bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of the 1.5‐Mb 17p deletion in families with hereditary neuropathy with liability to pressure palsies
Authors: Mariman E. C. M. , Gabreëls‐Festen A. A. W. M. , van Beersum S. E. C. , Valentijn L. J. , Baas F. , Bolhuis P. A. , Jongen P. J. H. , Ropers H. H. , Gabreëls F. J. M.
Published: January 2005

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder of the peripheral nerves leading to increased susceptibility to mechanical traction or compression. Some patients have been shown to be carriers of a 1.5‐Mb deletion in chromosome 17p11.2, which corresponds to the duplicated region present in most patients with Charcot‐Marie‐Tooth disease type 1A. Recently, evidence has been presented that the deletion is not the only cause of HNPP. To determine the prevalence of the 1.5‐Mb deletion, we have examined 22 unrelated families with HNPP in the following two ways: by polymerase chain reaction analysis of marker loci D17S122 and D17S261, and by gene dosage measurements with DNA probes for D17S122 (VAW409R3a) and D17S125 (VAW412R3a) and for the PMP‐22 gene. The efficiency and sensitivity of these methods is discussed. Our results show that the prevalence of the 17p deletion in our families with HNPP is 68%. One patient, presenting as a sporadic case, was found to be affected by a de novo deletion in the paternal chromosome. Single‐strand conformation analysis of the protein‐coding region of the PMP‐22 gene did not reveal any mutation in patients from the 7 families lacking the 17p deletion. As a group, these families could not be distinguished by clinical, electrophysiological, or morphological features from the families with the deletion.
The retinoblastoma gene is involved in malignant progression of astrocytomas
Authors: Henson John W. , Schnitker Bernd L. , Correa Katia M. , von Deimling Andreas , Fassbender Frank , Xu Hong‐Ji , Benedict William F. , Yandell David W. , Louis David N.
Published: January 2005

Loss of chromosome 13q occurs in up to 50% of human astrocytomas, suggesting the presence of an astrocytoma tumor suppressor gene on that chromosome. To determine whether the retinoblastoma susceptibility gene (Rb) on 13q 14 contributes to the formation of astrocytomas, we examined 85 tumors for loss of heterozygosity (LOH) at the intragenic Rb 1.20 locus. LOH was detercted in 16 of 54 informative high‐grade astrocytomas (30%), but was not detected in 12 low‐grade gliomas. Deletion mapping with flanking markers on 13q revealed that the Rb 1.20 region was preferentially targeted by the deletions. Tumors with LOH at Rb 1.20 were examined for mutations in the remaining Rb allele using single‐strand conformational polymorphism (SSCP) analysis and direct DNA sequencing. Mutations were detected in exon 8 (1 tumor), exon 24 (2 tumors), and intron 24 (1 tumor). Rb protein expression, as assessed by immunohistochemistry, was altered in 3 of 9 cases with LOH and in 1 tumor without LOH. Our results demonstrate that Rb inactivation contributes to the formation of high‐grade astrocytomas, and therefore implicate a second, known tumor suppressor gene in astrocytoma tumorigenesis.
Dystonia in Ashkenazi Jews: Clinical characterization of a founder mutation
Authors: Bressman Susan B. , de Leon Deborah , Kramer Patricia L. , Ozelius Laurie J. , Brin Mitchell F. , Greene Paul E. , Fahn Stanley , Breakefield Xandra O. , Risch Neil J.
Published: January 2005

A gene (DYT1) for idiopathic torsion dystonia maps to chromosome 9q34 in Ashkenazi Jewish families with early onset of symptoms. Further, there is linkage disequilibrium between DYT1 and a particular haplotype of alleles at 9q34 loci in this population. This implies that a large proportion of early‐onset idiopathic torsion dystonia in Ashkenazi Jews is due to a founder mutation in DYT1. To characterize the phenotypic range of this mutation, we studied 174 Ashkenazi Jewish individuals affected with idiopathic torsion dystonia. We used GT(n) markers on chromosome 9q34 (D9S62, D9S63, and ASS) and classified individuals as having (“carriers”), not having (“noncarriers”), or being ambiguous with respect to a DYT1‐associated haplotype. We assessed clinical features and found marked clinical differences between haplotype carriers and noncarriers. There were 90 carriers, 70 noncarriers, and 14 ambiguous individuals. The mean age at onset of symptoms was significantly lower in carriers than in noncarriers (12.5 ± 8.2 vs 36.5 ± 16.4 years). In 94% of carriers, symptoms began in a limb (arm or leg equally); rarely the disorder started in the neck (3.3%) or larynx (2.2%). In contrast, the neck, larynx, and other cranial muscles were the sites of onset in 79% of noncarriers; onset in the arms occurred in 21% and onset in the legs never occurred. Limb onset, leg involvement in the course of disease, and age at onset distinguished haplotype carriers from noncarriers with 90% accuracy. In conclusion, there are clinical differences between Ashkenazi Jewish individuals with idiopathic torsion dystonia who do or do not have a unique DYT1 mutation, as determined by a DYT1‐associated haplotype of 9q34 alleles. These differences suggest that early, limb‐onset idiopathic torsion dystonia and late, cervical cranial–onset idiopathic torsion dystonia are genetically distinct entities.
The role of calcium‐binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis
Authors: Alexianu Maria E. , Ho Bao‐Kuang , Mohamed A. Habib , La Bella Vincenzo , Smith R. Glenn , Appel Stanley H.
Published: January 2005

The factors contributing to selective motoneuron loss in amyotrophic lateral sclerosis (ALS) remain undefined. To investigate whether calcium‐binding proteins contribute to selective motoneuron vulnerability in ALS, we compared calbindin‐D28K and parvalbumin immunoreactivity in motoneuron populations in human ALS, and in a ventral spinal cord hybrid cell line selectively vulnerable to the cytotoxic effects of ALS IgG. In human autopsy specimens, immunoreactive calbindin‐D28K and parvalbumin were absent in motoneuron populations lost early in ALS (i.e., cortical and spinal motoneurons, lower cranial nerve motoneurons), while motoneurons damaged late or infrequently in the disease (i.e., Onuf's nucleus motoneurons, oculomotor, trochlear, and abducens nerve neurons) expressed markedly higher levels of immunoreactive calbindin‐D28K and/or parvalbumin. Motoneuron–neuroblastoma VSC 4.1 hybrid cells lost immunoreactive calbindin‐D28K and parvalbumin following dibutyryl‐cyclic AMP–induced differentiation and were killed by IgG from ALS patients. Undifferentiated calbindin/parvalbumin‐reactive VSC 4.1 cells were not killed, nor were other cell lines expressing high levels of calbindin‐D28K and parvalbumin immunoreactivity (substantia nigra–neuroblastoma hybrid cells and N18TG2 neuroblastoma parent cells). These studies suggest that decreased calbindin‐D28K and parvalbumin immunoreactivity may help explain the selective vulnerability of motoneurons in ALS.
Childhood Guillain‐Barré syndrome in Paraguay, 1990 to 1991
Authors: Hart David E. , Rojas Laura A. , Rosàrio Joana A. , Recalde Humberto , Romà Gustavo C.
Published: January 2005

During 1990 to 1991, through a national surveillance program for poliomyelitis, the Paraguayan Ministry of Health received reports of 50 children with incident acute flaccid paralysis (< 15 years old). On the basis of established criteria, 37 were diagnosed with Guillian‐Barré syndrome. The average annual incidence rate for 1990 to 1991 was 1.1/100,000 children. The clinical course was more benign than reported in other pediatric series. There were low rates of hospitalization (57%), respiratory compromise (8%), and intubation (5%). The overall severity, however, was similar to that described in previous reports, with a 3% case‐fatality rate and an 81% total recovery rate at 12 months. Seventy‐six percent of patients had symptom onset during January to April, the warmest months of the year. Thirty percent of patients had definite or possible exposure to organophosphate pesticides, and the peak use coincides with the peak incidence of Guillian‐Barré syndrome There was no correlation between occurrence of Guillian‐Barré syndrome and prior immunization.
Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate
Authors: Beal M. Flint , Henshaw D. Ross , Jenkins Bruce G. , Rosen Bruce R. , Schulz Jourg B.
Published: January 2005

A potential mechanism of neuronal injury in neurodegenerative diseases is a defect in energy metabolism that may lead to slow excitotoxic neuronal death. Consistent with this possibility, we showed that specific inhibitors of the electron transport chain produce excitotoxic lesions in vivo. In the present study we examined whether agents that improve energy metabolism can block lesions produced by the mitochondrial toxin malonate. Striatal lesions produced by the complex II inhibitor malonate were blocked in a dose‐dependent manner by oral pretreatment with coenzyme Q10. Administration of nicotinamide by Alzet pump for 1 week attenuated malonate‐induced lesions, but riboflavin had no effect. Administration of nicotinamide intraperitoneally just prior to and following induction of the lesions produced dose‐dependent neuroprotection. A combination of coenzyme Q10 with nicotinamide was more effective than either compound alone, as shown by both lesion size and magnetic resonance imaging in vivo. Both coenzyme Q10 and nicotinamide blocked adenosine triphosphate depletions and lactate increases. These results confirm that mitochondrial toxins produce striatal excitotoxic lesions by a mechanism involving energy depletion in vivo. Furthermore, they suggest novel neuroprotective strategies that may be useful in the treatment of both mitochondrial encephalopathies and neurodegenerative diseases.
High‐dose dextromethorphan in amyotrophic lateral sclerosis: Phase I safety and pharmacokinetic studies
Authors: Hollander Dave , Pradas Jesus , Kaplan Richard , McLeod Howard L. , Evans William E. , Munsat Theodore L.
Published: January 2005

Much interest has focused on the role of glutamate‐mediated excitotoxicity in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). We therefore conducted a phase I study of high‐dose dextromethorphan (DM) in ALS. DM is a selective, noncompetitive antagonist of the N‐methyl‐D‐aspartate subtype of the glutamate receptor. Thirteen patients were given DM in an escalating dose fashion, to a target of 10 mg/kg/day or the maximum tolerable dose, and then maintained on this dose for up to 6 months. Total daily doses ranged from 4.8 to 10 mg/kg (median, 7 mg/kg). Side effects were dose limiting in most patients. The most common side effects were light‐headedness, slurred speech, and fatigue. Detailed pharmacokinetic and neuropsychology studies were performed. This study demonstrates the feasibility of long‐term administration of high‐dose DM in ALS, as well as in other conditions associated with glutamate excitotoxicity.
Ragged Red Fibers in Normal Aging and Inflammatory Myopathy
Authors: Rifai Ziad , Welle Stephen , Kamp Cornelia , Thornton Charles A.
Published: January 2005

Ragged red fibers are an important marker for mitochondrial disease. To evaluate the hypothesis that mitochondrial dysfunction may play a role in the pathogensis of aging and inclusion body myositis, we studied the frequency of ragged red fibers in muscle biopsy specimens from 15 young and 13 old normal adults, and from 27 patients with inclusion body myositis, polymyositis, or dermatomyositis. Serial transverse cryostat sections were stained with modified Gomori trichrome, modified succinic dehydrogenase, and cytochrome c oxidase. The frequency of ragged red fibers, determined by measuring the percent number of succinic dehydrogenase–positive ragged red fiber equivalents, was significantly higher in old compared to young normal subjects (0.33 vs. 0.02%, p < 0.0001). With the exception of a single polymyositis biopsy specimen showing a large number of ragged red fibers, the frequency of ragged red fibers in patients with polymyositis or dermatomyositis was similar to that of age‐matched normal control subjects. The frequency of ragged red fibers was more than 1% in 7 of 8 patients with inclusion body myositis (maximum, 15%). The modified succinic dehydrogenase stain was more sensitive than the modified Gomori trichrome in detecting accumulation of mitochondria in muscle fibers. Cytochrome c oxidase activity was deficient in most ragged red fibers. We conclude that the number of ragged red fibers increases with normal aging and may reflect an age‐related decline in muscle mitochondrial oxidative metabolism. The frequent occurrence of ragged red fibers in inclusion body myositis suggests that mitochondrial function may be impaired in this disease.
The trends in incidence of primary brain tumors in the population of rochester, minnesota
Authors: Radhakrishnan Kurupath , Mokri Bahram , Parisi Joseph E. , O'Fallon W. Michael , Sunku Jayasimha , Kurland Leonard T.
Published: January 2005

A number of reports have suggested an increasing incidence of primary brain tumors, especially malignant astrocytomas, in the elderly population. To investigate this issue, we analyzed the incidence and temporal trends of primary intracranial neoplasms diagnosed in the population of Rochester, Minnesota, over the 40 years between 1950 and 1990. The incidence of symptomatic primary brain tumors (excluding patients diagnosed incidentally at autopsy and by neuroimaging studies) increased from 9.5 per 100,000 population per year in 1950 to 1969 to 12.5 per 100,000 per year in 1970 to 1989; this change was not statistically significant (χ2 trend, 1.89; p = 0.17). While the incidence of pituitary adenomas increased significantly between the two periods (χ2 trend, 4.44;p = 0.04), the incidence trends of all gliomas, malignant astrocytomas, and meningiomas showed no change among persons younger than 65 years as well as those 65 years and older. The number of patients incidentally found to have neoplasms by neuroimaging studies increased in the recent 20‐year period (χ2 trend, 4.08;p = 0.04). The average age‐ and sex‐adjusted incidence rates per 100,000 per year during the study period in the population of Roshester, Minnesota, for symptomatic tumors were 5.0 for all gliomas, 3.3 for malignant astrocytomas, 2.0 for meningiomas, and 2.4 for pituitary adenomas. In conclusion, our data indicate that the reported increase in the incidence of primary brain tumors is an artifact of improvement in diagnostic technology and practice.
Regional cerebral blood flow changes in motor cortical areas after transient anesthesia of the forearm
Authors: Sadato Norihiro , Zeffiro Thomas A. , Campbell Gregory , Konishi Junji , Shibasaki Hiroshi , Hallett Mark
Published: January 2005

To study the effect of deafferentation on cortical areas activated by movement of the proximal muscles, we measured regional cerebral blood flow with positron emission tomography and 15O‐labeled water. Flexion‐extension movements of the right elbow before deafferentation were associated with an increase of regional cerebral blood flow in the primary sensorimotor area bilaterally, posterior supplementary motor area bilaterally, ipsilateral cerebellum, contralateral putamen, premotor area, anterior cingulate area, and posterior parietal region. Transient anesthesia of the right forearm induced by ischemic block caused an increase of regional cerebral blood flow in the primary sensorimotor area bilaterally at rest, but there was no change of regional cerebral blood flow with movement, indicating that the movement‐related change in cerebral blood flow was reduced. These findings are consistent with increased excitability of neurons as a result of deafferentation. In the supplementary motor area, anesthesia did not induce any change in regional cerebral blood flow at rest, but there was a decline with movement, again indicating a reduction of the change in cerebral blood flow related to movement. This might be due to a reduction in sensory feedback because of the anesthesia.
Comparative study of selegiline plus L‐dopa–carbidopa versus L‐dopa–carbidopa alone in the treatment of parkinson's disease
Authors: Brannan Timothy , Yahr Melvin D.
Published: January 2005

The long‐term effect of selegiline (L‐deprenyl) in the treatment of Parkinson's disease has not been clearly delineated. We report on a group of patients whose treatment was initiated with selegiline (n = 43) and then subsequently included L‐dopa‐carbidopa (Sinemet) and in whom an extended period of observation was carried out; they are compared to a group of patients whose treatment consisted of L‐dopa‐carbidopa alone (n ' 39). In each, serial observations of the parkinsonian state and the response to treatment on a yearly basis for a period of 5 years were performed. No significant difference in the Hoehn‐Yahr stage or in the motor subscores of tremor, rigidity, bradykinesia, and gait‐posture was found between the two groups, nor was there a significant difference in the incidence of fluctuating responses or dyskinesias. The group that received combination therapy required less L‐dopa than did the group that received L‐dopa‐carbidopa alone during the first 3 years of treatment and a similar trend was evident in years 4 to 5. We conclude that minimal benefits accrued to the parkinsonian patients from long‐term use of selegiline. No clinical evidence to support the claim of “neuroprotective” properties was found. Selegiline's major usefulness is to modify the fluctuating therapeutic response seen with L‐dopa‐carbiodopa.
Detection of human T‐lymphotropic virus type I (HTLV‐I) tax RNA in the central nervous system of HTLV‐I–associated myelopathy/tropical spastic paraparesis patients by in situ hybridization
Authors: Lehky Tanya J. , Levin Michael C. , Flerlage Nick , Jacobson Steven , Fox Cecil H. , Koenig Scott , Izumo Shuji , Sato Elichi , Osame Mitsuhiro , Raine Cedric S.
Published: January 2005

Autopsy specimens from 3 patients with human T‐lymphotropic virus (HTLV‐I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) were examined for the presence of HTLV‐I in the central nervous system (CNS). In situ hybridization using an HTLV‐I tax RNA probe detected cells containing HTLV‐I RNA in spinal cord and cerebellar sections. HTLV‐I infected cells were located within the white matter and, in particular, within the anterior and lateral funiculi of the spinal cord. Consistent with previously described HAM/TSP pathology, there were perivascular infiltrates in these CNS specimens. Significantly, HTLV‐I RNA was not localized to these infiltrates but was detected deeper within the neural tissue. Furthermore, phenotypic analysis demonstrated that at least some of the infected cells were astrocytes. While previous polymerase chain reaction studies have demonstrated the presence of proviral HTLV‐I in CNS specimens, here we provide evidence for the in situ expression of HTLV‐I RNA in the CNS of HAM/TSP patients.
Experimental pneumococcal meningitis: Cerebrovascular alterations, brain edema, and meningeal inflammation are linked to the production of nitric oxide
Authors: Koedel Uwe , Bernatowicz Andrea , Paul Robert , Frei Karl , Fontana Adriano , Pfister Hans‐Walter
Published: January 2005

We investigated whether treatment with the nitric oxide synthase inhibitor N‐nitro‐L‐arginine (L‐NA) and the free radical scavenger superoxide dismutase influences cerebral blood flow changes, brain edema, and cerebrospinal fluid pleocytosis in early experimental pneumococcal meningitis. Compared to untreated infected rats, superoxide dismutase given 3 hours after infection significantly attenuated the increase of brain water content, intracranial pressure, and cerebrospinal fluid white blood cell count, but did not modulate the increase in regional cerebral blood flow. N‐Nitro‐L‐arginine treatment (5 mg/kg intravenously, followed by 5 mg/kg/hour) reversed the increase in regional cerebral blood flow; prevented an increase in brain water content, intracranial pressure, and cerebrospinal fluid nitrite concentrations; and reduced cerebrospinal fluid white blood cell count. With a closed cranial window preparation, N‐nitro‐L‐arginine prevented pneumococci‐induced dilatation of pial arterioles. When the effective dose was increased twofold, the effects of N‐nitro‐Lvarginine became more pronounced but resulted in the death of 4 of 5 rats, probably due to hemodynamic side effects. In primary cultures of rat cerebral endothelial cells, nitrite concentrations increased after pneumococcal stimulation, which could be prevented by NvnitrovLvarginine and cycloheximide. These data suggest that (a) nitric oxide accounts for regional cerebral blood flow changes and pial arteriolar dilatation in the early phase of experimental pneumococcal meningitis; (b) both superoxide radical and nitric oxide are involved as mediators of brain edema and meningeal inflammation; and (c) cerebral endothelial cells can be stimulated by pneumococci to release nitric oxide presumably via the inducible nitric oxide synthase.
Positron emission tomography and magnetic resonance spectroscopy of cerebral glycolysis in children with congenital lactic acidosis
Authors: Duncan D. B. , Herholz K. , Kugel H. , Roth B. , Ruitenbeek W. , Heindel W. , Wienhard K. , Heiss W.‐D.
Published: January 2005

Congenital lactic acidosis with neurological symptoms may be due to a variety of disorders of energy metabolism. We investigated whether positron emission tomography (PET) and proton magnetic resonance spectroscopy (1H MRS) are capable of demonstrating specific changes to facilitate diagnosis. A corresponding increase of cerebral lactate (with MRS) and rate of glycolysis (with PET) was observed in 2 children with biochemical evidence of defective mitochondrial respiration. No such increase was noted in a child with lactic acidosis due to stress and exercise but normal respiratory chain activity, and in a control case with an epilepsy syndrome without evidence of primary changes of energy metabolism. The results suggest that defects of oxidative phosphorylation may cause a massive increase of glycolysis to cover energy requirements, with corresponding accumulation of lactate in brain tissue. This mechanism can now be demonstrated in vivo and, with further experience, may potentially be used as a diagnostic marker of respiratory chain disorders in brain tissue.
Early‐onset ataxia with cardiomyopathy and retained tendon reflexes maps to the friedreich's ataxia locus on chromosome 9q
Authors: Palau Francisco , de Michele Giuseppe , Vilchez Juan J. , Pandolfo Massimo , Monrós Eugègnia , Cocozza Sergio , Smeyers Patricia , Lopez‐Arlandis José , Campanella Giuseppe , di Donato Stefano , Filla Alessandro
Published: January 2005

Absence of lower limb tendon reflexes has been considered an essential diagnostic criterion for Friedreich's ataxia (FA). However, preservation of knee and ankle jerks has been reported in a few patients. Linkage analysis to FA locus (FRDA) on chromosome 9q13‐21.1 was performed in 11 patients from 6 families with FA phenotype, including cardiomyopathy, but retained reflexes (FARR). A maximal lod score of 3.38 at recombination fraction theta equal to 0.00 was obtained demonstrating that FARR maps to the FRDA locus. These results suggest that FARR is a variant phenotype of FA.
Human immunodeficiency virus type 1 tat activates non—N‐methyl‐D‐aspartate excitatory amino acid receptors and causes neurotoxicity
Authors: Magnuson David S. K. , Knudsen Bodo E. , Geiger Jonathan D. , Brownstone Robert M. , Nath Avindra
Published: January 2005

The human immunodeficiency virus type 1 (HIV‐1) protein Tat is known to be released from HIV‐1‐infected cells. We show that micromolar concentrations of Tat depolarized young rat and adult human neurons. In addition, Tat, at similar concentrations, was toxic to human fetal neurons in culture. Tat‐induced responses were insensitive to the Na+ channel blocker tetrodotoxin, suggesting a direct effect of Tat on neurons. Tat‐induced depolarizations and cytotoxicity were blocked by the excitatory amino acid antagonist kynurenate. The N‐methylvD‐aspartate receptor antagonist Dv2vaminov5‐phosphonovalerate had little effect on Tatvinduced depolarizations but did provide protection from Tat neurotoxicity. These results suggest that Tat, released from HIVv1vinfected cells, may be an important mediator of neurotoxicity observed in HIV1 encephalopathy.
The gene for hereditary progressive dystonia with marked diurnal fluctuation maps to chromosome 14q
Authors: Tanaka H. , Endo K. , Tsuji S. , Nygaard T. G. , Weeks D. E. , Nomura Y. , Segawa M.
Published: January 2005

Hereditary progressive dystonia with marked diurnal fluctuation (HPD) is a childhood‐onset, postural dystonia that is characterized by marked diurnal fluctuation and a dramatic response to levodopa. Recently, the gene for dopa‐responsive dystonia (DRD), an autosomal dominant dystonia showing similarly marked response to levodopa, has been mapped to chromosome 14q. Since HPD and DRD share many clinical characteristics, we have analyzed microsatellite polymorphisms in the region of the DRD locus and obtained a maximal lod score of 2.0 at D14S52 without obligate recombination events in the affected individuals. The results strongly suggest that HPD and DRD are to be caused by mutations in the same gene on the long arm of chromosome 14.
The adhesion molecule and cytokine profile of multiple sclerosis lesions
Authors: Cannella Barbara , Raine Cedric S.
Published: January 2005

The expression of the adhesion molecules, vascular cell adhesion molecule‐1 (VCAM‐1) and intercellular adhesion molecule‐1 (ICAM‐1), and their respective receptors on leukocytes, very late activation antigen‐4 (VLA‐4) and lymphocyte function–associated antigen‐1 (LFA‐1), together with a selection of proinflammatory and immunomodulatory cytokines (interleukin [IL]‐1, IL‐2, IL‐4, IL‐10, tumor necrosis factor‐α [TNF‐α], transforming growth factor‐β [TGF‐β], and interferon‐γ [IFN‐γ]) was examined by immunocytochemistry in multiple sclerosis (MS) lesions of different ages and compared with central nervous system (CNS) tissue from other neurological diseases, both inflammatory and noninflammatory, and normal CNS tissue. These molecules play key roles in lymphocytic infiltration and interactions during tissue inflammation and are in large part normally not expressed by CNS cells. High levels of expression of all the molecules tested were found in MS, particularly in chronic active lesions. Positivity for all molecules was also seen in other neurological diseases, even in noninflammatory conditions. There was some suggestion that the VCAM‐1/VLA‐4 adhesion pathway was expressed at higher levels in chronic MS lesions, while ICAM‐1/LFA‐1 was used more uniformly in lesions of all ages. Of the cytokines examined, there was increased expression of TNF‐α and IL‐4 in MS; this was found to be statistically significant when compared with noninflammatory neurological diseases. The expression of most adhesion molecules and some cytokines was negligible in normal CNS tissue although low‐level reactivity for ICAM‐1 TGF‐β, IL‐4, TNF‐α, and IL‐10 was detected, perhaps indicative of immunoregulatory mechanisms. Microglial cells and astrocytes were the major CNS cell types expressing cytokines. The results indicate a potential in the CNS for widespread induced expression of molecules involved in the inflammatory cascade. No adhesion or cytokine molecule or pattern of expression unusual for MS was apparent.
Basement membrane reduplication and pericyte degeneration precede development of diabetic polyneuropathy and are associated with its severity
Authors: Giannini Caterina , Dyck Peter J.
Published: January 2005

In a recent paper, we showed that the number of endoneurial microvessels per square millimeter and the average luminal area and size distribution of these microvessels are not significantly different in sural nerves of patients with diabetes mellitus as compared to control subjects. Mural area, especially the component due to basement membrane reduplication and cellular debris, was unequivocally increased in diabetes mellitus. Because these latter changes are associated with a decrease in periendothelial cell area, we hypothesized that cellular degeneration, especially of pericytes, may account for basement membrane reduplication and increased frequency of cellular debris. In the present study, we showed that endoneurial microvessels undergo a statistically significant increase in basement membrane area, mural area, and frequency of cellular debris in diabetics without polyneuropathy and an even greater increase in diabetics with polyneuropathy. We also found that duration of diabetes mellitus was significantly associated with area occupied by reduplicated basement membrane and cellular debris, but not with mural and periendothelial area. None of the examined measurements was associated with age. Since the microvessel abnormalities we describe are already present before the development of polyneuropathy and increase with severity of polyneuropathy, it is likely that they reflect functional derangements of pericytes and microvessel function which precede and might be implicated in fiber degeneration.
Cerebrospinal fluid levels of amyloid β‐protein in alzheimer's disease: Inverse correlation with severity of dementia and effect of apolipoprotein e genotype
Authors: Nitsch Roger M. , Rebeck G. William , Deng Meihua , Richardson U. Ingrid , Tennis Marsha , Schenk Dale B. , Vigo‐Pelfrey Carmen , Lieberburg Ivan , Wurtman Richard J. , Hyman Bradley T. , Growdon John H.
Published: January 2005

Alzheimer's disease (AD) is characterized by formation in brain of neurofibrillary tangles and of amyloid deposits. The major protein component of the former is τ, while the latter are composed of amyloid β‐peptides (Aβ), which are derived by proteolytic cleavage of the amyloid β‐protein precursor (APP). Both β and various secretory APP derivatives including Aβ and APPs are present in human cerebrospinal fluid (CSF). To investigate whether clinical signs of AD are paralleled by changes in CSF levels of these proteins, we correlated quantitative measures of dementia severity with CSF concentrations of Aβ, of APPs, and of τ We found that levels of Aβ in CSF of AD patients were inversely correlated both to cognitive and to functional measures of dementia severity. In contrast, levels of APPs and of τ did not correlate with dementia severity. Apolipoprotein E (apoE) genotype did not influence CSF levels of Aβ, APPs, or τ, which were similar among AD patients with Apo E ε3/3, ε3/4, and ε4/4 alleles. These data indicate that CSF levels of Aβ decrease with advancing severity of dementia in AD and suggest that they are independent of a patient's Apo E genotype.
Cortical control of saccades
Authors: Pierrot‐Deseilligny Charles , Rivaud Sophie , Gaymard Bertrand , Müri René , Vermersch Anne‐Isabelle
Published: January 2005

A scheme for the cortical control of saccadic eye movements is proposed based partly on defects revealed by specific test paradigms in human with discrete lesions. Three different cortical areas are capable of triggering saccades. The frontal eye field disengages fixation, and triggers intentional saccades to visible targets, to remembered target locations, or to the location where it is predicted that the target will reappear (i.e., saccades concerned with intentional exploration of the visual environment). The parietal eye field triggers saccades made reflexively on the sudden appearance of visual targets (i.e., saccades concerned with reflexive exploration of the visual environment). The supplementary eye field is important for triggering sequences of saccades and in controlling saccades made during head or body movement (i.e., saccades concerned with complex motor programming). Three other areas contribute to the preparation of certain types of saccades. The prefrontal cortex (area 46 of Brodmann) plays a crucial role for planning saccades to remembered target locations. The inferior parietal lobule is involved in the visuospatial integration used for calculating saccade amplitude. The hippocampus appears to control the temporal working memory required for memorization of the chronological order of sequences of saccades.
The apolipoprotein E ε2 allele is associated with an increased risk of early‐onset alzheimer's disease and a reduced survival
Authors: van Duijn Cornelia M. , de Knijff Peter , Wehnert Anita , De Voecht Joke , Bronzova Juliana B. , Havekes Louis M. , Hofman Albert , van Broeckhoven Christine
Published: January 2005

It was suggested that in contrast to the E4 allele, the E2 allele of the apolipoprotein E gene (APOE *2) has a protective effect for late‐onset Alzheimer's disease and early‐onset Alzheimer's disease (EOAD). We studied the role of the APOE*2 allele in the pathogenesis of EOAD in a Dutch population‐based study of 175 probable EOAD patients with onset age at or before 65 years and 532 age‐matched controls. In our population, there was no evidence for a protective effect of the APOE*2 allele on the risk of EOAD. However, our data show that among EOAD patients, survival for APOE*2 carriers was significantly reduced. When restricting the analysis to patients ascertained early after diagnosis at a stage of disease when mortality is low, our data suggest an increased risk of EOAD for subjects with APOE2E2, APOE2E3, APOE3E4, and APOE4E4 genotypes.
Hereditary ceruloplasmin deficiency with hemosiderosis: A clinicopathological study of a japanese family
Authors: Morita Hiroshi , Ikeda Shu‐Ichi , Yamamoto Kanji , Morita Sayuri , Yoshida Kunihiro , Nomoto Shozo , Kato Masahiro , Yanagisawa Nobuo
Published: January 2005

A hereditary ceruloplasmin deficiency associated with severe iron deposition in visceral organ and brain tissues found on histopathological examination at autopsy is discussed. Three siblings of consanguineous Japanese parents were studied. Their clinical symptoms were progressive dementia, extrapyramidal disorders, cerebellar ataxia, and diabetes mellitus, all of which appeared when they were between 30 and 50 years old. All had serum ceruloplasmin deficiencies and increased serum ferritin concentrations. The dentate nucleus, thalamus, putamen, caudate nucleus, and liver of each one showed low signal intensities on T1‐ and T2‐weighted magnetic resonance images. Examination of the central nervous system revealed severe destruction of the basal ganglia and dentate nucleus, with considerable iron deposition in neuronal and glial cells, whereas the cerebral cortex showed mild iron deposition in glial cells without neuronal involvement. An electron microscopic study with energy‐dispersive x‐ray analysis showed iron depositions in the hepatocytes, of both the neural and glial cells of the brain. We consider this a new disease entity because of the primary ceruloplasmin deficiency.
Cognitive scores in carriers of huntington's disease gene compared to noncarriers
Authors: Foroud Tatiana , Siemers Eric , Kleindorfer Dawn , Bill Danield J. , Hodes M. E. , Norton James A. , Conneally P. Michael , Christian Joe C.
Published: January 2005

Huntington's disease (HD) is progressive neurodegenerative disorder recently shown to be due to an excess number of CAG trinucleotide repeats in the 5' translated region of chromosome 4. One of the cardinal features of HD is cognitive decline. While mental deterioration is obvious later in the disease course, the time of its onset is difficult to determine precisely. A sample of at‐risk individuals without signs or symptoms of HD by self‐report was studied. The Wechsler Adult Intelligence Test—Revised and a neurological rating scale were administered. The genotypes of 394 individual were then determined by polymerase chain reaction testing. On all portions of the WAIS‐R test, the mean score of the HD gene carriers was lower than that of the noncarriers. Scores on two of the performance subtests, the digit symbol and the picture arrangement, were significantly different in the two groups, even after the scores from all gene carriers who were diagnosed as affected based on their neurological motor examination were removed. The scores for the gene carriers on the various subtests were negatively correlated with the number of CAG repeats in the expanded HD allele. Such a relationship was not seen with the normal alleles of the noncarriers. Taken together, our results suggest that a deficit in cognitive function is an early finding of HD and that in this patient population, the degree of cognitive deficit is proportional to the number of CAG repeats in the HD allele.
Variance of age at onset in a Japanese family with amyotrophic lateral sclerosis associated with a novel cu/zn superoxide dismutase mutation
Authors: Aoki Masashi , Abe Koji , Houi Kouji , Ogasawara Masahito , Matsubara Yoichi , Kobayashi Takaaki , Mochio Soichiro , Narisawa Kuniaki , Itoyama Yasuto
Published: January 2005

Although about 5 to 10% of amyotrophic lateral sclerosis (ALS) cases are familial, the pathophysiology of ALS remians unknown. A new point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD) gene, resulting in an amino acid substitution of leucine84 by valine (L84V), in a Japanese patient with familial ALS (FALS) was identified. This L84V substitution was not observed in 57 normal Japanese control subjects. The enzymatic activities of Cu/Zn SOD of skin fibroblasts were significantly reduced to 75% of the control level in the affected patient. The progression of the disease with this mutation is very rapid, but the age at onset varies with sex or generation within a family.
Intracerebral involvement in scleroderma en coup de sabre: Report of a case with neuropathologic findings
Authors: Chung Marilda H. , Sum John , Morrell Martha J. , Horoupian Dikran S.
Published: January 2005

Linear scleroderma en coup de sabre (LScs) is a rare disorder not infrequently associated with neurologic symptoms, notably epilepsy. However, histopathologic documentation of intracerebral lesions in LScs is very limited and the etiology of the central nervous system symptoms has therefore never been convincingly established. We describe a 27‐year‐old woman with LScs and a long‐standing history of epilepsy. Radiographic studies demonstrated a focal, intraparenchymal lesion in the left frontal lobe directly subjacent to the area of scleroderma on the forehead and scalp. The resected cerebral lesion revealed localized band‐like sclerosis of the leptomeninges and associated vessels, as well as intraparenchymal calcifications and anomalous, ectatic vessels. These findings suggest that LScs may represent a neurocutaneous syndrome of vascular dysplasia similar to the Sturge‐Weber syndrome, rather than a localized form of collagen vascular disease, as suggested by some.
Magnetic stimulation over the cerebellum in humans
Authors: Ugawa Yoshikazu , Uesaka Yoshikazu , Terao Yasuo , Hanajima Ritsuko , Kanazawa Ichiro
Published: January 2005

Magnetic stimulation performed with a double‐cone coil placed over appropriate positions on the back of the head reduced the size of electromyographic responses evoked by magnetic cortical stimulation in the first dorsal interosseous muscle when it preceded the cortical stimulus by 5, 6, and 7 msec. No suppression of responses to electrical cortical stimulation occurred. Greater suppression was evoked by stronger cerebellar stimuli; lesser suppression was elicited by stronger cortical stimuli. These physiological findings correspond to those obtained with electrical cerebellar stimulation. The most effective position for magnetic stimulation over the back of the head was slightly rostral to the foramen magnum level on the ipsilateral side of the muscle studied. This indicates that the conditioning stimulus activates certain structures at the back of the head on the ipsilateral side of the muscle, consistent with the cerebellum, because the part of the cerebellum regulating limb muscles is positioned about there on the ipsilateral side. In 2 patients with only cerebellar dysfunction, this suppression effect was not elicited, which also supports that the suppression is caused by activity in cerebellar structures. We conclude that magnetic stimulation over the cerebellum with a doublecone coil elicits the same suppressive effect on the motor cortex as electrical stimulation, but with less discomfort; moreover, we believe that this effect is produced by activation of certain cerebellar structures.
Common variable immunodeficiency and inclusion body myositis: A distinct myopathy mediated by natural killer cells
Authors: Dalakas Marinos C. , Illa Isabel
Published: January 2005

Inclusion body myositis developed in two men, 36 and 48 years old with long‐standing common variable immunodeficiency. Immunophenotypic analysis of the endomysial cells showed an increased number of natural killer (NK) cells (defined as CD57+, CD56+, CD3−, CD8−, CD68−) accounting for 8.5 to 9.5% of the total cells, compared with a mean of 1% in sporadic inclusion body myositis. The remaining cells were CD8+, macrophages, and CD4+ T cells. NK cells were positive for intercellular cell adhesion molecule‐1 and invaded muscle fibers negative for major histocompatibility complex (MHC) class I. In contrast to ubiquitous endomysial expression of MHC class I antigen in sporadic inclusion body myositis, the MHC class I in common variable immunodeficiency and inclusion body myositis was absent or weakly expressed in only some of the muscle fibers surrounded by CD8+ cells. Enteroviral or retroviral RNA sequences were not amplified. Treatment with intravenous immunoglobulin improved strength in 1 patient whose repeated muscle biopsy specimen showed normal NK cells. We conclude that inclusion body myositis can develop in patients with common variable immunodeficiency. Common variable immunodeficiency with inclusion body myositis is an immune myopathy mediated by NK cells in a non–MHC class I–restricted cytotoxicity, and by CD8+ cells in an MHC class I–restricted process. This is the first description of an inflammatory myopathy in which NK cells participate in the myocytotoxic process.
Central motor reorganization after anastomosis of the musculocutaneous and intercostal nerves following cervical root avulsion
Authors: Mano Yukio , Nakamuro Takuya , Tamural Ryuji , Takayanagi Tetsuya , Kawanishi Kouichi , Tamai Susumu , Mayer Richard F.
Published: January 2005

In 4 patients with a complete upper limb palsy due to traumatic cervical root avulsion, surgical anastomosis of intercostal to musculocutaneous nerves was performed to restore function in the biceps brachii muscle. Four to 6 months after the operation, motor unit discharges were recorded from the biceps muscle on the operated side during deep breathing and by cortical magnetic stimulation. The motor unit discharges became independent from respirations gradually over 1 to 2 years. The latencies of the motor potentials evoked by cortical and thoracic root magnetic stimulation decreased gradually over 2 to 3 years. Motor cortex mapping of the reinnervated biceps muscle showed a gradual change over 4 to 33 months from the area of the intercostal muscles to that of the arm area, which was more lateral on the motor cortex. These findings suggest that reorganization of the motor cortex to arm flexor muscles occurs following peripheral nerve anastomosis.
Selective loss of glial glutamate transporter GLT‐1 in amyotrophic lateral sclerosis
Authors: Rothstein Jeffrey D. , Van Kammen Marleen , Levey Allan I. , Martin Lee J. , Kuncl Ralph W.
Published: January 2005

The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) is unknown, but defects in synaptosomal high‐affinity glutamate transport have been observed. In experimental models, chronic loss of glutamate transport can produce a loss of motor neurons and, therefore, could contribute to the disease. With the recent cloning of three glutamate transporters, i.e., EAAC1, GLT‐1, and GLAST, it has become possible to determine if the loss of glutamate transport in ALS is subtype specific. We developed C‐terminal, antioligopeptide antibodies that were specific for each glutamate transporter. EAAC1 is selective for neurons, while GLT‐1 and GLAST are selective for astroglia. Tissue from various brain regions of ALS patients and controls were examined by immunoblot or immunocytochemical methods for each transporter subtype. All tissue was matched for age and postmortem delay. GLT‐1 immunoreactive protein was severely decreased in ALS, both in motor cortex (71% decrease compared with control) and in spinal cord. In approximately a quarter of the ALS motor cortex specimens, the loss of GLT‐1 protein (90% decrease from control) was dramatic. By contrast, there was only a modest loss (20% decrease from control) of immunoreactive protein EAAC1 in ALS motor cortex, and there was no appreciable change in GLAST. The minor loss of EAAC1 could be secondary to loss of cortical motor neurons. As a comparison, glial fibrillary acidic protein, which is selectively localized to astroglia, was not changed in ALS motor cortex. Because there is no loss of astroglia in ALS, the dramatic abnormalities in GLT‐1 could reflect a primary defect in GLT‐1 protein, a secondary loss due to down regulation, or other toxic processes.
Multifocal motor neuropathy human sera block distal motor nerve conduction in mice
Authors: Roberts Mark , Willison Hugh J. , Vincent Angela , Newsom‐Davis John
Published: January 2005

Multifocal motor neuropathy (MMN) is associated with serum autoantibodies to gangliosides, but their pathogenic role is uncertain. We have used a novel approach to study the effects of serum and plasma from 8 patients with this syndrome, 6 of whom were anti‐GM1 positive. The nerve stimulus required to evoke muscle contraction and endplate potentials (EPPs) was measured in the mouse phrenic nerve—diaphragm preparation during 4 to 6 hours of direct application (plasma at 1:1 or serum 1:2 dilution) and following intraperitoneal injection of plasma (1 ml/day) for 1 to 5 days (“passive transfer”). Direct application of MMN serum or plasma produced a progressive increase in stimulus threshold, followed by complete block of nerve‐evoked muscle contraction in 3 cases, and an associated decline to about 50% of the EPP amplitude followed by sudden loss of EPPs. These effects were complement independent. Even with complete block of nerve‐evoked EPPs, miniature EPP (MEPP) frequency could be increased by raising external K+ to depolarize the nerve terminal directly. Passive transfer of 1 ml of MMN plasma (n = 5) for 3 days caused similar but less marked changes. These results demonstrate that serum factors in MMN can block nerve conduction at distal motor nerves.
Acute arcuate fiber demyelinating encephalopathy following epstein‐barr virus infection
Authors: Paskavitz James F. , Anderson C. Alan , Filley Christopher M. , Kleinschmidt‐DeMasters Bette K. , Tyler Kenneth L.
Published: January 2005

We describe a patient who presented with an acute monophasic illness characterized by behavioral abnormalities, visual illusions, and a seizure, who had magnetic resonance‐ and brain biopsy‐documented evidence of multifocal central nervous system demyelination. Serological studies were diagnostic of recent Epstein‐Barr virus infection and included evidence of intrathecal synthesis of Epstein‐Barr virus‐specific IgG antibodies against the viral capsid antigen. Viral DNA could not be amplified from cerebrospinal fluid by polymerase chain reaction, and viral antigen and genome were not detected in the brain biopsy specimen. The patient's clinical course, diagnostic studies, and neuropathological findings all support the diagnosis of a postinfectious Epstein‐Barr virus–mediated demyelinating encephalopathy.