same tissue samples, qualitative immunogold electron microscopy of human serum albumin indicated leakage of this protein (MW 65,000) from the vascular space into pericapillary regions. Thus the high Glut1 density observed in capillaries from acutely injured brain occurs concomitantly with compromised barrier function.

Occipital encephalocele and MURCS association: case report and review of central nervous system anomalies in MURCS patients.

The combination of MURCS association (Müllerian duct and renal agenesis, upper limb and rib anomalies) and occipital encephalocele occurred in a stillborn girl of 41 weeks gestation. The malformations are compatible with a defect in the organization of the paraxial mesoderm that gives rise to occipital, cervical, and thoracic somites and adjoining intermediate mesoderm. These structures contribute to the occipital bone, cervical spine, upper limbs, and urogenital system. Brain imaging may be useful in assessing MURCS patients, if cranial malformations prove to be clinically important in these individuals.

High expression of the Glut1 glucose transporter in human brain hemangioblastoma endothelium.

The principal glucose transporter at the blood-brain barrier is Glut1, and GLUT1 expression is downregulated in high grade gliomas. In the present study, glucose transporter expression was studied in surgically resected hemangioblastoma tissue. Light microscopic immunochemistry indicated the high expression of the Glut1 glucose transporter isoform throughout the central vascular endothelium of this tissue. Glial fibrillary acidic protein (GFAP) was observed only at the tumor border, with no GFAP immunoreactivity in stromal cells, pericytes or endothelia in the central tumor regions. It is generally believed that more Glut1 is found in erythrocytes than any other cell, but quantitative electron microscopic immunogold analyses of Glut1-immunoreactive sites per micron of capillary membrane showed the Glut1 density in tumor endothelial membranes glucose transporter was 2-3-fold higher than in human red cells. In the same tissue samples, qualitative immunogold electron microscopy of human serum albumin indicated that this protein (MW 65,000) moved freely from the vascular space into pericapillary regions, confirming the leaky barrier characteristics of the hemangioblastoma. These studies show that Glut1 expression may be high in endothelia that are highly permeable and devoid of astroglial contacts. Thus, human cerebral hemangioblastomas may provide a novel system for studying the induction of Glut1 in the blood-brain barrier.

The neuropathology of parkinsonism: an overview.

The neuropathology of parkinsonism is reviewed as it occurs in primary (idiopathic) and secondary extrapyramidal syndromes. Present understanding of the significance of Lewy bodies in Parkinson's disease, diffuse Lewy body disease, and Lewy body variant of Alzheimer's disease is emphasized. The neuropathology produced by a variety of secondary causes is also considered to demonstrate the diverse lesions that can result in parkinsonism.

Down-regulation of blood-brain glucose transport in the hyperglycemic nonobese diabetic mouse.

The intracarotid injection method has been utilized to examine blood-brain barrier (BBB) glucose transport in hyperglycemic (4-6 days) mice. In anesthetized mice, Brain Uptake Indices were measured over a range of glucose concentrations from 0.010-50 mmol/l; glucose uptake was found to be saturable and kinetically characterized. The maximal velocity (Vmax) for glucose transport was 989 +/- 214 nmol.min-1.g-1. and the half-saturation constant estimated to be 5.80 +/- 1.38 mmol/l. The unsaturated Permeability Surface area product (PS) is = 171 + 8 microliters.min.-1.g-1. A rabbit polyclonal antiserum to a synthetic peptide encoding the 13 C-terminal amino acids of the human erythrocyte glucose transporter immunocytochemically confirmed the presence of the GLUT1 isoform in non-obese diabetic (NOD) mouse brain capillary endothelia. These studies indicate that a down-regulation of BBB glucose transport occurs in these spontaneously hyperglycemic mice; both BBB glucose permeability (as indicated by PS product) and transporter maximal velocity are reduced (in comparison to normoglycemic CD-1 mice), but the half-saturation constant remains unchanged.

Neuropathology of Rett syndrome: case report with neuronal and mitochondrial abnormalities in the brain.

Neuronal changes in the brain of a Rett syndrome patient were examined in a frontal lobe biopsy performed at age 3 years and in the postmortem brain at age 15 years. In the brain biopsy, frontal cortex contained numerous scattered pyramidal neurons with cytoplasmic vacuolation and increased cytoplasmic density, with no neuronophagia or inflammation detected; electron microscopy showed these neurons to have large, lucent-appearing mitochondria, very abundant ribosomal content, and some lipofuscin granules. Postmortem brain 12 years later showed scattered neurons in frontal cortex, substantia nigra, and cerebellar folia, with increased electron density of the cytoplasm, stacks of ribosomal endoplasmic reticulum, and large amounts of disorganized membranous material, including autophagic-type organelles. Mitochondria of these neurons contained electron-dense, finely granular matrix inclusions; in the substantia nigra, some spherical mitochondrial inclusions completely filled the matrix space. Golgi preparations of (autopsy) frontal cortex and cerebellar folia showed truncation and thickening of dendrites and a degenerate appearance of cortical pyramidal neurons, similar to changes found in aged brain. Synaptophysin immunohistochemistry indicated that the density of synapses was not greatly altered compared to controls in frontal cortex and cerebellum. The patient also had a second genetic defect, severe combined immunodeficiency with thymic aplasia, which may be X-linked.